Pharmacotherapy for hypertension‐induced left ventricular hypertrophy

Abstract

Background

Hypertension is the leading preventable risk factor for cardiovascular disease and premature death worldwide. One of the clinical effects of hypertension is left ventricular hypertrophy (LVH), a process of cardiac remodelling. It is estimated that over 30% of people with hypertension also suffer from LVH, although the prevalence rates vary according to the LVH diagnostic criteria. Severity of LVH is associated with a higher prevalence of cardiovascular disease and an increased risk of death.

The role of antihypertensives in the regression of left ventricular mass has been extensively studied. However, uncertainty exists regarding the role of antihypertensive therapy compared to placebo in the morbidity and mortality of individuals with hypertension‐induced LVH.

Objectives

To assess the effect of antihypertensive pharmacotherapy compared to placebo or no treatment on morbidity and mortality of adults with hypertension‐induced LVH.

Search methods

Cochrane Hypertension’s Information Specialist searched the following databases for studies: Cochrane Hypertension Specialised Register (to 26 September 2020), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library; 2020, Issue 9), Ovid MEDLINE (1946 to 22 September 2020), and Ovid Embase (1974 to 22 September 2020). We searched the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov for ongoing trials. We also searched Epistemonikos (to 19 February 2021), LILACS BIREME (to 19 February 2021), and Clarivate Web of Science (to 26 February 2021), and contacted authors and funders of the identified trials to obtain additional information and individual participant data. There were no language restrictions.

Selection criteria

Randomised controlled trials (RCTs) with at least 12 months’ follow‐up comparing antihypertensive pharmacological therapy (monotherapy or in combination) with placebo or no treatment in adults (18 years of age or older) with hypertension‐induced LVH were eligible for inclusion. The trials must have analysed at least one primary outcome (all‐cause mortality, cardiovascular events, or total serious adverse events) to be considered for inclusion.

Data collection and analysis

Two review authors screened the search results, with any disagreements resolved by consensus amongst all review authors. Two review authors carried out the data extraction and analyses. We assessed risk of bias of the included studies following Cochrane methodology. We used the GRADE approach to assess the certainty of the body of evidence.

Main results

We included three multicentre RCTs. We selected 930 participants from the included studies for the analyses, with a mean follow‐up of 3.8 years (range 3.5 to 4.3 years). All of the included trials performed an intention‐to‐treat analysis. We obtained evidence for the review by identifying the population of interest from the trials' total samples. None of the trials provided information on the cause of LVH. The intervention varied amongst the included trials: hydrochlorothiazide plus triamterene with the possibility of adding alpha methyldopa, spironolactone, or olmesartan. Placebo was administered to participants in the control arm in two trials, whereas participants in the control arm of the remaining trial did not receive any add‐on treatment.

The evidence is very uncertain regarding the effect of additional antihypertensive pharmacological therapy compared to placebo or no treatment on mortality (14.3% intervention versus 13.6% control; risk ratio (RR) 1.02, 95% confidence interval (CI) 0.74 to 1.40; 3 studies; 930 participants; very low‐certainty evidence); cardiovascular events (12.6% intervention versus 11.5% control; RR 1.09, 95% CI 0.77 to 1.55; 3 studies; 930 participants; very low‐certainty evidence); and hospitalisation for heart failure (10.7% intervention versus 12.5% control; RR 0.82, 95% CI 0.57 to 1.17; 2 studies; 915 participants; very low‐certainty evidence). Although both arms yielded similar results for total serious adverse events (48.9% intervention versus 48.1% control; RR 1.02, 95% CI 0.89 to 1.16; 3 studies; 930 participants; very low‐certainty evidence) and total adverse events (68.3% intervention versus 67.2% control; RR 1.07, 95% CI 0.86 to 1.34; 2 studies; 915 participants), the incidence of withdrawal due to adverse events may be significantly higher with antihypertensive drug therapy (15.2% intervention versus 4.9% control; RR 3.09, 95% CI 1.69 to 5.66; 1 study; 522 participants; very low‐certainty evidence). Sensitivity analyses limited to blinded trials, trials with low risk of bias in core domains, and trials with no funding from the pharmaceutical industry did not change the results of the main analyses. Limited evidence on the change in left ventricular mass index prevented us from drawing any firm conclusions.

Authors' conclusions

We are uncertain about the effects of adding additional antihypertensive drug therapy on the morbidity and mortality of participants with LVH and hypertension compared to placebo. Although the incidence of serious adverse events was similar between study arms, additional antihypertensive therapy may be associated with more withdrawals due to adverse events. Limited and low‐certainty evidence requires that caution be used when interpreting the findings. High‐quality clinical trials addressing the effect of antihypertensives on clinically relevant variables and carried out specifically in individuals with hypertension‐induced LVH are warranted.

Plain language summary

What are the main benefits and risks of drugs for reducing blood pressure in the treatment of people with thickening of the heart muscle caused by high blood pressure?

Key messages

Given the lack of robust evidence, the benefits and risks of adding additional drugs for reducing blood pressure to treat people with thickening of the heart muscle and high blood pressure are unclear.

It is unclear if adding drugs for reducing blood pressure causes more serious harms in patients than placebo (dummy treatment) or no treatment; however, it may increase treatment discontinuation due to unwanted effects.

There is a need for future studies to better understand the benefits and harms of adding drugs for reducing blood pressure in people with thickening of the heart muscle caused by high blood pressure.

What is thickening of the heart muscle?

Thickening of the heart muscle is a condition where the muscle gets bigger and affects the function of the heart. This can happen when the heart has worked too hard over time and is mainly caused by high blood pressure. People with thickening of the heart muscle can experience shortness of breath, fatigue, chest pain, heart palpitations, and dizziness or fainting.

How is thickening of the heart muscle treated?

Thickening of the heart muscle can be treated with drugs for reducing blood pressure.

What did we want to find out?

We wanted to find out if adding drugs for reducing blood pressure was better than placebo or no drug treatment at preventing illness and death in people with thickening of the heart muscle and high blood pressure.

We also wanted to learn if the addition of drugs for reducing blood pressure was associated with any unwanted or harmful effects.

What did we do?

We searched for studies that investigated the addition of drugs for reducing blood pressure compared with placebo or no drug treatment.

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as methods and sizes of participant groups.

What did we find?

We found 3 studies that involved 930 people with thickening of the heart muscle and high blood pressure. The largest study was in 692 people, and the smallest study was in 15 people. Study participants were of both genders and on average between 66 and 75 years old. Participants were followed for between three and four years. The studies were conducted in several countries in Europe, Asia, and North and South America. One study received pharmaceutical industry funding.

It is uncertain if adding drugs for reducing blood pressure has an effect on death, development of heart and blood vessel diseases, or on hospitalisation for heart failure. It is unclear if adding drugs for reducing blood pressure causes more serious harms than placebo or no drug treatment, but it may increase treatment discontinuations due to unwanted effects. It is unclear if adding drugs for reducing blood pressure has an effect on heart muscle mass.

What are the limitations of the evidence?

Our confidence in the evidence is lacking because of the small number of identified studies. The available evidence is based on a small percentage of people with thickening of the heart muscle and high blood pressure identified from larger populations in the included studies. Further evidence may change our results.

How up‐to‐date is the evidence?

The evidence is current to September 2020.

Summary of findings

Summary of findings 1. Antihypertensive therapy versus placebo or no treatment for hypertension‐induced left ventricular hypertrophy.

Antihypertensive therapy versus placebo or no treatment for hypertension‐induced left ventricular hypertrophy
Patients or population: adults (18 years of age or older) with hypertension‐induced left ventricular hypertrophy Setting: outpatients Intervention: antihypertensive pharmacological therapy (either monotherapy or in combination) Comparison: placebo or no treatment
Outcome	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
	With placebo/no treatmenta	With antihypertensive therapy
All‐cause mortality Mean follow‐up: 3.5 to 4.3 years	136 per 1000	139 per 1000 (101 to 190)	RR 1.02 (0.74 to 1.40)	930 (3 studies)	Very lowb
Cardiovascular events Mean follow‐up: 3.5 to 4.3 years	115 per 1000	125 per 1000 (89 to 178)	RR 1.09 (0.77 to 1.55)	930 (3 studies)	Very lowb
Total serious adverse events Mean follow‐up: 3.5 to 4.3 years	481 per 1000	491 per 1000 (428 to 558)	RR 1.02 (0.89 to 1.16)	930 (3 studies)	Very lowc
Hospitalisation for heart failure Mean follow‐up: 3.5 to 4.3 years	125 per 1000	103 per 1000 (71 to 146)	RR 0.82 (0.57 to 1.17)	915 (2 studies)	Very lowb
Withdrawal due to adverse events Mean follow‐up: 3.5 years	49 per 1000	151 per 1000 (83 to 277)	RR 3.09 (1.69 to 5.66)	522 (1 study)	Very lowd
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^aControl group estimates come from pooled estimates of control groups. 
^bDowngraded two levels for serious imprecision and one level for indirectness. 
^cDowngraded one level for imprecision, one level for indirectness, and one level due to high risk of bias. 
^dDowngraded one level for imprecision, one level for indirectness, and one level due to publication bias.

Background

Description of the condition

A medical glossary is provided in Appendix 1.

Hypertension is a common and treatable medical condition. However, discrepancies exist in the cutpoints used for diagnosis of hypertension. According to the International Society of Hypertension, the European Society of Cardiology, and the European Society of Hypertension, hypertension is defined as systolic blood pressure values greater than or equal to 140 mmHg or diastolic blood pressure values greater than or equal to 90 mmHg, or both (ESC/ESH 2018; ISH 2020). In contrast, the American College of Cardiology and the American Heart Association consider systolic blood pressures greater or equal to 130 mmHg and diastolic blood pressures greater than or equal to 80 mmHg as hypertension (ACC‐AHA 2017).

Estimates of the overall prevalence of hypertension are greatly influenced by the cutpoint established to its categorisation, the methods used to establish the diagnosis, and the population studied (ACC‐AHA 2017). According to a study carried out with 135 population‐based studies from 90 countries, the prevalence of hypertension (defined as average systolic blood pressure ≥ 140 mmHg, average diastolic blood pressure ≥ 90 mmHg, or use of antihypertensive medication) was 31.1% in 2010 (Mills 2016).

Several factors have been identified as underlying causes of hypertension, many of which are modifiable, such as overweight and obesity, unhealthy diet, physical inactivity, or excess alcohol intake (ACC‐AHA 2017). In addition, hypertension becomes progressively more common with advanced age, with a prevalence of more than 60% in people aged more than 60 years (ESC/ESH 2018).

Hypertension is the leading preventable risk factor for cardiovascular disease and premature death worldwide (Mills 2020). Globally in 2017 high blood pressure was the first cause of death and disability‐adjusted life years worldwide, accounting for 10.4 million deaths and 218 million disability‐adjusted life years (GBD 2017). The Non‐Communicable Risk Factor Collaboration estimated that the prevalence of adults with high blood pressure (defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg) increased from 594 million in 1975 to 1.13 billion in 2015, with a larger increase in low‐ and middle‐income countries (NCD‐RisC 2017).

Published evidence has shown associations between high systolic blood pressure and increased cardiovascular risk. A review including results from 61 prospective observational studies found that at 40 to 69 years of age, each difference of 20 mmHg in systolic blood pressure or 10 mmHg in diastolic blood pressure was associated with a more than two‐fold difference in stroke death rate, and with two‐fold differences in death rates from ischaemic heart disease and other vascular causes (Lewington 2002). Another study analysing the association between blood pressure and occurrence of cardiovascular diseases found that people with hypertension had a lifetime risk of overall cardiovascular disease at 30 years of age of 63.3% compared with 46.1% for those with normal blood pressure, and developed cardiovascular diseases five years earlier (Rapsomaniki 2014).

One of the clinical effects of hypertension is left ventricular hypertrophy (LVH), a process of cardiac remodelling. Cardiac remodelling may be defined as genome expression, molecular, cellular, and interstitial changes that are manifested clinically as changes in size, shape, and function of the heart after cardiac injury (Cohn 2000). Cardiac remodelling is linked to heart failure progression. Individuals with major remodelling demonstrate progressive worsening of cardiac function, and it may underlie a sizeable proportion of cardiovascular morbidity and mortality (Cohn 2000).

Hypertension‐induced remodelling of the left ventricle is often grouped into three different geometric patterns: concentric remodelling, concentric LVH, and eccentric LVH (Yildiz 2020). LVH can be diagnosed by electrocardiography criteria, echocardiography criteria, or cardiac magnetic resonance imaging criteria (see Appendix 2). Its prevalence in people with hypertension varies between 36% according to more restrictive diagnostic criteria and 41% according to less conservative ones (Cuspidi 2012).

A meta‐analysis that included six cross‐sectional studies with 60,949 participants also found that left ventricular mass index (LVMI) and global LVH prevalence rates increased in prehypertensive patients compared with normotensive patients, as well as in hypertensive patients compared with prehypertensive patients. The review also found that concentric remodelling was the most common abnormal pattern in normotensive and prehypertensive patients, followed by eccentric and concentric LVH, whereas in hypertensive patients the most frequent altered left ventricular pattern was eccentric LVH. The review found prevalence rates of LVH, as defined by left ventricular mass/h criteria, of 2.5% in normotensive, 6.1% in prehypertensive, and 14.9% in hypertensive individuals (Cuspidi 2019b).

A study included in the review that analysed the 10‐year incidence of LVH found that the risk of developing LVH was significantly greater in prehypertensive patients who progressed to sustained hypertension than in those with persistent prehypertension. This may suggest that the long‐term transition from normal cardiac morphology to LVH is mainly driven by the progression from prehypertension to sustained hypertension (Cuspidi 2019a).

Factors influencing left ventricular geometry in people with hypertension include, amongst others, severity, duration, and rapidity of onset of the increased pressure load; the volume load; age, ethnicity, and sex; comorbidities such as coronary artery disease, diabetes mellitus, obesity, and valvular heart disease; and genetic factors (Aronow 2017). Black individuals with hypertension are more likely than white individuals with hypertension to develop concentric LVH (Aronow 2017). Women with hypertension are more likely than men with hypertension to develop concentric LVH (Aronow 2017).

LVH is considered to be the most potent predictor of morbidity and overall mortality in the hypertensive population, and an independent risk factor for coronary heart disease, sudden death, heart failure, atrial fibrillation, and stroke (Bauml 2010; Llancaqueo 2012; Pérez de la Isla 2010). Severity of the LVH is in turn associated with a higher prevalence of cardiovascular disease (González‐Juanatey 2007). Mortality of individuals with LVH is three to four times higher than in individuals without LVH (Águila‐Marín 2013).

Description of the intervention

Prevention or regression of left ventricular geometric changes with blood pressure control may be an effective way of decreasing future adverse cardiovascular events in individuals with hypertension (Oktay 2016). Indeed, current guidelines recommend treating hypertensive patients with LVH with antihypertensives (Hypertension Canada 2020). In this regard, a stricter blood pressure control is advocated in people at higher risk, such as those with LVH (ESC/ESH 2018).

Drugs currently available for lowering blood pressure include (WHO 2019):

• antihypertensives (Anatomical, Therapeutic, Chemical (ATC) classification code: C02);

• diuretics (ATC code: C03);

• beta‐blocking agents (ATC code: C07);

• calcium channel blockers (ATC code: C08);

• agents acting on the renin‐angiotensin system (ATC code: C09).

Pharmacotherapy should be selected on an individual basis, taking into account that people with certain associated pathologies will benefit more from particular classes of drugs.

How the intervention might work

Cardiac adaptation in response to pressure overload in conditions such as hypertension usually turns into an increase in left ventricular mass influenced by various physiological and pathological stimuli (Lorell 2000; Schmieder 2000), triggering an increase in force‐generating units (sarcomeres) in the myocyte. The implication is that mechanical input transduces into biochemical events that modify gene transcription in the nucleus. The parallel addition of sarcomeres causes an increase in myocyte width, which in turn increases wall thickness; thus an increase in pressure can be offset (Lorell 2000).

Cardiomyocyte hypertrophy is one of many structural alterations occurring in hypertensive heart disease. Fibroblasts undergo hyperplasia and conversion to myofibroblasts, along with hypertrophy of vascular smooth muscle cells. Noncellular elements related to myocardial remodelling include expansion of interstitial and perivascular collagen that make up the extracellular matrix. Changes in intramyocardial capillary density and arteriolar thickening compound cardiac ischaemia in people with hypertension. These remodelling events are orchestrated via effects of biomechanical stress on the extracellular matrix that, in turn, signal stretch‐activated ion channels leading to intracellular transmission of signals to the nucleus, upregulating hypertrophic gene expression. Similar transduction occurs from cytokine signalling via intracellular calcium handling to myocardial transformation. In the short term, increasing wall thickness in proportion to increased pressure helps to normalise myocardial stress. However, long‐term outcomes clearly worsen with progressive hypertrophy, with increasing LVMI translating to commensurate increases in adverse cardiovascular events and all‐cause mortality (Raman 2010).

Regression of left ventricular mass is based on a reduction of wall thickness by all of the antihypertensive drug classes (Fagard 2009). LVH regression may be due to a decrease in both the myocyte volume and the fibrosis in the interstitium by afterload reduction as the main mechanism (Verdecchia 2004). Different drug classes may have different effects on the magnitude of left ventricular mass reduction (Devereux 2004; Gradman 2006; Klingbeil 2003).

Why it is important to do this review

Reviews comparing different antihypertensive drug classes in LVH regression are inconsistent, and do not analyse the repercussion on cardiovascular events or mortality (Fagard 2009; Roush 2018; Soliman 2017). In this regard, uncertainty remains on the prognostic relevance and the impact of LVH regression in terms of major clinical endpoints in people with hypertension‐induced LVH. To date, no systematic review specifically comparing the effects of antihypertensive drug treatment with placebo or no treatment on the morbidity and mortality of people with LVH and hypertension has been published.

Objectives

To assess the effect of antihypertensive pharmacotherapy compared to placebo or no treatment on morbidity and mortality of adults with hypertension‐induced LVH.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) with at least 12 months' follow‐up that analysed at least one of our primary outcomes.

Types of participants

Adults (18 years of age or older) with high blood pressure with LVH caused by hypertension.

In the case of clinical trials that included patients in whom the cause of the LVH was not specified and with coexisting pathologies other than hypertension that can lead to LVH (e.g. aortic stenosis, aortic regurgitation, mitral regurgitation, dilated cardiomyopathy, hypertrophic cardiomyopathy, ventricular septal defect, or infiltrative cardiac processes such as Fabry disease and Danon disease), we planned to select and include subgroups of participants with both LVH and hypertension without other alternative causes of LVH.

We identified these specific subgroups of patients through individual patient data from the included studies. If it was not possible to obtain individual patient data, we planned to include the study if ≥ 80% of the participants had LVH and hypertension without other possible causes of LVH. In the case of studies that did not explicitly provide data regarding the cause of the LVH, or when this could not be inferred from the participants' baseline characteristics, the study was included. We planned to carry out a sensitivity analysis by excluding studies with no specific information regarding the cause of LVH.

Types of interventions

Intervention

Antihypertensive pharmacological therapy (either in monotherapy or in combination):

• antihypertensives;

• diuretics;

• beta‐blocking agents;

• calcium channel blockers;

• agents acting on the renin‐angiotensin system.

Control

Placebo or no treatment.

We excluded trials with multidimensional interventions.

Types of outcome measures

Primary and secondary outcomes were established. We analysed the outcomes at longest follow‐up in clinical trials with at least 12 months' follow‐up time.

Primary outcomes

• All‐cause mortality.

• Cardiovascular events (myocardial infarction (fatal or non‐fatal), stroke (fatal or non‐fatal), or atrial fibrillation).

• Total serious adverse events. Serious adverse events were defined according to the International Conference on Harmonisation (ICH) Guidelines as events that at any dose result in death, are life‐threatening, require inpatient hospitalisation or prolongation of existing hospitalisation, result in persistent or significant disability, or are a congenital anomaly/birth defect, and any important medical event that may have jeopardised the participant or requires intervention to prevent it (ICH‐GCP 1997). These events were not required to have a causal relationship with the antihypertensive treatment.

Secondary outcomes

• Hospitalisation for heart failure.

• Reduction of the left ventricular mass index (LVMI).

• Total adverse events.

• Withdrawal due to adverse events.

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist searched the following databases with no language, publication year, or publication status restrictions:

• Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (to 26 September 2020);

• Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 9) via the Cochrane Register of Studies (to 22 September 2020);

• Ovid MEDLINE and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions (from 1946 to 22 September 2020);

• Ovid Embase (from 1974 to 22 September 2020);

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) (to 22 September 2020);

• World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch) (to 26 September 2020).

The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, we combined them with subject strategy adaptations of the sensitivity‐ and precision‐maximising search strategy designed by Cochrane for identifying randomised controlled trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions) (Higgins 2021). The search strategies for major databases are presented in Appendix 3.

Searching other resources

• The Cochrane Hypertension Information Specialist searched the Hypertension Specialised Register segment (which included searches of MEDLINE and Embase for systematic reviews) to retrieve existing reviews relevant to this systematic review, in order to scan their reference lists for additional trials. The Specialised Register also included searches for controlled trials in AMED (Allied and Complementary Medicine Database), CAB Abstracts and Global Health, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ProQuest Dissertations & Theses, and Web of Science.

• In addition to the above electronic databases, we searched LILACS BIREME (Latin American and Caribbean Health Science Information database) (lilacs.bvsalud.org/es/; to 19 February 2021), Epistemonikos (www.epistemonikos.org/es; to 19 February 2021), and Clarivate Web Of Science (www.recursoscientificos.fecyt.es/; to 26 February 2021).

• We checked bibliographies of the included studies and any relevant systematic reviews identified for further references to relevant trials.

• Where necessary, we contacted the authors and funders of key papers and abstracts to request additional information.

• We searched clinical study reports for additional information about relevant trials.

Data collection and analysis

Study screening was carried out by pairs of review authors. Any discrepancies were resolved by consensus amongst all the review authors. Two review authors independently carried out the data extraction using a specially designed data extraction form. The same two review authors assessed risk of bias of the trials and the overall quality of the evidence.

Selection of studies

We summarised data using standard Cochrane methodologies (Higgins 2021). We applied no language restrictions.

Two review authors screened the search results for potentially relevant trials and independently assessed these for inclusion or exclusion based on the inclusion criteria, using a predesigned eligibility form. Any disagreements were resolved through discussion until consensus was reached. One review author acted as referee.

We selected studies for inclusion following the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We:

• merged search results using Covidence (Covidence), removing duplicate records of the same report;

• examined titles and abstracts to remove obviously irrelevant reports;

• retrieved the full texts of reports deemed potentially relevant;

• linked multiple reports of the same study;

• examined the full‐text reports to determine study eligibility;

• contacted investigators to clarify study eligibility (or to request further information, such as missing results) where appropriate;

• made final decisions on study inclusion and proceeded to data collection.

The study selection process was illustrated using a PRISMA flow diagram.

Data extraction and management

Two review authors extracted data from the included trials using a spreadsheet data extraction form, and another review author checked the data entry.

We extracted the following data.

• Eligibility criteria of the trials.

• Demographics (age, gender, ethnicity, country).

• Diagnosis method, diagnosis criteria.

• Diabetes, chronic renal failure.

• Left ventricular ejection fraction (LVEF).

• Outcome data (all‐cause mortality, cardiovascular events, total serious adverse events, hospitalisation for heart failure, reduction of the LVMI, total adverse events, withdrawal due to adverse events).

• Intervention data: type and regimens.

In the case of a discrepancy, one review author acted as referee to achieve final consensus.

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias for each included trial using the domain‐based risk of bias tool described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any discrepancies were discussed until consensus was achieved. One review author acted as referee during discussions.

We assessed the following risk of bias domains according to the definitions for each classification provided below (Higgins 2011).

Generation of allocation sequence (checking for possible selection bias)

For each included trial, we planned to describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the methods as follows.

• Low risk (any truly random process, e.g. random number table; computer random number generator).

• High risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number).

• Unclear risk, if the trial was reported as randomised, but the method used for the allocation sequence generation was not described.

Allocation concealment (checking for possible selection bias)

For each included trial, we planned to describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocation could have been foreseen, in advance of or during recruitment, or changed after assignment.

We assessed the methods as follows.

• Low risk (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes).

• High risk (open random allocation; unsealed or non‐opaque envelopes; alternation; date of birth).

• Unclear risk, if the trial was reported as randomised, but the method used to conceal the allocation was not described.

Blinding or masking (checking for possible performance bias)

For each included trial, we planned to describe the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant had received. We judged trials to be at low risk of bias if they were blinded, or if we determined that lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as follows.

• Low, high, or unclear risk for participants.

• Low, high, or unclear risk for personnel.

• Low, high, or unclear risk for outcome assessors.

We performed a sensitivity analysis to analyse results from blinded studies separately.

Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

• Low risk (any one of the following): no missing outcome data; reasons for missing outcome data were unlikely to be related to the true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) amongst missing outcomes was not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.

• High risk (any one of the following): reason for missing outcome data was likely to be related to the true outcome, with an imbalance in either numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was enough to induce clinically relevant bias in the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) amongst missing outcomes was enough to induce clinically relevant bias in observed effect size; ‘as‐treated' analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

• Unclear risk (any one of the following): insufficient reporting of attrition or exclusions to permit a judgement of low or high risk (e.g. number randomised not stated, reasons for missing data not provided); the study did not address this outcome.

Selective reporting (reporting bias due to selective outcome reporting)

For each included trial, we described how we investigated the possibility of selective outcome reporting and what we found.

We assessed the methods as follows.

• Low risk (any one of the following): the trial protocol was available, and all of the trial’s prespecified (primary and secondary) outcomes that were of interest in the review were reported in the prespecified way; or the trial protocol was unavailable but it was clear that the published reports included all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon).

• High risk (any one of the following): not all of the study’s prespecified primary outcomes were reported; one or more primary outcomes were reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting was provided, such as an unexpected adverse effect); one or more outcomes of interest in the review were reported incompletely so that they could not be entered in a meta‐analysis; the trial report failed to include results for a key outcome that would be expected to have been reported for such a trial.

• Unclear: insufficient information to permit a judgement of low or high risk.

Other bias (bias due to problems not covered elsewhere in the tool)

For each included trial, we described any important concerns regarding other possible sources of bias (baseline imbalance, sponsorship bias, confirmation bias, bias of the presentation data, etc.).

• Low risk of bias: the trial appeared to be free of other factors that could put it at risk of bias.

• High risk of bias: there were other factors in the trial that could put it at risk of bias, e.g. no sample size calculation made.

• Unclear risk of bias: the trial may or may not be free of other factors that could put it at risk of bias.

Measures of treatment effect

For each binary outcome, such as all‐cause mortality, cardiovascular events, total serious adverse events, hospitalisation by heart failure, total adverse events, and withdrawals due to adverse events, we estimated the risk ratio (RR) with 95% confidence intervals (CI).

For continuous outcomes (reduction of the LVMI), we calculated the mean difference (MD) with 95% CI.

Unit of analysis issues

For all prespecified primary and secondary outcome variables, we performed the analyses based on the number of randomised participants. For reduction of the LVMI, we assessed the change in LVMI in addition to estimating the differences between study arms in the number of participants who had a reduction of LVMI.

Dealing with missing data

We contacted the corresponding author of the included trial(s) to obtain information on missing data. If we were unable to obtain further information, we would carry out the analysis based on available participant information as our main analysis, that is the denominator for each outcome in each trial was the number randomised minus the number of participants whose outcomes were known to be missing.

We assessed the percentage of dropouts for each included trial and for each study group. We considered an intention‐to‐treat analysis for all trials that either reported this analysis or provided sufficient information to perform such an analysis. Otherwise, we included the analysis that was used, and conducted a sensitivity analysis including only results derived from an intention‐to‐treat analysis.

Assessment of heterogeneity

We used the I² statistic and the Q test to measure statistical heterogeneity between the trials. The I² statistic describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (Higgins 2021).

Assessment of reporting biases

We planned to assess publication bias and other bias using a funnel plot in the case of 10 or more included trials (Sterne 2011).

Data synthesis

We performed meta‐analyses using a fixed‐effect model. We explored the robustness of the results using the random‐effects model. We reported the fixed‐effect model results for all outcomes, except in cases where the 95% CIs obtained through random‐effects models were wider than those from the fixed‐effect model.

We performed the meta‐analyses according to the Cochrane guidance (Higgins 2021). We used Review Manager Web to analyse the data (RevMan Web 2020). We considered the results of the meta‐analyses only in the absence of substantial heterogeneity (I² < 60%).

Trial sequential analysis

Meta‐analysis of cumulative data runs the risk of random errors (‘play of chance') due to sparse data and repetitive analyses of the same data (Brok 2008; Brok 2009; Thorlund 2010; Thorlund 2017; Wetterslev 2008; Wetterslev 2009). To assess the risk of random errors in our cumulative meta‐analyses, we planned to conduct diversity‐adjusted trial sequential analyses based upon the proportion with the outcome in the control group; an a priori set relative risk reduction of 20%; an alpha of 5%, a beta of 20%; and the squared diversity in the meta‐analysis (CTU 2011; Thorlund 2009; Thorlund 2017). We planned to conduct sensitivity analyses of the trial sequential analysis to estimate the need for further trials.

Subgroup analysis and investigation of heterogeneity

Where possible, we planned to explore the potential causes of substantial heterogeneity (I² > 60%) for a primary outcome (all‐cause mortality, cardiovascular events, and total serious adverse events) by conducting subgroup analyses according to the following aspects.

• Participant gender

• Participant ethnicity

• Left ventricular ejection fraction: < 40% compared to ≥ 40%

• Drug group

Sensitivity analysis

We tested the robustness of the results using several sensitivity analyses, restricting the analyses to the following.

• Blinded trials

• Trials at low risk of bias (see definition below)

• Non‐industry‐sponsored trials

• Trials that provided information regarding the cause of the LVH

• Trials with results derived from an intention‐to‐treat analysis

As we considered it unlikely that many trials would be at low risk of bias in all domains, we planned to choose three core domains instead of all domains as at low risk of bias: generation of random sequence and allocation concealment, incomplete outcome data, and selective reporting bias.

Summary of findings and assessment of the certainty of the evidence

We used GRADE approach to assess the certainty of the body of evidence associated with specific outcomes (all‐cause mortality, cardiovascular events, total serious adverse events, hospitalisation for heart failure, and withdrawal due to adverse events) (Guyatt 2011a). The GRADE approach appraises the certainty of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The GRADE approach considers within‐study risk of bias (methodological quality), directness of the evidence, heterogeneity of the data, precision of effect estimates, and risk of publication bias (Balshem 2011; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h; Guyatt 2011i; Guyatt 2013). We created a summary of findings table summarising this information (Table 1).

Results

Description of studies

For details on included, excluded, and ongoing studies and studies awaiting classification, see Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies; and Characteristics of studies awaiting classification.

Results of the search

The screening process is shown in Figure 1. We identified 1970 records through database searching, seven of which were excluded as duplicates. We identified two additional references through searching Clarivate Web of Science. We screened the remaining 1965 records based on title and abstract, excluding 1671 records. We obtained and reviewed the full texts of the remaining 294 articles and excluded 280 of them. Of the 14 potentially eligible articles, we classified four as ongoing studies and seven as awaiting classification (corresponding to eight studies). We included three studies in both in the qualitative and quantitative synthesis (meta‐analysis). We also searched and reviewed other publications corresponding to the trials identified through the database searches.

1.

PRISMA flow diagram

Included studies

We included three studies in the review (EWPHE 1991; SUPPORT 2015; TOPCAT 2014).

The European Working Party on High Blood Pressure in the Elderly trial analysed the effect of hydrochlorotiazide plus triamterene on the morbidity and mortality of individuals 60 years of age or older diagnosed with hypertension (EWPHE 1991). Around 36% of participants in each study arm had cardiovascular complications at entry. The study did not intend to determine outcomes in individuals with hypertension and LVH, and the trial investigators did not describe a specific LVH diagnostic criteria. During the study, standard 12‐lead electrocardiograms (ECG) were obtained from trial participants, and the review authors established the criteria 'RV1 + SV5 ≥ 35 AND RaVL > 12' by consensus to identify the subgroup of participants with LVH. Information regarding the cause of the LVH was not available, nor data on possible coexisting pathologies other than hypertension that could lead to LVH.

The Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial evaluated the influence on cardiovascular outcomes of adding spironolactone to baseline treatment in adult patients with symptomatic heart failure (New York Heart Association (NYHA) class II‐IV) and LVEF of at least 45% (TOPCAT 2014). Participants were to present with systolic blood pressure under 140 mmHg; those patients with systolic blood pressure > 140 mmHg and ≤ 160 mmHg were eligible for enrolment if on three or more medications to control blood pressure. Individuals with known infiltrative or hypertrophic obstructive cardiomyopathy or pericardial constriction were excluded. Trial investigators defined LVH using the American Society of Echocardiography (ASE) criteria, which refers to LVMI > 115 g/m² in men or > 95 g/m² in women (Lang 2005). Information on the cause of the LVH was not available, therefore we included participants with hypertension and LVH and excluded those with aortic stenosis, aortic regurgitation and/or mitral regurgitation, as these conditions represent possible causes of LVH. None of the trial participants had obstructive cardiomyopathy.

The supplemental benefit of angiotensin receptor blocker in hypertensive patients with stable heart failure (NYHA class II‐IV) using olmesartan trial aimed to evaluate whether additive treatment with olmesartan reduced mortality and morbidity in hypertensive adult patients with stable heart failure (SUPPORT 2015). Trial investigators used the ASE criteria to define LVH (Lang 2005), which was a LVMI greater than 115 g/m² in males and greater than 95 g/m² in females. Data regarding the cause of the LVH were not provided, therefore we selected trial participants with hypertension and LVH, excluding those participants with dilated or hypertrophic cardiomyopathy, or both, which may correspond to possible causes of LVH.

Study design

Study designs of the included trials are shown in Table 2. In all three studies allocation was made on an individual basis, and a parallel design was used. All three trials were multicentre. In EWPHE 1991, centres in Belgium, the UK, Finland, France, Italy, the Netherlands, Ireland, Portugal, Norway, and Germany were involved. The TOPCAT 2014 trial was carried out in various centres in the USA, Canada, Russia, Georgia, Argentina, and Brazil. In SUPPORT 2015, all participating centres were in Japan. The three trials had two treatment arms. In all of the included trials analyses were carried out using the intention‐to‐treat principle. Participant mean follow‐up was 4.1 years (range 3.4 to 4.6 years).

1. Study designs of the included trials.

	EWPHE 1991	TOPCAT 2014	SUPPORT 2015
Participants, no.	840	3445	1147
Population of interest, no.	15	692	223
Design	Parallel	Parallel	Parallel
Unit of allocation	Individual	Individual	Individual
Setting	Multicentre, international	Multicentre, international	Multicentre, Japan
Recruitment start date	NR	August 2006	October 2006
Recruitment end date	NR	January 2012	March 2010
Recruitment method	NR	NR	NR
Number of arms	2	2	2
Analysis	Intention‐to‐treat	Intention‐to‐treat	Intention‐to‐treat

NR: not reported

EWPHE 1991 was carried out in consultation with the World Health Organization and supported by the Belgian National Research Foundation and the Belgian Hypertension Committee through a grant from Merck Sharp & Dohme and Smith, Kline & French. TOPCAT 2014 was funded by the National Heart, Lung and Blood Institute, US National Institutes of Health. SUPPORT 2015 was supported in part by grants‐in‐aid from the Ministry of Health, Labour, and Welfare and the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

Trial participants

The TOPCAT 2014 trial had the largest sample size (n = 3445), followed by SUPPORT 2015 (n = 1147), and EWPHE 1991 (n = 840). Baseline characteristics of all trial participants are shown in Table 3. There were no baseline imbalances between treatment arms in any of the trials. In EWPHE 1991, 17.7% of participants left the study before the nine‐month follow‐up visit (n = 85 control group, n = 64 active group); these participants were not included in the mortality analysis. Overall, 36.4% of participants stopped the trial prematurely, with no significant differences between study arms (n = 157 control group, n = 149 intervention group; P = 0.18). The main causes of the premature stop were lost to follow‐up (41.8%); discontinuing trial medication for more than three months (17.0%); and the occurrence of a non‐fatal intercurrent disease (12.4%). The mean age of trial participants was 68.7 years (range 65.7 to 71.8 years). In TOPCAT 2014, 9.0% of participants were withdrawn or lost to follow‐up (n = 151 control group, n = 160 intervention group), with no statistically significant differences between treatment arms (P = 0.589). In SUPPORT 2015, 0.1% of trial participants were withdrawn or lost to follow‐up (three in the control group and six in the intervention group), with no significant differences between study arms (P = 0.327). One participant was excluded. Whereas in the SUPPORT 2015 trial males were predominant (74.7%), the majority of participants in EWPHE 1991 and TOPCAT 2014 were female. In TOPCAT 2014 93% of participants were white. The other two trials did not provide information on race.

2. Baseline characteristics of all trial participants.

	EWPHE 1991	TOPCAT 2014	SUPPORT 2015
Population	Elderly hypertensive patients	Individuals ≥ 50 years with symptomatic heart failure and LVEF ≥ 45%	Hypertensive patients aged 20 to 79 years with stable symptomatic chronic heart failure
Number of participants randomised	840	3445	1147
Baseline imbalances	No	No	No
Excluded, no. (%)	149 (17.7%)	0	1 (0.1%)
Withdrawn or lost to follow‐up, no. (%)	306 (36.4%)	311 (9.0%)	9 (0.8%)
Follow‐up in years, mean (SD)	4.6 (2.9)	3.4 (1.7)	4.2 (1.2)
Age in years, mean (SD)	71.8 (8.0)	68.6 (9.6)	65.7 (10.2)
Sex, no. males (%)	254 (30.2%)	1670 (48.5%)	857 (74.7%)
Race/ethnicity, no. (%)	NR	Black: 302 (8.8%) White: 3062 (88.9%) Hispanic: 50 (1.5%) Asian: 19 (0.6%) Other: 12 (0.3%)	NR
History of diabetes mellitus, no. (%)	72 (8.6%)	1118 (32.5%)	548 (47.8%)
History of chronic renal failure, no. (%)	2 (0.2%)	1330 (38.6%)	0
Previous myocardial infarction, no. (%)	56 (6.7%)	893 (25.9%)	0
Previous stroke, no. (%)	48 (5.7%)	265 (7.7%)	NR
History of atrial fibrillation, no. (%)	22 (2.6%)	1214 (35.2%)	479 (41.8%)
History of hypertension, no. (%)	840 (100%)	3147 (91.3%)	1147 (100%)
Number of antihypertensives, mean (SD)	NR	3.0 (0.9)	2.7 (1.1)
LVEF (%), mean (SD)	NR	57.1 (7.4)	54.1 (14.7)
LVEF < 40%, no. (%)	NR	0	200 (17.5%)
LVEF ≥ 40%, no. (%)	NR	3445 (100%)	939 (81.9%)
Cause of the LVH	NR	NR	NR

LVEF: left ventricular ejection fraction; LVH: left ventricular hypertrophy; NR: not reported; SD: standard deviation

The population of interest in this review, which corresponds to participants with hypertension and LVH without other possible causes of LVH, constituted a subgroup of participants from all of the included trials. Baseline characteristics of included study participants are shown in Table 4. LVH diagnostic criteria were predefined by trial investigators in TOPCAT 2014 and SUPPORT 2015. In EWPHE 1991, a definition of LVH was not stated, therefore we established the criteria for identifying trial participants with LVH according to available ECG data. Information regarding the cause of the LVH was not available for any of the included trials. We obtained individual‐level participant data for all trials, through which we selected participants with hypertension and LVH without other possible causes of LVH.

3. Baseline characteristics of the included study participants.

	EWPHE 1991	TOPCAT 2014	SUPPORT 2015
Number of participants (%)	15 (1.8%)	692 (20.1%)	223 (19.4%)
Baseline imbalances	Yes	Yes	No
Characteristics with imbalances	RV5	Previous stroke	NA
Excluded, no.	0	0	0
Withdrawn or lost to follow‐up, no. (%)	NR	100 (14.5%)	3 (1.3%)
Follow‐up in years, mean (SD)	3.6 (3.1)	3.5 (1.7)	4.3 (1.2)
Age, mean (SD)	75.7 (6.0)	66.6 (9.4)	66.0 (10.4)
Sex, no. males (%)	6 (40.0%)	335 (48.4%)	162 (72.6%)
Race/ethnicity, no. (%)	NR	Black: 46 (6.6%) White: 642 (92.8%) Hispanic: 3 (0.4%) Asian: 1 (0.1%)	NR
History of diabetes mellitus, no. (%)	1 (6.7%)	117 (25.6%)	96 (43.0%)
History of chronic renal failure, no. (%)	0	229 (33.1%)	0
Previous myocardial infarction, no. (%)	3 (20%)	227 (32.8%)	0
Previous stroke, no. (%)	3 (20.0%)	66 (9.5%)	NR
History of atrial fibrillation, no. (%)	0	230 (33.2%)	92 (41.3%)
Number of antihypertensives, mean (SD)	NR	3.0 (0.9)	2.7 (1.1)
LVEF (%), mean (SD)	NR	56.9 (7.7)	60.4 (13.2)
LVEF < 40%, no. (%)	NR	0	15 (6.7%)
LVEF ≥ 40%, no. (%)	NR	692 (100%)	208 (93.3%)
Cause of the LVH	NR	NR	NR

LVEF: left ventricular ejection fraction; LVH; left ventricular hypertrophy; NR: not reported; SD: standard deviation

The population of interest was 20.1% of all trial participants in TOPCAT 2014, 19.4% in SUPPORT 2015, and 1.8% in EWPHE 1991. We found imbalances between treatment arms in RV₅ in EWPHE 1991 (26.6 mm (standard deviation (SD) 8.1) in the control group; 16.9 mm (SD 7.8) in the intervention group; P = 0.028) and in history of stroke in TOPCAT 2014 (12% in the control group; 6.6% in the intervention group; P = 0.011). The percentage of included participants who were withdrawn or lost to follow‐up was 14.5% in TOPCAT 2014 and 1.3% in SUPPORT 2015, with no significant differences between treatment arms in any of the cases. Mean follow‐up was 3.8 years (range 3.5 to 4.3 years), and mean age of participants was 69.4 years (range 66.0 to 75.7 years). The prevalence of diabetes mellitus at baseline in the included trials ranged from 6.7% to 43.0%. Individuals with history of chronic kidney failure, myocardial infarction and/or atrial fibrillation accounted for 20% to 40% of all participants included in the review. A total of 7.4% participants had a previous stroke. Participants included in the review extracted from TOPCAT 2014 trial received a mean of three antihypertensives at baseline; those from SUPPORT 2015 received a mean of 2.7 antihypertensives at baseline. Mean basal LVEF was approximately 60% in participants in TOPCAT 2014 and SUPPORT 2015. Almost all of the participants included from these trials had an LVEF of at least 40%. LVEF was not measured in EWPHE 1991.

Characteristics of interventions and comparisons

In EWPHE 1991, the intervention consisted of treatment with hydrochlorotiazide plus triamterene or matching placebo. In the first phase, participants received one capsule containing 25 mg of hydrochlorotiazide plus 50 mg of triamterene daily or placebo. The dosage could be increased after not less than two weeks to two capsules per day. If after no less than one month blood pressure remained high with this therapeutic regimen, the second phase was started with the addition of alpha methyldopa or matching placebo. This treatment was started at a daily dose of half a tablet of 500 mg in the evening and was increased when necessary by half a tablet at intervals of not less than two weeks, until: a blood pressure of less than 160/90 mmHg was reached; or a total daily dose of four 500 mg tablets was obtained; or intolerable adverse reactions occurred, precluding a further increase in dosage. During the trial, 57% of participants in the intervention arm received only hydrochlorotiazide plus triamterene, and 42.5% required addition of alpha methyldopa. In the control arm, 32.5% of participants received only hydrochlorotiazide plus triamterene matching placebo, and 67.5% received additional methyldopa matching placebo. Participants could receive diuretics, calcium channel blockers, beta‐adrenoreceptor blocking agents, or Rauwolfia alkaloids for periods of less than three months. Participants requiring these treatments for three months or more terminated the trial. During the trial, there were no significant differences between study arms in the incidence of concomitant treatment with short‐term (less than three months) vasodilators plus other antihypertensives (19.6 per 1000 person years in the control arm versus 11.8 per 1000 person years in the intervention arm; P > 0.05), but short‐term beta‐blockers were less frequently prescribed in the intervention group (13.0 per 1000 person years in the control arm versus 5.1 per 1000 person years in the intervention arm; P < 0.05).

In TOPCAT 2014, the active drug used as intervention was the diuretic spironolactone, which was initiated at a dose of 15 mg once daily. All participants tolerating this dose without adverse events were up‐titrated by protocol to the target dose of 30 mg once daily at week‐four visit. Additional up‐titration to a maximum dose of 45 mg once daily was permitted at the site investigator's discretion after the month‐four visit for participants with refractory heart failure symptoms and acceptable laboratory parameters (potassium, creatinine). Participants in the intervention and control arms continued to receive other treatment for heart failure and coexisting illnesses throughout the trial.

In SUPPORT 2015, the intervention consisted on adding olmesartan for participants in the active treatment group. The drug was initiated at a dose of 5 to 10 mg; physicians were encouraged to increase the dose up to 40 mg/day where possible. No angiotensin receptor blockers were allowed in the control group.

In the EWPHE 1991 and TOPCAT 2014 trials, participants in the control group received a placebo identical in appearance to the active treatment. Participants in the control group of SUPPORT 2015 trial did no receive any add‐on treatment.

Excluded studies

We excluded a total of 280 articles for the following reasons: 169 used a different comparator; 58 had a different follow‐up period; 22 had a different study design; 13 studied a different patient population; 11 studied a different intervention; 3 analysed different outcomes; and 4 provided no specific data for the population of interest and the data could not be obtained. Further details for six of these (Black 2001; Hernández 2000; HOPE 2003; RENAAL 2005; TCCGIH 1994; VALIDD 2007) are provided in the Characteristics of excluded studies section.

Studies awaiting classification

We assessed eight studies as awaiting classification (CHARM 1999; FEVER 2005; HYVET 2001; PROFESS 2007; RALES 1999; Syst‐Eur 1991; TRANSCEND 2004; VAL‐HeFT 2001). In all of these studies, participants with hypertension and LVH were a subgroup of the total trial participants, and specific data for this subgroup were not published. We contacted the authors and funders of these studies in order to obtain the necessary data, but had not received a response or trial data by publication of this review.

Ongoing studies

We found four ongoing studies (ChiCTR‐INR‐16008079; ChiCTR‐IPR‐16009507; NCT02893358; NCT03315832). We will follow up with these studies upon their completion to assess their possible inclusion in future updates of the review.

Risk of bias in included studies

The risk of bias assessment of the included trials is shown in Figure 2. We judged two trials as having a high risk of bias in at least one domain (EWPHE 1991; SUPPORT 2015). We assessed the remaining trial as having an unclear risk of bias in one domain and low risk of bias in the all other domains (TOPCAT 2014).

2.

Risk of bias summary

Allocation

We judged EWPHE 1991 and SUPPORT 2015 trials as having an unclear risk of bias for random sequence generation, as neither the protocol nor the publication provided information regarding the method used for randomisation. We assessed this domain as low risk of bias in TOPCAT 2014, as details regarding the randomisation method used were provided both in the protocol and in the main publication. Randomisation was carried out using permuted blocks, and a randomisation software (NERI’s Verandi software package) was used to allocate participants to either spironolactone or placebo.

We assessed EWPHE 1991 and SUPPORT 2015 trials as having an unclear risk of bias for allocation concealment. Even though randomisation was stratified according to participating centre, age, and sex in both studies, and additionally by the presence or absence of cardiovascular complications in the case of EWPHE 1991, there was no specific information regarding allocation concealment either in the study protocols or in the publications. We judged TOPCAT 2014 as having a low risk of bias in this domain.

Blinding

We considered EWPHE 1991 trial to have a low risk of bias for blinding of participants and personnel, as the trial was double‐blinded, and the protocol specified that tablets of active treatment and matching placebos were identical in shape, taste, and colour. In TOPCAT 2014, both participants and treating physicians were blinded, and the placebo and active treatment were identical in appearance, therefore we assessed this trial as at low risk of bias for this domain. We judged SUPPORT 2015 as having a high risk of bias for blinding of participants and personnel, as it was an open‐label study, and participants in the control arm did not receive placebo.

We judged all three trials as having low risk of bias for blinding of outcome assessment. In EWPHE 1991, deaths and other terminating events were classified and coded by two investigators who were not aware of the treatment that participants received. In TOPCAT 2014, individual components of the primary outcome, myocardial infarctions and strokes, were adjudicated by a clinical events committee that was unaware of treatment assignments. In SUPPORT 2015, endpoints were assessed in a blinded fashion.

Incomplete outcome data

Considering published and unpublished information as well as obtained individual‐level participant data, we judged the three trials as having a low risk of attrition bias. In all three studies, analyses were conducted according to the intention‐to‐treat principle (Table 2). In EWPHE 1991, 17.7% of trial participants left the study before the nine‐month follow‐up visit and were not included in the mortality analysis. Overall, 36.4% of trial participants stopped the trial prematurely, suggesting no differences between study arms (n = 157 control group, n = 149 intervention group; P = 0.18). Measures of the outcome variables prespecified in the review protocol were available for all participants included in the review (Table 3; Table 4).

In TOPCAT 2014, there may be no differences between groups either in the percentage of participants who discontinued the study (9.3% spironolactone arm versus 8.8% placebo arm) or in those with unknown vital status at last expected visit (3.9% spironolactone arm versus 3.8% placebo arm). Of participants who discontinued the study, 100 were in the subgroup included in the review (47 in the intervention group and 53 in the control group; P = 0.784) (Table 4).

In SUPPORT 2015, there may be no differences between groups in the number of participants lost to follow‐up either in the trial total population (six participants in the intervention group and three participants in the control group; P = 0.327) or in the population of interest for the review (two participants in the intervention group and one participant in the control group; P = 0.698), and these participants were included in the analyses. One participant in the control group was excluded due to lack of information, and no participants in the intervention group were excluded (Table 3; Table 4).

Selective reporting

We judged the EWPHE 1991 trial as having a high risk of reporting bias. The double‐blind phase of the study was ended when participants were lost to follow‐up or when a study‐terminating event occurred (e.g. death; cerebral or subarachnoid haemorrhage; non‐controllable congestive heart failure; increase in LVH; serum creatinine increase; rise in diastolic blood pressure; non‐hypertensive conditions requiring continuous long‐term (three months or more) therapy with diuretics, calcium channel blockers, beta‐adrenoceptor blocking agents, or Rauwolfia alkaloids), amongst other reasons. Data were analysed by intention‐to‐treat; however, in the case of participants who discontinued the study, only the date of death was registered. These methodological considerations could have led to an underestimation of the total clinical events.

We considered both TOPCAT 2014 and SUPPORT 2015 trials to have a low risk of reporting bias. Although information regarding some of the outcomes prespecified in trial protocols was not provided in the study publications, we identified all data needed for analysing the outcomes of interest for the review through individual‐level participant data.

Other potential sources of bias

In all three studies, participants with hypertension and LVH constituted a subgroup of all trial participants. In addition, it was not possible to ensure that LVH was caused by hypertension, as data on the cause of the LVH were not available in any of the studies. However, it was possible through individual‐level participant data to identify participants with coexisting pathologies other than hypertension that can potentially lead to LVH, and we did not include those participants in the analyses.

In EWPHE 1991, participants with hypertension and LVH did not correspond to a predefined subgroup of participants, and this subgroup represented 1.8% of the total population of the trial. Furthermore, the trial was supported by grants from pharmaceutical companies. We therefore judged EWPHE 1991 as having a high risk of other bias.

We classified TOPCAT 2014 and SUPPORT 2015 trials as having an unclear risk of other bias, since participants with hypertension and LVH without other possible causes of LVH represented around 20% of total populations of the trials.

Effects of interventions

See: Table 1

Table 1 shows the results and the certainty of the evidence for the following predefined outcome variables: all‐cause mortality, cardiovascular events, total serious adverse events, hospitalisation for heart failure, and withdrawal due to adverse events.

We obtained published and unpublished information as well as individual‐level participant data for all three trials (EWPHE 1991; SUPPORT 2015; TOPCAT 2014), through which we extracted and analysed specific data for participants with hypertension and LVH without other potential causes of LVH. The EWPHE 1991 trial contributed 15 participants (10 in the intervention group and five in the control group); TOPCAT 2014 692 participants (n = 334 in the intervention group and n = 358 in the control group); and SUPPORT 2015 223 participants (n = 124 in the intervention group and n = 99 in the control group), for a total of 930 participants.

All‐cause mortality

Results are shown in Analysis 1.1 and Table 1. We analysed all‐cause mortality using data from the three trials, totalling 930 participants. We identified 67 deaths (14.3%) in the intervention arm and 63 (13.6%) in the control arm. Differences between arms were not statistically significant (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.74 to 1.40; I² = 0%). In absolute terms, antihypertensive therapy was associated with 3 more deaths per 1000 participants than in the control arm (139 versus 136 per 1000 participants).

1.1. Analysis.

Comparison 1: All‐cause mortality, Outcome 1: All‐cause mortality

Sensitivity analysis restricting to blinded trials, EWPHE 1991 and TOPCAT 2014, did not change the results (RR 1.04, 95% CI 0.72 to 1.50; I² = 0%; n = 707). Additionally, when excluding the EWPHE 1991 trial, which received grants from pharmaceutical companies, we obtained similar results (RR 1.01, 95% CI 0.72 to 1.40; I² = 0%).

Results from TOPCAT 2014, the only study with low risk of bias in core domains (random sequence generation, allocation concealment, incomplete outcome data, and selective reporting bias), showed that there may be no difference between groups (RR 1.03, 95% CI 0.70 to 1.51; n = 692).

Cardiovascular events

Results for participants who suffered at least one cardiovascular event are shown in Analysis 2.4 and Table 1. We carried out an estimation of the effect with data from the three trials (n = 930 participants). The three trials provided data for fatal or non‐fatal myocardial infarction and fatal or non‐fatal stroke (EWPHE 1991; SUPPORT 2015; TOPCAT 2014). Additionally, the TOPCAT 2014 and SUPPORT 2015 trials provided information regarding atrial fibrillation. In EWPHE 1991, arrhythmias events were described globally; specific data for atrial fibrillation events were not available.

2.4. Analysis.

Comparison 2: Cardiovascular events, Outcome 4: At least 1 cardiovascular event

A total of 59 participants (12.6%) in the intervention arm and 53 participants (11.5%) in the control arm suffered at least one cardiovascular event. We found that there may be no differences between arms in relative terms (RR 1.09, 95% CI 0.77 to 1.55; I² = 0%). In absolute terms, there were 10 more participants with cardiovascular events in the intervention arm per 1000 participants (125 versus 115 per 1000 participants).

Sensitivity analysis restricting to blinded trials, EWPHE 1991 and TOPCAT 2014, did not change the results (RR 1.00, 95% CI 0.63 to 1.57; I² = 0%; n = 707). Excluding the only trial with grants from the pharmaceutical industry (EWPHE 1991), we obtained similar results (RR 1.09, 95% CI 0.77 to 1.55; I² = 0%). Results from the TOPCAT 2014 trial, the only study with low risk of bias in core domains, showed that there may be no difference between groups (RR 0.97, 95% CI 0.61 to 1.54; n = 692).

Results for each type of cardiovascular event individually (fatal and non‐fatal myocardial infarction, fatal and non‐fatal stroke, and atrial fibrillation) are shown in Analysis 2.1, Analysis 2.2, and Analysis 2.3. We also found that there may be no differences between groups for these outcome variables. In relative terms, the difference in the incidence of myocardial infarction was RR 1.22, 95% CI 0.57 to 2.62 (I² = 1%, three studies, n = 930); for stroke RR 0.67, 95% CI 0.35 to 1.28 (I² = 0%, three studies, n = 930); and for atrial fibrillation RR 1.60, 95% CI 0.93 to 2.75 (I² = 0%, two studies, n = 915).

2.1. Analysis.

Comparison 2: Cardiovascular events, Outcome 1: Myocardial infarction

2.2. Analysis.

Comparison 2: Cardiovascular events, Outcome 2: Stroke

2.3. Analysis.

Comparison 2: Cardiovascular events, Outcome 3: Atrial fibrillation

Total serious adverse events

Results for participants who suffered at least one serious adverse event are shown in Analysis 3.1 and Table 1. We estimated results using data from the three trials (n = 930 participants). The TOPCAT 2014 trial provided a standardised definition of serious adverse events and analysed them systematically. In EWPHE 1991 and SUPPORT 2015 trials, a definition of serious adverse events was not established, thus we constructed the outcome variable following the definition provided by the International Conference on Harmonisation (ICH) (ICH‐GCP 1997). For EWPHE 1991, we considered all‐cause mortality, myocardial infarction, stroke, moderate and severe congestive heart failure, and severe increase in serum creatinine as serious adverse events. In SUPPORT 2015, serious adverse events included all‐cause death, myocardial infarction, stroke, hospitalisation due to heart failure, hospitalisation for any cardiovascular reason, new‐onset atrial fibrillation, fatal arrhythmia, and development of renal failure.

3.1. Analysis.

Comparison 3: Total serious adverse events, Outcome 1: Total serious adverse events

According to above‐mentioned criteria, 229 participants (48.9%) had at least one serious adverse event in the active treatment arm, compared with 222 participants (48.1%) in the control arm, suggesting no difference between groups (RR 1.02, 95% CI 0.89 to 1.16; I² = 0%). In absolute terms, there were more participants with serious adverse events in the active‐treatment arm (491 versus 481 per 1000 participants).

Sensitivity analysis restricting to blinded trials, EWPHE 1991 and TOPCAT 2014 (RR 1.01, 95% CI 0.87 to 1.18; I² = 0%; n = 707), and to trials with no pharmaceutical industry funding, TOPCAT 2014 and SUPPORT 2015 (RR 1.01, 95% CI 0.88 to 1.16; I² = 0%), did not change the results. Results from the TOPCAT 2014 trial, the only study with low risk of bias in core domains, showed that there may be no difference between groups (RR 1.00, 95% CI 0.86 to 1.17; n = 692).

Hospitalisation for heart failure

Results for participants who were hospitalised for heart failure are shown in Analysis 4.1 and Table 1, and are derived from data from the TOPCAT 2014 and SUPPORT 2015 trials (n = 915). Forty‐nine participants (10.7%) in the treatment arm and 57 participants (12.5%) in the control arm were hospitalised for heart failure. There was no evidence of a difference between groups in relative terms (RR 0.82, 95% CI 0.57 to 1.17; I² = 0%). In absolute terms, more participants in the control arm (125 versus 103 per 1000 participants) were hospitalised for heart failure.

4.1. Analysis.

Comparison 4: Hospitalisation for heart failure, Outcome 1: Hospitalisation for heart failure

Sensitivity analysis restricting to TOPCAT 2014, the only study with low risk of bias in core domains and the only blinded study that provided data for this outcome, showed no differences between groups (RR 0.68, 95% CI 0.40 to 1.16; n = 692).

Reduction of the left ventricular mass index

We estimated both the differences in the number of participants who had reduction of LVMI (Analysis 5.1) and the change in LVMI (Analysis 5.2). Data regarding these variables were only available for the TOPCAT 2014 trial (n = 54).

5.1. Analysis.

Comparison 5: Reduction of the left ventricular mass index, Outcome 1: Participants with reduction of the left ventricular mass index

5.2. Analysis.

Comparison 5: Reduction of the left ventricular mass index, Outcome 2: Reduction of the left ventricular mass index

We found that there may be no differences between groups in participants with reduction of LVMI (60% in the intervention arm versus 69% in the control arm; RR 0.87, 95% CI 0.58 to 1.30). There was no evidence of a difference between groups in change in LVMI (mean difference −0.30, 95% CI −5.87 to 5.27).

Total adverse events

The TOPCAT 2014 and SUPPORT 2015 trials provided data for this outcome (n = 915). A total of 313 of 458 participants (68.3%) in the treatment group and 307 of 457 participants (67.2%) in the control group experienced at least one adverse event, suggesting no differences between groups (RR 1.07, 95% CI 0.86 to 1.34; I² = 64%). However, the estimate showed substantial heterogeneity.

Results were similar when restricting to TOPCAT 2014, the only study with low risk of bias in core domains and the only blinded study that provided data for this outcome (RR 0.99, 95% CI 0.90 to 1.09).

Withdrawal due to adverse events

Results for participants who withdrew from the trials due to adverse events are shown in Analysis 6.1 and Table 1. Data were only available for the TOPCAT 2014 trial (n = 522). In this trial, 15.2% of participants receiving antihypertensive therapy withdrew (39 out of 257) compared with 4.9% (13 out of 265) receiving placebo. The difference in relative terms was statistically significant, favouring placebo (RR 3.09, 95% CI 1.69 to 5.66). In absolute terms, 102 more participants withdrew due to adverse events in the intervention arm compared to the placebo arm (151 versus 49 per 1000 participants).

6.1. Analysis.

Comparison 6: Withdrawal due to adverse events, Outcome 1: Withdrawal due to adverse events

Sensitivity analysis

Results of the sensitivity analyses of the principal outcomes are shown in the corresponding sections. We carried out sensitivity analyses limited to blinded trials (EWPHE 1991; TOPCAT 2014); to trials with no pharmaceutical industry funding (SUPPORT 2015; TOPCAT 2014); and to the only trial with low risk of bias in core domains (TOPCAT 2014). It was not possible to perform analyses limiting to trials providing information on the cause of LVH, as none of the studies provided this information. We did not carry out sensitivity analysis restricting to trials derived from an intention‐to‐treat analysis, as all the included studies were analysed on this basis.

We did not perform subgroup analyses and trial sequential analyses as we did not find substantial heterogeneity in any of the primary outcomes.

Discussion

We identified three RCTs that met the review inclusion criteria (EWPHE 1991; SUPPORT 2015; TOPCAT 2014). EWPHE 1991 analysed the effect of hydrochlorotiazide plus triamterene on morbi‐mortality of elderly hypertensive patients. TOPCAT 2014 evaluated the influence on cardiovascular outcomes of adding spironolactone to baseline treatment in adults with symptomatic heart failure (NYHA class II‐IV) and left ventricular ejection fraction of at least 45%. SUPPORT 2015 assessed the effect of additive treatment with olmesartan in hypertensive patients with stable heart failure (NYHA class II‐IV). Through the individual participant level data from the three trials, we analysed data from participants with hypertension and LVH without other potential causes of LVH, amounting to a total of 930 participants.

Summary of main results

Based on the available evidence from RCTs, we are very uncertain about the effects of adding additional antihypertensive drugs on the morbi‐mortality of individuals with hypertension and LVH.

The evidence for all‐cause mortality was uncertain (RR 1.02, 95% CI 0.74 to 1.40). The percentage of people who died during the trials was around 14% in both groups. Sensitivity analyses restricting to blinded trials (EWPHE 1991; TOPCAT 2014), and separately to the only trial with low risk of bias (TOPCAT 2014), did not change the results.

Adding additional antihypertensive treatment may also fail to achieve benefit with respect to cardiovascular events (RR 1.09, 95% CI 0.77 to 1.55). 12.6% of the participants in the intervention arm and 11.5% of the participants in the control arm suffered at least one cardiovascular event. Sensitivity analyses revealed similar results. We also found that there may be no differences in the incidence of fatal or non‐fatal myocardial infarction (RR 1.22, 95% CI 0.57 to 2.62); fatal or non‐fatal stroke (RR 0.67, 95% CI 0.35 to 1.28); and atrial fibrillation (RR 1.60, 95% CI 0.93 to 2.75) when analysed separately.

There may be no differences between study arms in participants who were hospitalised for heart failure (RR 0.82, 95% CI 0.57 to 1.17). A total of 10.7% of participants in the treatment arm and 12.5% in the control arm were hospitalised due to heart failure during the trials' follow‐up. When restricting the analysis to the only blinded trial with low risk of bias that provided information for this variable (TOPCAT 2014), results were similar.

The confidence intervals for these outcome variables were wide, thus we cannot discard important benefits or important harms with additional antihypertensive drugs.

With regard to safety, withdrawals due to adverse events may be three‐fold higher in participants with additive antihypertensive treatment (RR 3.09, 95% CI 1.69 to 5.66), based on very low‐certainty evidence. A total of 15.2% of participants receiving antihypertensive therapy withdrew from the trials due to adverse events, compared to a 4.9% receiving placebo. However, as data for this variable corresponded to a single trial (TOPCAT 2014), caution is warranted when drawing conclusions.

Secondarily, we analysed incidence of adverse events. The proportion of participants who suffered at least one serious adverse event was around 48% to 49% in each study arm, thereby showing that there may be no differences between groups (RR 1.02, 95% CI 0.89 to 1.16). The results did not change after carrying out the sensitivity analyses. The proportion of participants suffering at least one adverse event of any type was somewhat higher (between 67% and 68% in each arm), but there may be no differences between groups (RR 1.07, 95% CI 0.86 to 1.34).

The limited available data showed that there may be no difference between study arms when analysing the outcome reduction of the LVMI (RR 0.87, 95% CI 0.58 to 1.30) and change in the LVMI (mean difference −0.30, 95% CI −5.87 to 5.27).

We did not carry out subgroup analyses as none of the primary outcomes revealed substantial heterogeneity. With regard to both primary and secondary outcome variables, heterogeneity was 1% or less in all cases except for the variable participants suffering at least one adverse event of any type, which showed an I² of 64% (P = 0.52).

Overall completeness and applicability of evidence

LVH is a secondary manifestation of hypertension and independently predicts the future cardiovascular disease events (ACC‐AHA 2017). Current guidelines advocate that hypertensive patients with LVH should be treated with antihypertensive therapy in order to decrease the rate of subsequent cardiovascular events (ESC/ESH 2018; Hypertension Canada 2020). Nevertheless, limited data derived from trials were available. The population of interest for the review constituted a subgroup of participants from the three included trials (20.1% from all trial participants in TOPCAT 2014, 19.4% from SUPPORT 2015, and 1.8% from EWPHE 1991). Despite this limitation, individual participant data permitted the identification of participants with hypertension and LVH, and exclusion of those with other possible causes of LVH. This approach enabled us to carry out meta‐analyses to assess the effect of antihypertensive therapy on all of the prespecified outcome variables. In addition, we ruled out heterogeneity for the primary outcomes, and performed sensitivity analyses to assess the robustness of the obtained results when restricting to blinded trials, to trials with low risk of bias in core domains, and to non‐industry‐funded trials. Results of the sensitivity analyses did not change the main findings.

The obtained results may have been influenced by the characteristics of the population included in the review. The mean age of participants included in the meta‐analyses was around 66 to 76 years, and except in the EWPHE 1991 trial, for which LVEF data were not available, almost all of the participants had an LVEF of 40% or more. Moreover, we did not include participants with other coexisting pathologies apart from high blood pressure that can lead to LVH, such as dilated and/or hypertrophic cardiomyopathy, aortic stenosis, and aortic and/or mitral regurgitation. All of these issues must be considered when interpreting the findings and when extrapolating results to other settings.

As we did not identify any completed RCT specifically focusing on people with high blood pressure and LVH caused by hypertension and fulfilling our remaining inclusion criteria, there is a need for RCTs to draw firm conclusions on the effect of antihypertensive therapy on morbi‐mortality of this specific population. We identified some ongoing trials that may help to broaden the existing evidence base on this issue (ChiCTR‐INR‐16008079; ChiCTR‐IPR‐16009507; NCT02893358). ChiCTR‐INR‐16008079 is an RCT designed by researchers from Shanghai Jiaotong University School of Medicine to analyse if treatment with spironolactone delays the progression of heart failure in adults with essential hypertension, echocardiographic signs of LVH, and preserved ejection fraction. Amongst other outcomes, the incidence of hospitalisation due to heart failure and cardiac death will be evaluated. Another trial carried out by the same investigators, ChiCTR‐IPR‐16009507, will assess the effect of spironolactone on the progression of diastolic dysfunction in individuals with essential hypertension, echocardiographic signs of LVH, suspected left ventricular diastolic dysfunction, and preserved ejection fraction. As in the preceding trial, hospitalisation due to heart failure and cardiac death will be evaluated. Antihypertensive Treatment in Masked Hypertension for Target Organ Protection (ANTI‐MASK) is a double‐blinded phase IV RCT that compares allisartan versus placebo in individuals with masked hypertension and at least one kind of target organ damage (LVH, large arterial stiffness, and microalbuminuria) (NCT02893358). The primary outcome will be improvement in target organ damage at one year. Secondarily, the incidence rate of all‐cause death and cardiovascular events (stroke and myocardial infarction) at one year will be assessed. These ongoing trials specifically target people with hypertension and LVH, and consequently are expected to help consolidate the existing evidence.

Another aspect to consider is that most of the participants included in the review (those from TOPCAT 2014 and SUPPORT 2015) were receiving around three antihypertensive drugs at baseline. With the available studies, the possible benefits that could be obtained with the intervention were from adding another antihypertensive to the baseline treatment (intensifying antihypertensive treatment), not of initially receiving an antihypertensive treatment.

Although the results of this review were found to be inconclusive, they could assist physicians who treat patients with hypertension and LVH in making decisions regarding the optimal therapeutic management, balancing the potential benefits and risks of introducing antihypertensive therapy.

Quality of the evidence

We rated the certainty of the evidence for all outcomes as very low. In the case of all‐cause mortality, cardiovascular events, and hospitalisation for heart failure, we downgraded the certainty of the evidence two levels due to imprecision and one additional level due to indirectness. Regarding imprecision, assuming a minimal important difference threshold of 10% for all‐cause mortality, myocardial infarction, stroke, and hospitalisation for heart failure as established by the National Institute for Health and Care Excellence (NICE) for adults with primary hypertension (NICE 2019), the 95% CI around the pooled estimate of effect for these outcomes crossed this threshold to the left and to the right side. As for indirectness, the target population of the included trials did not exactly coincide with the population of interest for the review, as they included patients presenting specific conditions, such as class II‐IV heart failure in TOPCAT 2014 and SUPPORT 2015, or elderly patients in EWPHE 1991. Participants that apart from fulfilling the trial inclusion criteria had hypertension and LVH were only a minor percentage of the total populations of the trials, for which we extracted data from individual participant‐level data. Additionally, in the case of cardiovascular events, the lack of blinding of participants and personnel in the SUPPORT 2015 trial could have affected the obtained results.

For the outcome total serious adverse events, we downgraded the certainty of the evidence one level each for imprecision, indirectness, and high risk of bias. With regard to imprecision and assuming a minimal important difference threshold of 15% (NICE 2019), the 95% CI around the pooled estimate of effect crossed this threshold to the left right side. In addition, the high risk of bias related to lack of blinding in the SUPPORT 2015 trial could have influenced the adjudication of serious adverse events. Moreover, of the three included trials, only TOPCAT 2014 trial provided a standardised definition of serious adverse events and analysed them systematically. In TOPCAT 2014, a serious adverse event was defined as an adverse event that met one or more of the following criteria: fatal, life‐threatening, requires in‐patients hospitalisation or prolongation of existing hospitalisation, persistent or significant disability/incapacity, congenital anomaly/birth defect, resulted in permanent impairment damage of a body function/structure, or required intervention to prevent permanent impairment of a body function/structure. In EWPHE 1991 and SUPPORT 2015, a definition of serious adverse events was not established, therefore we adopted the definition provided by the International Conference on Harmonisation (ICH) (ICH‐GCP 1997). In both cases, we constructed the serious adverse event outcome following this definition and through individual participant‐level data from the trials.

We downgraded the certainty of the evidence one level for imprecision, one level for indirectness, and a further level for publication bias in the case of withdrawals due to adverse events. With respect to publication bias, only TOPCAT 2014 provided information regarding withdrawals due to adverse events, therefore data were only available for a reduced number of participants from the entire population considered in the review.

Despite the constraint that participants with hypertension and LVH were only a minor percentage of trial populations, the obtained results can be considered robust, as we carried out the analyses on the basis of both published and unpublished information from the trials, including the original participant‐level data. In addition, we performed sensitivity analyses in order to minimise the possible uncertainty. This approach guarantees the validity of the findings.

Potential biases in the review process

We carried out searches in multiple databases in order to identify all potentially eligible trials. Two review authors screened the search results, and disagreements were resolved with the inclusion of a third review author and by consensus from all review authors. We additionally contacted main investigators, corresponding authors, and promoters of many of the potentially eligible trials identified during the screening process to further investigate if the trials included at least some participants with hypertension and LVH, and to obtain unpublished information for the included trials. Two review authors carried out data extraction and management of individual‐level participant data, and discrepancies were discussed until consensus was reached. The two review authors who carried out data extraction and analyses independently assessed the risk of bias of the trials and the certainty of the evidence using the GRADE approach. This strategy enhances the quality of the process.

However, there are some matters that should be taken into account when interpreting the results of the review. First, we did not identify any study specifically addressing people with high blood pressure and LVH caused by hypertension. We built evidence by identifying through individual‐level participant data the specific participants who suffered hypertension and LVH from the included trials. In this regard, characteristics of the target population varied amongst the included trials. TOPCAT 2014 involved adults with symptomatic heart failure (NYHA class II‐IV) and LVEF of at least 45%, and SUPPORT 2015 included hypertensive adults with stable heart failure. In contrast, EWPHE 1991 specifically addressed elderly hypertensive patients and excluded those with congestive heart failure not corrected without diuretics or antihypertensive drugs, or both.

The TOPCAT 2014 trial was designed to evaluate the effect of spironolactone versus placebo on morbidity, mortality, and quality of life in individuals with heart failure with preserved ejection fraction, not specifically with hypertension. In this trial, spironolactone was initiated at a dose of 15 mg once daily, which could be up‐titrated during the trial to a maximum of 45 mg daily. These doses are lower than those usually used when the drug is intended to reduce blood pressure, in which case starting doses are generally 50 to 100 mg per day, with the possibility of titration up to 200 mg per day. This issue may have led to a lower magnitude of effect of the intervention than would have been expected if the drug had been used with the intention of lowering blood pressure. However, the aim of the review was to analyse whether there were differences in benefits and harms when comparing a group of participants who received antihypertensive drugs of any type to a group of participants who received placebo, independently of the doses used.

None of the included trials provided information regarding the cause of the LVH, therefore it was not possible to ensure that the cause of the LVH was hypertension. However, where possible, we identified and excluded from the analyses participants who had coexisting pathologies other than hypertension that could potentially have caused the LVH. Another aspect that should be considered is the inconsistency in the LVH diagnostic criteria. In both TOPCAT 2014 and SUPPORT 2015 trials participants underwent echocardiograms during the trial, and in both cases trial investigators established the American Society of Echocardiograhy (ASE) criteria to diagnose LVH. According to these criteria, people with LVH were those with an LVMI greater than 115 g/m² in males and greater than 95 g/m² in females. In contrast, the EWPHE 1991 trial investigators did not define a specific LVH criteria. Trial participants underwent standard 12‐lead ECG during the trial, but echocardiograms were not performed. Based on the available information, the review authors established the criteria for LVH to select the subgroup of participants of interest for the review by consensus. In this case, we considered participants with LVH as those with 'RV1 + SV5 ≥ 35 AND RaVL > 12'.

Agreements and disagreements with other studies or reviews

Although the role of antihypertensive treatment in the regression of left ventricular mass in people with LVH hypertension has been studied extensively, there is still debate regarding which drug class provides the greatest magnitude of change. Moreover, regression of left ventricular mass is a subrogate endpoint, and thus may not necessarily translate into significant benefits in clinically relevant endpoints. At present, uncertainty persists regarding the prognostic relevance and the impact in terms of major clinical variables of LVH regression in people with hypertension. In this regard, to date no reviews specifically comparing antihypertensive drug treatment with placebo or no treatment in individuals with LVH and hypertension has been published. To our knowledge this is the first systematic review analysing the potential benefit of adding additional antihypertensive therapy compared to placebo in the morbidity and mortality of individuals with hypertension and LVH, which is crucial to determine in order to optimise patient management. We obtained evidence by identifying and selecting subpopulations of interest from clinical trials.

The review by Pierdomenico 2010 carried out a meta‐analysis on the impact of echocardiographic LVH regression on the incidence of cardiovascular events in hypertensive patients. Hypertensive patients with LVH regression or persistent normal left ventricular mass were compared with those with LVH persistence or LVH development. Five studies were identified, including 3149 participants (mean age range 48 to 66 years, 58% men), with a follow‐up duration of three to nine years. LVH regression/persistent normal left ventricular mass was associated with a significant benefit in cardiovascular events compared with LVH persistence/LVH development (adjusted hazard ratio 0.54, 95% CI 0.35 to 0.84; I² = 59%).

Several reviews have compared the effect of some antihypertensive drug classes versus other antihypertensive drug classes in left ventricular mass regression; however, there is a marked inconsistency in the results of these reviews. Fagard 2009 compared the effect of diuretics, beta‐blockers, calcium channel blockers, angiotensin‐converting enzyme inhibitors, and angiotensin receptor blockers on left ventricular mass regression in individuals with hypertension. The review included evidence up to December 2008. A total of 75 publications were identified, involving 6001 participants (mean age 53.8 years). All participants had hypertension, and 43.6% of the studies also required the presence of LVH. Drug treatment consisted of monotherapy in 59% of the studies, whereas the remaining studies permitted add‐on therapy. Median study duration was six months (range two to 48 months). Regression of left ventricular mass was significantly lower with beta‐blockers than with angiotensin receptor blockers (9.8% versus 12.5%), with no significant differences found in any of the other comparisons between drug classes. Beta‐blockers showed significantly less mass regression than the other four drug classes combined (P < 0.01), and regression was more pronounced with angiotensin receptor blockers than with the other classes (P < 0.01). However, the review findings did not coincide with those from a later review published in 2018 (Xing 2018).

Xing 2018 compared the efficacy of fat‐soluble and selective beta1 receptor blockers with other antihypertensive drug classes (angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics) on regression of LVH. A total of 41 RCTs involving 2566 participants with hypertension and LVH were included. Bayesian network meta‐analyses showed that beta‐blockers had greater efficacy in LVH regression when compared with diuretics (mean difference 13.04, 95% CI 3.38 to 22.59) or calcium channel blockers (mean difference 10.90, 95% CI 1.98 to 19.49), but differences were not found when beta‐blockers were compared to angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers. The probabilities of being amongst the most efficacious treatments were: beta‐blockers (72%), angiotensin receptor blockers (27%), angiotensin‐converting enzyme inhibitors (0.01%), calcium channel blockers (0.00%), and diuretics (0.00%).

Roush 2018 identified 12 RCTs that compared diuretics (chlorthalidone, indapamide, and potassium‐sparing diuretic/hydrochlorothiazide) to renin–angiotensin system inhibitors in reducing left ventricular mass. Left ventricular mass reduction was 37% greater with diuretics than with renin–angiotensin system inhibitors. Compared with renin–angiotensin system inhibitors, diuretics significantly reduced end‐systolic left ventricular internal dimension. The strength of the evidence was rated as at least moderate.

The review by Yang 2013 assessed the effect of angiotensin receptor blockers versus placebo or non‐angiotensin receptor blockers, and the impact of combined treatment with angiotensin receptor blockers and angiotensin‐converting enzyme inhibitors on LVH and left ventricular function in individuals on maintenance dialysis, based on evidence published up to November 2010. Six RCTs (207 participants) were included. Angiotensin receptor blockers led to a significantly greater regression of LVMI when compared with placebo/non‐angiotensin receptor blockers, whilst no significant differences were found between treatments in change in LVEF. The addition of angiotensin‐converting enzyme inhibitors to angiotensin receptor blockers did not show an added benefit when compared to treatment with angiotensin receptor blockers alone.

None of these reviews analysed the effect of different antihypertensive drug classes on cardiovascular events or mortality.

Our review, which compared antihypertensive therapy to placebo or no treatment, did not find a benefit of adding antihypertensive drugs on incidence of cardiovascular events or mortality in participants with hypertension and LVH, although the certainty of the evidence was very low. Limited data on the regression of LVMI limited our ability to draw any conclusions.

Authors' conclusions

Implications for practice.

We are uncertain about the effects of adding additional antihypertensive drugs on cardiovascular events, hospitalisation for heart failure, or mortality compared to placebo or no treatment in individuals with left ventricular hypertrophy (LVH) and hypertension. Confidence intervals were wide, therefore we cannot discard important benefits and important harms with additional antihypertensive therapy. The evidence for risk of suffering serious adverse events is very uncertain. However, withdrawal due to adverse events may significantly increase with the addition of antihypertensive drugs. Given the scarce data on the change in left ventricular mass index, we cannot draw any confident conclusions on this endpoint.

The certainty of the evidence is very low, therefore we cannot draw any firm conclusions on the potential effect of adding additional antihypertensives to baseline treatment in individuals with LVH and hypertension. Clinicians and health policymakers must outweigh the potential benefits and risks when planning to add more antihypertensive drugs.

Implications for research.

High‐quality clinical trials addressing the role of adding additional antihypertensive drugs specifically in individuals with LVH caused by hypertension are warranted. In addition, future studies must assess the impact on clinically relevant variables. It is also crucial to systematically analyse the incidence of serious adverse events, following internationally accepted definitions. Additionally, efforts should be made to improve transparency on reporting trial results and to facilitate access to primary documents such as study protocols, statistical analysis plans, final reports, and datasets.

History

Protocol first published: Issue 1, 2016

Appendices

Appendix 1. Medical glossary

Term	Definition	Source
A
Adverse events; drug toxicity	Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic procedures. Does not include accidental or intentional poisoning, for which specific headings are available.	PubMed – MeSH terms
Atrial fibrillation	Abnormal cardiac rhythm characterised by rapid, unco‐ordinated firing of electrical impulses in the upper chambers of the heart (heart atria). In such cases, blood cannot be effectively pumped into the lower chambers of the heart (heart ventricles). The cause is abnormal impulse generation.	Cochrane Library – MeSH terms
E
Echocardiography	Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic.	Cochrane Library – MeSH terms
Electrocardiography	Recording of the moment‐to‐moment electromotive forces of the heart as projected onto various sites on the body's surface, delineated as a scalar function of time. The recording is monitored by a tracing on slow‐moving chart paper or by observing it on a cardioscope, which is a cathode ray tube display.	Cochrane Library – MeSH terms
H
Heart failure	A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic needs of the body. The cause can be structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond the heart's capacity. Chronic heart failure is more common than acute heart failure, which results from a sudden insult to cardiac function, such as in myocardial infarction.	PubMed – MeSH terms
Hypertension	Persistently high systemic arterial blood pressure. Based on multiple readings (blood pressure determination), hypertension is currently defined as when systolic pressure is consistently 140 mmHg or higher or when diastolic pressure is consistently 90 mmHg or higher.	Cochrane Library – MeSH terms
Hypertension‐induced left ventricular hypertrophy	An increase in left ventricular mass resulting from elevated pressure load	Cochrane Library – MeSH terms
Hypertrophy, left ventricular	Enlargement of the left ventricle of the heart. This increase in ventricular mass is attributed to sustained abnormal pressure or volume loads and is a contributor to cardiovascular morbidity and mortality.	Cochrane Library – MeSH terms
M
Magnetic resonance imaging	Non‐invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves that can be reconstructed into computerised images. The concept includes proton spin tomographic techniques.	Cochrane Library – MeSH terms
Myocardial infarction	Necrosis of the myocardium caused by an obstruction of the blood supply to the heart (coronary circulation)	Cochrane Library – MeSH terms
Mortality	All deaths reported in a given population	Cochrane Library – MeSH terms
S
Safety	Freedom from exposure to danger and protection from the occurrence or risk of injury or loss. It suggests optimal precautions in the workplace, on the street, in the home, etc., and includes personal safety as well as the safety of property.	Cochrane Library – MeSH terms
Stroke	A group of pathological conditions characterised by sudden, non‐convulsive loss of neurological function due to brain ischaemia or intracranial haemorrhages. Stroke is classified by the type of tissue necrosis, such as the anatomic location, vasculature involved, aetiology, age of the affected individual, and haemorrhagic versus non‐haemorrhagic nature (Adams 1997).	Cochrane Library – MeSH terms
W
Withdrawal due to adverse drug effects	Physiological and psychological symptoms associated with withdrawal from the use of a drug after prolonged administration or habituation. The concept includes withdrawal from smoking or drinking, as well as withdrawal from an administered drug.	Cochrane Library – MeSH terms

Appendix 2. Left ventricular hypertrophy diagnosis criteria

Method	Diagnosis criteria	Source
Electrocardiogram	Romhilt‐Estes Point Score SCORE ESTES: 4 point: probable LVH ≥ 5 point: LVH diagnosed Voltage criteria = 3 points ST‐T abnormalities without digital = 3, with digital = 1 Electrical axis deviation > −15 degrees = 2 QRS duration > 0.09 second = 1 Intrinsicoid deflection > 0.04 second = 1 SCORE ROMHILT: 4 point: probable LVH ≥ 5 point: LVH diagnosed Amplitude of R or S in limb leads > 2 mV or S in V1 or V2 > 3 mV or R in V5 or V6 > 3 mV = 3 points ST segment changes with or without digital = 1 or 2 points, respectively Left atrial enlargement = 3 points Left axis deviation > 30 degrees = 2 points QRS duration > 0.09 second and intrinsicoid deflection in V5 and V6 > 0.05 = 1 point each ROMHILT‐ESTES POINT SCORE: 4 point: probable LVH ≥ 5 point: LVH diagnosed Voltage criteria (3 points): Any S or R in limb leads ≥ 20 mm SV1, SV2, RV5, or RV6 ≥ 30 mm ST‐T wave changes of LVH (3 points, 1 point on digitalis) Left atrial abnormality (3 points): Terminal component of the P wave in V1 ≥ 1 mm and ≥ 40 ms Left axis deviation (2 points): QRS axis of −30 degrees or more negative Prolonged QRS duration (1 point): ≥ 90 ms Delayed intrinsicoid deflection time (1 point): ≥ 50 ms in V5 or V6	Romhilt 1968 Ang 2008 Giuliani 1996 Fisch 1993 Bauml 2010
	Sokolow‐Lyon criteria SV1 + RV5‐V6 ≥ 3.5 mV or max RV5/6 ≥ 2.6 mV	Ang 2008
	McPhie The sum of the tallest R and deepest S in the precordial leads > 45 mm	Ang 2008
	The sum of 12‐lead QRS voltages Sum of max (R + S) amplitude in each of the 12 leads > 179 mm	Ang 2008
	Minnesota code R AVL > 12 mm R V5 or V6 plus S V1 or V2 > 35 mm R V6 > R V4 R V6 > R V5 S V2 > 24 mm R D1 plus S D3 > 25 mm RV5/V6 > 2.6 mV, RI/II/III/aVF > 2.0 mV or RaVL > 1.2 mV	Malmqvist 2001 Ang 2008
	Cornell voltage criteria SV3 + RV1 ≥ 20 mm in women or SV3 + RV1 ≥ 28 mm in men	González‐Juanatey 2007
	Manning R DI > 13 mm	Romhilt 1969
	Mazzoleni R aVL > 7.5 mm	Romhilt 1969
	Cornell Product (RaVL + SV3) x QRS duration ≥ 2436 mm/ms	Ang 2008
	Lewis Index (RI + SIII) − (RIII + SI) > 1.7 mV	Ang 2008
	Gubner‐Ungerleider RI + SIII ≥ 2.2 mV	Ang 2008
	Simonson Simonson studies as the upper limits of normal (97.5 percentile) for the R‐wave amplitude of 20 mm are any standard lead of 25 mm in precordial V5 and 44 mm for the amount of S in V1 and R in V5. Above these values is considered LVH.	Ang 2008
	Perugia Score Positivity of at least 1 of the following: SV3 + RaVL > 2.4 mV Left ventricular strain pattern Romhilt–Estes point score ≥ 5	Ang 2008
	Framingham Score RI + SIII > 2.5 mV, SV1/2 + RV5/6 > 3.5 mV, SV1/2/3 > 2.5 mV + RV4/5/6 > 2.5 mV plus left ventricular strain pattern	Ang 2008
Echocardiogram	American Society of Echocardiography criteria Normal values: relative wall thickness ≤ 0.42, left ventricular mass index (g/m2) ≤ 95 and ≤ 115, according to female or male, respectively. In function of left ventricular mass index and relative wall thickness normal values, 3 patterns of LVH are possible: Concentric remodelling: when relative wall thickness is increased with normal left ventricular mass index. Concentric hypertrophy: when relative wall thickness and left ventricular mass index are increased. The ratio of ventricular wall thickness to radius (relative wall thickness) is increased and refers to a ventricle with thick walls relative to cavity volume. Eccentric hypertrophy (or volume‐overload): when relative wall thickness is normal, and left ventricular mass index is increased. The ratio is decreased and refers to a ventricle with an expanded cavitary volume in proportion to wall thickness.	Lang 2005
	Simpson criteria The American Society of Echocardiography with the European Association of Echocardiography has issued the following criteria for LVH using modified Simpson's rule: Estimated left ventricular mass of 201 to 227 g (103 to 116 g/m2) for men and 151 to 171 g (89 to 100 g/m2) for women is mildly abnormal. Estimated left ventricular mass of 228 to 254 g (117 to 130 g/m2) for men and 172 to 182 g (101 to 112 g/m2) for women is moderately abnormal. Estimated left ventricular mass > 255 g (> 131 g/m2) for men and > 193 g (> 113 g/m2) for women is severely abnormal.	Lang 2005
Magnetic resonance imaging	Uses the tracing of the contour of myocardial and epicardial border of the left ventricle (in a range of transverse cuts extending across the ventricular chamber) from base to apex; the software performs automated calculation of left ventricular mass. Sex‐specific values of LVH were defined as: left ventricular mass/height ≥ 39 g/m2 (women) and ≥ 48 g/m2 (men). Diagnosis criteria by magnetic resonance imaging: Asymmetric forms of remodelling and hypertrophy were defined as having a septal‐to‐lateral wall thickness ratio > 1.5. Remodelling subtypes: Individuals may be classified by presence or absence of LVH (horizontal axis) and by geometry (vertical axis), depending on mass‐to‐volume ratio. If mass‐to volume ratio is high, geometry is classified as concentric. The paradigm of Khouri 2010 subdivides the 2 LVH classes by whether chamber dilation is present. Imaging magnetic resonance‐based volumetric analysis overcomes the limitation of the use of linear parameters to calculate volume. Their major findings are that concentric or eccentric LVH can each be classified into 2 subgroups, yielding 4 distinct geometric patterns. LVH based on whether or not left ventricular concentricity (to reflect wall thickness) and LVEDV are increased: This approach leads to a 4‐tiered classification of LVH. Increased concentricity without increased LVEDV (“thick hypertrophy”). Increased LVEDV without increased concentricity (“dilated hypertrophy”). Increased concentricity with increased LVEDV (“both thick and dilated hypertrophy”). Neither increased concentricity nor increased LVEDV (“indeterminate hypertrophy”).	Dweck 2012 Khouri 2010
Abbreviations: LVEDV: left ventricular end‐diastolic volume; LVH: left ventricular hypertrophy

Appendix 3. Search strategies

Database: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) <1946 to September 21, 2020>
Search Date: 22 September 2020
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 hypertrophy, left ventricular/ 
2 lvh.tw,kf. 
3 lv hypertrophy.tw,kf. 
4 (left adj2 ventricul$ adj2 (enlargement or hypertroph$)).tw,kf. 
5 or/1‐4 
6 exp antihypertensive agents/ 
7 exp thiazides/
8 exp sodium potassium chloride symporter inhibitors/
9 ((loop or ceiling) adj diuretic?).tw,kf.
10 (amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or hydrochlorothiazide or hydroflumethiazide or methyclothiazide or metolazone or polythiazide or trichlormethiazide or veratide or thiazide?).tw,kf. 
11 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide).tw,kf. 
12 or/7‐11 
13 exp angiotensin‐converting enzyme inhibitors/ 
14 ((angiotensin or dipeptidyl) adj3 (convert$ or enzyme or inhibit$ or recept$ or block$)).tw,kf.
15 ((ace or renin) adj3 inhibit$).tw,kf. 
16 acei.tw,kf.
17 exp enalapril/ 
18 (alacepril or altiopril or benazepril or captopril or ceronapril or cilazapril or delapril or derapril or enalapril or fosinopril or idapril or imidapril or lisinopril or moexipril or moveltipril or pentopril or perindopril or quinapril or ramipril or spirapril or temocapril or trandolapril or zofenopril or aliskiren or enalkire or remikiren).tw,kf. 
19 or/13‐18 
20 exp losartan/
21 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten).tw,kf. 
22 (arb or arbs).tw,kf.
23 or/20‐21 [ARBS] 
24 exp calcium channel blockers/ 
25 (calcium channel block$ or amlodipine or amrinone or bencyclane or bepridil or cinnarizine or conotoxins or diltiazem or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or magnesium sulfate or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or verapamil or omega‐agatoxin iva or omega‐conotoxin gvia or omega‐conotoxins).tw,kf. 
26 (calcium adj2 (inhibit$ or antagonist? or block$)).tw,kf. 
27 or/24‐26 
28 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or methyl dopa or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp. 
29 (reserpine or serpentina or rauwolfia or serpasil).mp. 
30 (clonidine or adesipress or arkamin or caprysin or catapres$ or catasan or chlofazolin or chlophazolin or clinidine or clofelin$ or clofenil or clomidine or clondine or clonistada or clonnirit or clophelin$ or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m‐5041t or normopresan or paracefan or st‐155 or st 155 or tesno timelets).mp. 
31 exp hydralazine/ 
32 (hydralazin$ or hydrallazin$ or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1‐hydrazinophthalazine or apressin or nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat).tw,kf. 
33 or/28‐32
34 exp adrenergic beta‐antagonists/ 
35 adrenergic beta antagonist?.tw,kf.
36 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).tw,kf. 
37 (beta adj2 (antagonist? or receptor? or adrenergic? block$)).tw,kf. 
38 or/34‐37 
39 exp adrenergic alpha antagonists/ 
40 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).tw,kf. 
41 (andrenergic adj2 (alpha or antagonist?)).tw,kf.
42 ((andrenergic or alpha or receptor?) adj2 block$).tw,kf. 
43 or/39‐42 
44 6 or 12 or 19 or 23 or 27 or 33 or 38 or 43
45 hypertension/ 
46 essential hypertension/ 
47 (antihypertens$ or hypertens$).tw,kf.
48 ((elevat$ or high$ or rais$) adj2 (blood pressur$ or bp)).tw,kf. 
49 or/45‐48 
50 randomized controlled trial.pt. 
51 controlled clinical trial.pt. 
52 randomi?ed.ab. 
53 placebo.ab. 
54 clinical trials as topic/ 
55 randomly.ab. 
56 trial.ti. 
57 or/50‐56 
58 animals/ not (humans/ and animals/) 
59 57 not 58 
60 5 and 44 and 49 and 59

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Hypertension Group Specialised Register via Cochrane Register of Studies (CRS‐Web) Search Date: 26 September 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 MeSH DESCRIPTOR Hypertrophy, Left Ventricular AND INSEGMENT
#2 LVH AND INSEGMENT
#3 LV hypertrophy AND INSEGMENT
#4 (left NEAR2 ventric* NEAR2 enlargement) AND INSEGMENT
#5 (left NEAR2 ventric* NEAR2 hypertrophy) AND INSEGMENT
#6 (#1 OR #2 OR #3 OR #4 OR #5) AND INSEGMENT
#7 RCT:DE AND INSEGMENT
#8 Review:ODE AND INSEGMENT
#9 (#7 OR #8) AND INSEGMENT
#10 #6 AND #9 AND INSEGMENT

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Cochrane Central Register of Controlled Trials (CENTRAL Issue 8, 2020) via Cochrane Register of Studies (CRS‐Web)
Search Date: 22 September 2020
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 MeSH DESCRIPTOR Hypertrophy, Left Ventricular AND CENTRAL:TARGET
#2 (left NEAR2 ventric* NEAR2 (enlargement OR hypertrophy)) AND CENTRAL:TARGET
#3 (lvh OR lv hypertrophy) AND CENTRAL:TARGET
#4 (#1 OR #2 OR #3) AND CENTRAL:TARGET
#5 MESH DESCRIPTOR Hypertension AND CENTRAL:TARGET
#6 MESH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET
#7 (antihypertens* OR hypertens*) AND CENTRAL:TARGET
#8 (elevat* OR high* OR rais*) NEAR2 (blood pressur* OR bp) AND CENTRAL:TARGET
#9 (#5 OR #6 OR #7 OR #8) AND CENTRAL:TARGET
#10 #4 AND #9 AND CENTRAL:TARGET

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Embase <1974 to 2020 September 21> 
Search Date: 22 September 2020
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 heart left ventricle hypertrophy/ 
2 lvh.tw. 
3 lv hypertrophy.tw. 
4 (left adj2 ventricul$ adj2 (enlargement or hypertroph$)).tw.
5 or/1‐4 
6 exp antihypertensive agent/
7 exp thiazide diuretic agent/ 
8 exp loop diuretic agent/
9 ((loop or ceiling) adj diuretic?).tw.
10 (amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or hydrochlorothiazide or hydroflumethiazide or methyclothiazide or metolazone or polythiazide or trichlormethiazide or veratide or thiazide?).tw. 
11 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide).tw. 
12 or/7‐11 
13 exp dipeptidyl carboxypeptidase inhibitor/ 
14 angiotensin converting enzyme inhibit$.tw.
15 (ace adj2 inhibit$).tw. 
16 acei.tw. 
17 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw. 
18 or/13‐17 
19 exp angiotensin receptor antagonist/ 
20 (angiotensin adj3 receptor antagon$).tw. 
21 (angiotensin adj3 receptor block$).tw. 
22 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten).tw. 
23 (arb or arbs).tw.
24 or/19‐23 
25 calcium channel blocking agent/ 
26 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM).tw. 
27 (calcium adj2 (antagonist? or block$ or inhibit$)).tw.
28 or/25‐27 
29 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or methyl dopa or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp. 
30 (reserpine or serpentina or rauwolfia or serpasil).mp. 
31 (clonidine or adesipress or arkamin or caprysin or catapres$ or catasan or chlofazolin or chlophazolin or clinidine or clofelin$ or clofenil or clomidine or clondine or clonistada or clonnirit or clophelin$ or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m‐5041t or normopresan or paracefan or st‐155 or st 155 or tesno timelets).mp. 
32 hydralazine/ 
33 (hydralazin$ or hydrallazin$ or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1‐hydrazinophthalazine or apressin or nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat).tw. 
34 or/29‐33 
35 exp beta adrenergic receptor blocking agent/
36 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).tw. 
37 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw. 
38 or/35‐37 
39 exp alpha adrenergic receptor blocking agent/ 
40 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).tw. 
41 (andrenergic adj2 (alpha or antagonist?)).tw. 
42 ((andrenergic or alpha or receptor?) adj2 block$).tw. 
43 or/39‐42 
44 6 or 12 or 18 or 24 or 28 or 34 or 38 or 43 
45 exp hypertension/ 
46 (hypertens$ or antihypertens$).tw. 
47 ((elevat$ or high$ or rais$) adj2 (blood pressur$ or bp)).tw. 
48 or/45‐47 
49 double blind$.mp. 
50 placebo$.tw. 
51 blind$.tw. 
52 or/49‐51 
53 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 
54 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/
55 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti.
56 52 not (53 or 54 or 55) 
57 5 and 44 and 48 and 56

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: ClinicalTrials.gov Search Date: 22 September 2020

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Condition or disease: Hypertension AND Left Ventricular Hypertrophy 
Other terms: randomized 
Study type: Interventional Studies (Clinical Trials)

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: International Clinical Trials Registry Platform (WHO ICTRP)
Search Date: 26 September 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
hypertens* AND left ventricular hypertrophy

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Epistemonikos
Search Date: 19 February 2021

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Hypertroph*

Publication type filter: "Primary studies"

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: LILACS Bireme
Search Date: 19 February 2021

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

ventricular AND hypertrophy AND randomized

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Clarivate Web of Science
Search Date: 26 February 2021

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

#1 "ventricular hypertrophy" OR LVH

#2 hypertension OR "high blood pressure"

#3 RCT OR randomized OR randomised

#4 #1 AND #2 AND #3

Data and analyses

Comparison 1. All‐cause mortality.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality	3	930	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.74, 1.40]

Comparison 2. Cardiovascular events.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Myocardial infarction	3	930	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.57, 2.62]
2.2 Stroke	3	930	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.35, 1.28]
2.3 Atrial fibrillation	2	915	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.93, 2.75]
2.4 At least 1 cardiovascular event	3	930	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.77, 1.55]

Comparison 3. Total serious adverse events.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Total serious adverse events	3	930	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.89, 1.16]

Comparison 4. Hospitalisation for heart failure.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Hospitalisation for heart failure	2	915	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.57, 1.17]

Comparison 5. Reduction of the left ventricular mass index.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Participants with reduction of the left ventricular mass index	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.58, 1.30]
5.2 Reduction of the left ventricular mass index	1	54	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐5.87, 5.27]

Comparison 6. Withdrawal due to adverse events.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Withdrawal due to adverse events	1	522	Risk Ratio (M‐H, Fixed, 95% CI)	3.09 [1.69, 5.66]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

EWPHE 1991.

Study characteristics
Methods	The European Working Party on High Blood Pressure in the Elderly (EWPHE) was a double‐blind multicentre trial with a follow‐up of up to 5 years that analysed the influence of antihypertensive therapy on morbidity and mortality.
Participants	Hypertensive patients of at least 60 years of age. Inclusion criteria: Age of 60 years of more or more at randomisation. Blood pressure in sitting position on placebo during the run‐in period: systolic: not less than 160 mmHg and nor more than 239 mmHg; diastolic: not less than 90 mmHg and not more than 119 mmHg. Willingness of patients to co‐operate (informed consent, either oral or written, was obtained) and likelihood of regular follow‐up should be feasible. Exclusion criteria: Certain specific causes of blood pressure elevation: specific causes of systolic blood pressure elevation, such as hyperthyroidism. Conditions correctable by surgery, such as coarctation of the aorta, Cushing's and Conn's syndrome, renovascular hypertension, phaeochromocytoma. Certain complications of hypertension: presence of: vascular retinopathy grade III (haemorrhages or exudates) or grade IV (papilloedema); congestive heart failure, not corrected without diuretics and/or antihypertensive drugs (low salt diet and cardiac glycosides, however, not allowed); enlarging or dissecting aneurysm; severe renal failure (serum creatinine of 2.5 mg % or more); history of: repeated severe nasal bleeding, not controlled by local measures; certified cerebral or subarachnoid haemorrhages; hypertensive encephalopathy. Certain other diseases: acute hepatitis or active cirrhosis; severe diseases not related to hypertension (e.g. carcinoma, insulin dependent diabetes); a physical deformity prohibiting a sitting position; orthostatic hypotension, severe enough to prohibit antihypertensive drug therapy; clinical gout: repeated attacks, or a single attack due to thiazides, or serum uric acid of 10 mg % or more on repeated examinations, despite uricosuric therapy; conditions not related to hypertension which necessitate the continued administration of diuretics, beta‐blocking agents, or Rauwolfia derivatives. Lack of co‐operation. The double‐blind part of the study was terminated for 1 of the following reasons: Completion of the study period: this was originally 5 years, but was later on extended, along with the study as a whole, to 1 July 1984. Lost to follow‐up: a participant was considered lost to follow‐up when (s)he decided not to continue the study. Interruption of all study treatment during more than 3 months (in the total study period). By 1 of the following terminating events: death; cerebral or subarachnoid haemorrhage; papilloedema, retinal haemorrhage, or retinal exudates; expanding or dissecting aneurysm; congestive heart failure not controllable without diuretic or antihypertensive drugs, hypertensive encephalopathy; evidence of an increase in left ventricular hypertrophy on both voltage ECG criteria and cardio‐thoracic ratio (X‐ray) criterion; serum creatinine increase; rise in diastolic blood pressure; any reason necessitating breaking the individual medication code; non‐hypertensive conditions requiring continuous long‐term (3 months or more) therapy with diuretics, calcium channel blockers, beta‐adrenoceptor blocking agents, or Rauwolfia alkaloids. Whenever possible, other treatments were used in such circumstances, e.g. for heart failure digitalis instead of diuretics, for angina pectoris other anti‐anginal drugs instead of beta‐receptor blockers, for psychoneurosis agents other than Rauwolfia alkaloids; other interfering diseases or medical conditions in which the doctor felt that continuation of the trial was not possible, such as individuals who developed a carcinoma.
Interventions	Hydrochlorotiazide plus triamterene versus matching placebo. In the first phase, all participants received 1 capsule containing 25 mg of hydrochlorotiazide plus 50 mg of triamterene daily or matching placebo. The dosage could be increased after not less than 2 weeks to 2 capsules per day. If after not less than 1 month the blood pressure remained high with this therapeutic regimen (i.e. sitting blood pressure at or above 160/90 mmHg), the second phase was started with the addition of alpha methyldopa or matching placebo. This treatment was started at a daily dose of half a tablet of 500 mg in the evening and was increased when necessary by half a tablet at intervals of not less than 2 weeks, until: either a blood pressure of less than 160/90 mmHg was reached; a total daily dosage of four 500 mg tablets was obtained; or intolerable adverse reactions occurred, precluding a further increase in dosage. Tablets and matching placebo were identical in shape, taste, and colour. Participants could receive diuretics, calcium channel blockers, beta‐adrenoreceptor blocking agents, or Rauwolfia alkaloids during periods shorter than 3 months. Participants requiring those treatments for 3 months or more terminated the trial.
Outcomes	Outcome variables were not prespecified in the study protocol.
Notes	Criteria of LVH: "Echocardiography was not routinely performed in the EWPHE trial and the left ventricular hypertrophy diagnosis was mainly based on the ECG findings" (Amery et al. The European Working Party on High Blood Pressure in the Elderly. American Journal of Medicine 1991;90(3A):1S‐4). Standard 12‐lead ECG were obtained from trial participants at randomisation and at each yearly visit thereafter. The height of the R wave in aVL (RaVL) and in V5 (RV5), and the depth of the S wave in V1 (SV1) were measured. Trial investigators did not indicate in any of the publications a specific diagnostic criteria for LVH. We therefore established by consensus the LVH diagnostic criteria to identify the subgroup of interest as follows: RV1 + SV5 ≥ 35 AND RaVL > 12. The population of interest corresponds to trial participants with hypertension and LVH. It was not possible through the protocol, publications, or individual participant data to determine whether there were participants with pathologies other than hypertension that can lead to LVH (e.g. aortic stenosis, aortic or mitral regurgitation, dilated cardiomyopathy, hypertrophic cardiomyopathy, ventricular sept defect). Individual‐level participant data were obtained from investigators at the University of Leuven. Funding: The trial was carried out in consultation with the World Health Organization and supported by the Belgian National Research Foundation and the Belgian Hypertension Committee through a grant from Merck Sharp & Dohme and Smith, Kline & French. These companies supplied and prepared Aldomet tablets of 500 mg of methyldopa and Dyazide capsules of 25 mg of hydrochlorothiazide and 50 mg of triamterene, and matching placebos. Yearly meetings of the EWPHE were also sponsored by the European Economic Community, Imperial Chemical Industries, and Astra; J Vanhollenbeke from Boehringer Pharma Belgium collaborated in performing the quality control. Contact information: Dr Lutgarde Thijs (lutgarde.thijs@kuleuven.be). University of Leuven, Leuven (Belgium)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Neither the protocol nor the publications provided information regarding random sequence generation.
Allocation concealment (selection bias)	Unclear risk	"Near the end of the run‐in period the initial record forms are sent to the co‐ordinating office and the patients are stratified for each collaborating centre into one of eight categories combining age, sex and the presence or absence of cardiovascular complications of their high blood pressure" "The patient's stratification and treatment randomization is designed in such a fashion that in each of the participating centres the same number of patients will receive active or placebo treatment (stratification per centre)" (Amery A et al. European working party on high blood pressure in elderly (EWPHE): organization of a double‐blind multicentre trial on antihypertensive therapy in elderly patients. Clinical Science and Molecular Medicine. Supplement 1973;45(Suppl 1):71s‐3s). Neither the published protocol nor the original protocol provided additional data regarding allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Long‐term effects of antihypertensive treatment on various electrocardiogram (ECG) voltages and the association between ECG findings at randomization and subsequent mortality were evaluated in the double‐blind, placebo‐controlled trial of elderly hypertensive patients, conducted by the European Working Party on High Blood Pressure in the Elderly (EWPHE)" (Van Hoof R et al. The effect of antihypertensive treatment on electrocardiogram voltages in the EWPHE trial. Journal of Cardiovascular Pharmacology 1991;17(Suppl 2):S101‐4). "Together with the numbered drug containers, the treating physician received a sealed envelope, carrying on the outside the patients number and containing inside information on the drug therapy. The envelope was available in the clinics, usually held by the hospital pharmacist, and had to be returned unopened to the C.O. upon completion of the double‐blind part of the study" (An international trial of antihypertensive therapy in elderly patients. Objectives, protocol and organization. European Working Party on High Blood Pressure in the Elderly (EWPHE). Archives Internationales de Pharmacodynamie et de Thérapie 1985;275(2):300‐34). "Tablets and matching placebos were identical in shape, taste and colour" (Amery A et al. European working party on high blood pressure in elderly (EWPHE): organization of a double‐blind multicentre trial on antihypertensive therapy in elderly patients. Clinical Science and Molecular Medicine. Supplement 1973;45(Suppl 1):71s‐3s)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Data were sent to the coordinating office every three months on specially designed forms and deaths and other terminating events were classified independently by two investigators into previously agreed categories. These investigators were not aware of the treatment group to which the patients had been assigned" (Amery A et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985;1(8442):1349‐54). "Data on concomitant diseases and symptoms were recorded at entry to the study and at yearly intervals, and coded according to the Eighth Revision of the International Statistical Classification of Diseases. Details of concomitant non‐antihypertensive treatments and routine laboratory values were available at entry and at three‐month intervals throughout the trial. Drug treatment was coded by both generic name and class of therapy. All coding was performed by persons who did not know what treatment the patient was receiving” (Fletcher AE. Adverse treatment effects in the trial of the European Working Party on High Blood Pressure in the Elderly. American Journal of Medicine 1991;90(3A):42S‐44S).
Incomplete outcome data (attrition bias) All outcomes	Low risk	17.7% of trial participants left the study before the 9‐month follow‐up visit (n = 85 control group, n = 64 active group) and were not included in the mortality analysis: "Eighty five of the 424 patients randomised to placebo and 64 of the 416 patients randomised to active treatment left the study before the follow up visit at nine months; these patients were therefore not included in the present analyses" (Staessen J et al. Relation between mortality and treated blood pressure in elderly patients with hypertension: report of the European Working Party on High Blood Pressure in the Elderly. BMJ 1989;298(6687):1552‐6). "Similar proportions of patients were lost to follow‐up in the two groups: 14.2% of treated patients and 16.3% of placebo patients. Among those lost to follow‐up, eight of the treated patients and nine of the placebo patients withdrew from the study with mention of a side effect or concomitant disease. More treated than placebo patients stopped medication because of side effects and concomitant disease (14 vs seven) or poor compliance (five vs two). In the treated group, the side effects reported as the reasons for withdrawal included gastric pain in four, gout, dizziness, and nausea in three each, and lethargy in one patient; and in the placebo group, headache, tinnitus, dyspnea, gastric pain, and lethargy in one each, and nonspecific psychiatric problems in two patients" (Fletcher AE. Adverse treatment effects in the trial of the European Working Party on High Blood Pressure in the Elderly. American Journal of Medicine 1991;90(3A):42S‐44S). "During randomised treatment 128 patients defaulted from follow‐up and 52 refused to continue their randomised treatment for various reasons but continued to attend. 38 patients were withdrawn from randomised treatment because of serious intercurrent illnesses (mainly neoplasms). Withdrawal was less frequent in the actively treated group (p= 0.022). One centre with 21 patients withdrew from the trial before its end. In another centre the double‐blind phase was terminated in 29 patients, each followed for five years, because this was the duration to which the patients had agreed. Eleven patients were withdrawn from randomised treatment by the local investigators owing to a moderate increase in blood pressure that did not, however, reach the previously established study‐terminating criteria. Similarly, 17 patients were withdrawn by the local investigators on discovery that the patients were no longer hypertensive during a brief period without treatment. In six patients the treatment code was broken‐eg, at the request of an anaesthetist. Two patients had treatment stopped in error and two others were withdrawn because the double‐blind drug supply was not available. There were 291 patients still in the double‐blind part of the trial when it was stopped in the summer of 1984" (Amery A et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985;1(8442):1349‐54). Overall, 36.4% of trial participants stopped the trial prematurely, without existing differences between groups (n = 157 control group, n = 149 intervention group; P = 0.18). Main causes of the premature stop were lost to follow‐up (41.8%); discontinuing trial medication for more than 3 months (17.0%); and the occurrence of a non‐fatal intercurrent disease (12.4%). However, results for the outcome variables established in the review protocol were available for all the trial participants included in the review.
Selective reporting (reporting bias)	High risk	The double‐blind part of the study was terminated for 1 of the following reasons (An international trial of antihypertensive therapy in elderly patients. Objectives, protocol and organization. European Working Party on High Blood Pressure in the Elderly (EWPHE). Archives Internationales de Pharmacodynamie et de Thérapie 1985;275(2):300‐34): Completion of the study period Lost to follow‐up By 1 of the following terminating events: death; cerebral or subarachnoid haemorrhage; papilloedema, retinal haemorrhage, or retinal exudates; expanding or dissecting aneurysm; congestive heart failure non‐controllable without diuretic or antihypertensive drugs; hypertensive encephalopathy; evidence of an increase in left ventricular hypertrophy; serum creatinine increase; rise in diastolic blood pressure; any reason necessitating breaking the individual medication code; non‐hypertensive conditions requiring continuous long‐term (3 months or more) therapy with diuretics, calcium channel blockers, beta‐adrenoceptor blocking agents, or Rauwolfia alkaloids; other interfering diseases or medical conditions for which the doctor felt that continuation of the trial was not possible, such as participants who developed a carcinoma. Data were analysed by intention‐to‐treat; however, in the case of participants who discontinued the study, only the date of death was registered: "patients who were randomized and left the double‐blind part of the study were followed on whatever treatment was felt necessary. These patients were followed up to July 1, 1984 and only the date and cause of death were recorded" (An international trial of antihypertensive therapy in elderly patients. Objectives, protocol and organization. European Working Party on High Blood Pressure in the Elderly (EWPHE). Archives Internationales de Pharmacodynamie et de Thérapie 1985;275(2):300‐34). All of these methodological considerations could have lead to an underestimation of the total clinical events.
Other bias	High risk	Participants with LVH do not correspond to a predefined subgroup of participants and represent 1.8% of the trial total population. The trial was carried out in consultation with the World Health Organization and supported by the Belgian National Research Foundation and the Belgian Hypertension Committee through a grant from Merck Sharp & Dohme and Smith, Kline & French. These companies supplied and prepared Aldomet tablets of 500 mg of methyldopa and Dyazide capsules of 25 mg of hydrochlorothiazide and 50 mg of triamterene, and matching placebos. Yearly meetings of the EWPHE were also sponsored by the European Economic Community, Imperial Chemical Industries, and Astra; J Vanhollenbeke from Boehringer Pharma Belgium collaborated in performing the quality control (Amery A et al. The European Working Party on High Blood Pressure in the Elderly. American Journal of Medicine 1991;90(3A):1S‐4S; Amery A et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985;1(8442):1349‐54).

SUPPORT 2015.

Study characteristics
Methods	The supplemental benefit of angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial is a prospective 1:1 randomised open‐label blinded endpoint trial aimed at analysing whether additive treatment with olmesartan reduces mortality and morbidity with a follow‐up of at least 3 years (NCT00417222).
Participants	Adult hypertensive patients with stable heart failure. Inclusion criteria: Patients with NYHA class II through IV chronic heart failure Patients with a history of hypertension or who are treated with antihypertensive medications Patients aged 20 years or older and less than 80 years at the entry Stable patients who had angiotensin‐converting enzyme inhibitor and/or beta‐blocker Patients who were not treated with angiotensin II receptor blocker Exclusion criteria: Patients with renal dysfunction (serum creatinine ≥ 3.0 mg/dL) or those under chronic haemodialysis Drug hypersensitivity to olmesartan Severe liver dysfunction History of angioedema Malignant tumour or life‐threatening illness of poor prognosis; Pregnant or possibly pregnant patients Cardiovascular surgery within 6 months prior to the date of study entry Acute myocardial infarction within 6 months prior to the date of study entry Percutaneous coronary intervention with or without stent implantation within 6 months prior to the date of study entry
Interventions	Additive olmesartan versus control group. Olmesartan was initiated at a dose of 5 to 10 mg, after which physicians were encouraged to increase the dose up to 40 mg/day where possible. No angiotensin receptor blockers were allowed in the control group.
Outcomes	Primary outcome measures: A composite of the following outcomes: all‐cause death, non‐fatal acute myocardial infarction, non‐fatal stroke, hospital admission due to worsening heart failure. Secondary outcome measures: Cardiovascular death; death due to heart failure; sudden death, acute myocardial infarction, stroke; hospital admission for any cardiovascular reason; fatal arrhythmia or appropriate ICD discharge; newly diagnosed diabetes; development of renal failure; new‐onset atrial fibrillation;need to modify treatment procedures for heart failure; decrease in LVEF; increase in B‐type natriuretic peptide levels (≥ 2‐fold increase if the baseline level was ≥ 50 pg/mL, and increase to 100 pg/mL if the baseline level was < 50 pg/mL); changes in serum markers for metabolic syndrome (high‐sensitivity C‐reactive protein, adiponectin, microRNAs).
Notes	Criteria of LVH: The American Society of Echocardiography criteria were used by trial investigators to define LVH. According to these criteria, patients with LVH were those with a left ventricular index greater than 115 g/m2 in males and greater than 95 g/m2 in females at baseline. The population of interest corresponds to trial participants with hypertension and LVH, excluding those participants with dilated or hypertrophic cardiomyopathy, or both. Individual participant‐level data were obtained from investigators at Tohoku University Graduate School of Medicine. Funding and conflicts of interests: The study was supported in part by the grants‐in‐aid from the Ministry of Health, Labour, and Welfare and from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The Department of Evidence‐based Cardiovascular Medicine, Tohoku University Graduate School of Medicine is supported in part by unrestricted research grants from pharmaceutical companies. The corresponding author received lecture fees from pharmaceutical companies. Contact information: Dr Shimokawa (shimo@cardio.med.tohoku.ac.jp), Dr Nochioka (nochioka@cardio.med.tohoku.ac.jp). Tohoku University Graduate School of Medicine, 1‐1 Seiryo‐machi, Aoba‐ku, Sendai 980‐8574, Japan
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Neither the published protocol nor the original protocol provided by study investigators provided information regarding randomisation method.
Allocation concealment (selection bias)	Unclear risk	The following information was provided by study investigators: "randomization was stratified according to center, age and sex". Neither the published protocol nor the original protocol provided by study investigators provided further information regarding allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study (protocol page 32). Participants in the control group did not receive a placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded endpoint assessment (protocol page 32)
Incomplete outcome data (attrition bias) All outcomes	Low risk	"The primary and secondary endpoints were analyzed based on the time to the first occurrence, according to the intention‐to‐treat principle, including all patients of lost to follow‐up censored at the day of the last contact" (Sakata et al. 2015, page 917). 2 participants in the intervention group and 1 in the control group were withdrawn or lost to follow‐up from the population of interest for the review; these participants were included in the analyses. 1 participant from the control group was excluded due to lack of information, and no participants from the intervention group were excluded (Sakata et al. 2015, Figure 1).
Selective reporting (reporting bias)	Low risk	The main publication provided information about all of the outcome variables pre‐established in the protocol, except for changes in serum markers for metabolic syndrome (high‐sensitivity C‐reactive protein, adiponectin, and microRNAs), which constitutes a secondary outcome measure (protocol table 2, Sakata et al. 2015). However, this variable is out of the scope of the review.
Other bias	Unclear risk	Participants with hypertension and LVH constituted a pre‐established subgroup (Sakata et al. 2015: eTable 4). However, participants with hypertension and LVH without dilated or hypertrophic cardiomyopathy, or both, represented 19% of the total population of the trial.

TOPCAT 2014.

Study characteristics
Methods	The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) is a international, double‐blind, randomised, placebo‐controlled study aimed at evaluating the efficacy of spironolactone relative to placebo (NCT00094302).
Participants	Patients at least 50 years old with symptomatic heart failure (NYHA class II‐IV) and LVEF of 45% or more. Inclusion criteria: Male or female aged ≥ 50 years Symptomatic heart failure LVEF ≥ 45% Controlled systolic blood pressure (systolic blood pressure < 140 mmHg); those with blood pressure > 140 mmHg and ≤ 160 mmHg were eligible for enrolment if on ≥ 3 medications to control blood pressure Serum potassium < 5.0 mmol/L before randomisation At least 1 hospital admission in the last 12 months for which heart failure was a major component of the hospitalisation or B‐type natriuretic peptide (BNP) ≥ 100 pg/mL or N‐terminal pro‐BNP ≥ 360 pg/mL in the last 60 days and not explained by another disease entity Women of child‐bearing potential must have a negative serum/urine pregnancy test within 72 hours before randomisation; not be lactating; and agree to use an effective method of contraception during the entire course of study participation Willing to comply with scheduled visits Informed consent form signed by the individual before participation in the trial Exclusion criteria: patients with known infiltrative or hypertrophic obstructive cardiomyopathy or known pericardial constriction primary uncorrected valvular heart disease or any valvular disease expected to lead to surgery atrial fibrillation myocardial infarction or stroke in the last 90 days systolic blood pressure > 160 mmHg use of any aldosterone antagonist or potassium‐sparing medication in the last 14 days
Interventions	Spironolactone versus placebo. Spironolactone was initiated at a dose of 15 mg once daily. All participants tolerating this dose without adverse events were up‐titrated by protocol to the target dose of 30 mg once daily at week‐4 visit. Additional up‐titration to a maximum dose of 45 mg once daily was permitted at the site investigator's discretion after the month‐4 visit for participants with refractory heart failure symptoms and acceptable laboratory parameters (potassium, creatinine). Placebo and spironolactone were identical in appearance and packaging. Study participants continued to receive other treatment for heart failure and coexisting illnesses throughout the trial.
Outcomes	Primary outcome: Cardiovascular mortality, aborted cardiac arrest, or hospitalisation for the management of heart failure as a composite.* Secondary outcomes: All‐cause mortality;* cardiovascular mortality;* all‐cause hospitalisation; cardiovascular‐related hospitalisation; hospitalisation for the management of heart failure;* fatal and non‐fatal myocardial infarction;* fatal and non‐fatal stroke;* aborted cardiac arrest;* sudden death;* hospitalisation for the management of ventricular tachycardia;* cardiovascular mortality or cardiovascular‐related hospitalisation as a composite; sudden death, aborted cardiac arrest, or hospitalisation for management of ventricular tachycardia;* new‐onset diabetes mellitus;* development of atrial fibrillation;* deterioration of renal function; hyperkalaemia. *Adjudicated by the Clinical Endpoints Committee. Quality of life scales were also applied.
Notes	Criteria of LVH: LVH was defined by trial investigators using the American Society of Echocardiography (ASE) criteria, which specify LVMI as > 115 g/m2 in men or > 95 g/m2 in women (Shah et al. 2014 pages 3‐4). The population of interest corresponds to participants with hypertension and LVH, excluding participants with aortic stenosis, aortic regurgitation and/or mitral regurgitation. None of the trial participants had obstructive cardiomyopathy. Individual participant‐level data were obtained from the National Heart, Lung and Blood Institute (US National Institutes of Health). Funding and conflicts of interest: The trial was funded by the National Heart, Lung and Blood Institute (US National Institutes of Health). Some of the authors of the main publications declared having received grants and fees from pharmaceutical companies.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Eligible participants were randomly assigned to receive either spironolactone or placebo in a 1:1 ratio with the use of permuted blocks" (Pitt et al. 2014 page 1384). "Subjects will be assigned in the order they are enrolled into the study, to receive the allocated treatment according to a computer‐generated randomization plan using NERI’s Verandi software package" (trial protocol version 1.7 (2009) page 11). "After verifying key eligibility criteria and supplying clinical center information, the randomization software will return a Treatment Allocation Code (A thru L) corresponding to either spironolactone or placebo" (trial protocol version 1.7 (2009) page 10).
Allocation concealment (selection bias)	Low risk	"Eligible participants were randomly assigned to receive either spironolactone or placebo in a 1:1 ratio with the use of permuted blocks" (Pitt et al. 2014 page 1384). "After verifying key eligibility criteria and supplying clinical center information, the randomization software will return a Treatment Allocation Code (A thru L) corresponding to either spironolactone or placebo" (trial protocol version 1.7 (2009) page 10).
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Double‐blind" (Desai et al. 2011 page 968). "Subjects and treating physicians will be blinded to whether subjects are receiving spironolactone or placebo" (trial protocol version 1.7 (2009) page 10). "Placebo and spironolactone are identical in appearance" (Desai et al. 2011 page 968). "The treatment allocation code may be broken if an emergency situation arises that in the Investigator´s opinion requires knowledge of the code. A request of unblinding should only be made in situations where knowledge of the treatment assignment will actually affect the subsequent care or decision‐making process for care of the trial subject. It should be assumed that the trial subject will remain in the trial and will continue adherence to the trial protocol after the event is resolved. Therefore, every effort should be made to maintain trial participation in a blinded nature. It is anticipated that code breaks will be very rare and that all subjects will be appropriately monitored for safety" (trial protocol version 1.7 (2009) page 10).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"All occurrences of the individual components of the primary outcome, as well as myocardial infarctions and strokes, were adjudicated by a clinical end‐point committee at Brigham and Women’s Hospital according to prespecified criteria; members of the committee were unaware of the study‐drug assignments" (Pitt et al. 2014 page 1385). "Clinical endpoints of pre‐specified types will be adjudicated by a clinical events committee in a blinded fashion" (trial protocol version 1.7 (2009) page 1).
Incomplete outcome data (attrition bias) All outcomes	Low risk	"All randomly assigned participants were included in all analyses according to the intention to‐treat principle" (Pitt et al. 2014 page 1385). Both the percentage of participants discontinuing the study and percentage of participants with unknown vital status at last expected visit were similar between study arms: "Total of 311 participants ‐ 160 in the spironolactone group (9.3%) and 151 in the placebo group (8.8%) ‐ discontinued study participation before the last expected study visit for reasons other than death. Vital status as of the last expected study visit was unknown for 67 participants in the spironolactone group (3.9%) and 65 participants in the placebo group (3.8%)" (Pitt et al. 2014 page 1387). Of the participants who discontinued the study, 100 were in the subgroup included in the review (47 in the intervention group and 53 in the control group; P = 0.784).
Selective reporting (reporting bias)	Low risk	Data regarding some of the outcome variables prespecified in the protocol were not reported in the publications (cardiovascular‐related hospitalisation, sudden death, hospitalisation for the management of ventricular tachycardia, new‐onset diabetes, development of atrial fibrillation) (Desai et al. 2011 Appendix B). However, the data of interest for the outcomes prespecified in the review protocol were identified through individual participant‐level data provided by the US National Institutes of Health.
Other bias	Unclear risk	Participants with hypertension and LVH do not correspond to a predefined subgroup of participants. Additionally, participants with hypertension and LVH without other causes of LVH represented 20% of the total population of the trial.

ECG: electrocardiogram
ICD: implantable cardioverter‐defibrillator
LVEF: left ventricular ejection fraction
LVH: left ventricular hypertrophy
LVMI: left ventricular mass index
NYHA: New York Heart Association

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Black 2001	At baseline, LVH was present only in 24 patients and the main publication did not provide results for the outcomes of interest for this subgroup of participants with hypertension and LVH. Astra Zeneca was contacted through their Data Request Portal in order to apply for individual participant data from the trial. A formal request including the review protocol, Statistical Analysis Plan and Curriculum vitae of the main investigator (LL) was presented to the company. The company first denied the request indicating that it was not possible to identify the trial, and later they ratified the denial indicating that the requested study was out of their scope. The corresponding author of the trial was also contacted with no response.
Hernández 2000	All participants were on immunosuppressive treatment, which can constitute a cause of LVH.
HOPE 2003	The trial included patients with both LVH and hypertension (5.6% of the total population), but data for this subpopulation were not published. The Canadian Institutes of Health Research was contacted to request individual participant data from the trial and indicated that the Institution does not hold the data from the trial. Dr. Yusuf from McMaster University was contacted, who confirmed that McMaster University is the owner of the data. However, the investigator indicated that they were unable to provide information from the trial.
RENAAL 2005	The total population of the trial presented both diabetes and nephropathy, which can in themselves constitute a cause of LVH, so it could not be assumed that hypertension was the only potential cause of LVH.
TCCGIH 1994	After translation of the full text, it was not possible to determine whether the trial population included participants with LVH.
VALIDD 2007	LVH was present in 10 (<3%) randomised patients. Data regarding reduction of LVMI for the patients with hypertension and LVH were not provided. The trial was funded by Novartis Pharmaceuticals. Trial data were not available in the data sharing platform used by Novartis Pharmaceuticals (https://www.clinicalstudydatarequest.com/Default.aspx). A specific request was submitted through the data sharing platform on December 1, 2020. On April 1, 2021 the responsible person responded that they are not able to provide access to trial data considering that the trial is very old (last patient visit was in 2006).

LVH: left ventricular hypertrophy

LVMI: left ventricular mass index

Characteristics of studies awaiting classification [ordered by study ID]

CHARM 1999.

Methods	Candesartan in Heart Failure‐Assessment of Reduction in Mortality and Morbidity (CHARM) was a programme designed to investigate the effect of candesartan cilexetil, a long‐acting angiotensin II type 1 receptor blocker, in a broad spectrum of patients with symptomatic heart failure.
Participants	Eligible patients were men or women at least 18 years old with symptomatic congestive heart failure (CHF) corresponding to NYHA class II‐IV for at least 4 weeks before randomisation. Assessment of LVEF and a history of tolerability of angiotensin converting enzyme (ACE) inhibitors were used to designate participants into 1 of 3 specified component studies: Patients with depressed left ventricular systolic function (LVEF ≤ 40%) and not treated with an ACE inhibitor (due to intolerance) Patients with depressed left ventricular systolic function (LVEF ≤ 40%) and treated with an ACE inhibitor Patients with preserved left ventricular systolic function (LVEF > 40%) and not treated with an ACE inhibitor
Interventions	Participants were randomised to candesartan or placebo in a 1‐to‐1 ratio. The dose of candesartan was titrated from 4 to 8 mg up to the target dose of 32 mg every second week based on tolerability. Participants may also be treated with other CHF therapies including diuretics, digitalis, a beta‐blocker, and spironolactone.
Outcomes	The primary objective was to analyse whether candesartan, when compared with placebo, reduced the combined endpoint of cardiovascular death or hospitalisation for the management of CHF. Also analysed were incidence of non‐fatal myocardial infarction, non‐fatal stroke, coronary revascularisation, functional state and symptoms, safety, and tolerability, amongst others.
Notes	10.8% of all CHARM programme participants (821 out of 7599) had LVH and hypertension. Specific results for participants with both LVH and hypertension were not published. We contacted the corresponding author (Dr Hawkins) to obtain individual‐level participant data from the trial, who referred us to Dr McMurray. We have yet to receive a response. The CHARM programme was funded by AstraZeneca, which was responsible for data collection and analysis.

FEVER 2005.

Methods	The Felodipine Event Reduction (FEVER) study was a double‐blind, multicentre, randomised, parallel‐group trial that analysed the incidence of stroke and other cardiovascular events in hypertensive patients for an average of 40 months.
Participants	Chinese hypertensive patients aged 50 to 79 years with 1 or 2 additional cardiovascular risk factors, whose blood pressure 6 weeks after switching from previous antihypertensive therapy to low‐dose hydrochlorothiazide (12.5 mg a day) was in the range of 140 to 180 mmHg (systolic) or 90 to 100 mmHg (diastolic)
Interventions	Felodipine 5 mg once a day versus placebo
Outcomes	The primary endpoint was the time to first stroke (fatal or non‐fatal). Secondary endpoints were: all cardiovascular events, all cardiac events, coronary events, heart failure, percutaneous transluminal coronary angioplasty or coronary artery by‐pass graft, all‐cause death, cardiovascular death, new‐onset diabetes, renal failure, and cancer.
Notes	A total of 9711 randomly assigned participants were included in the intention‐to‐treat analysis. 1069 of these participants (11.0%) had LVH at baseline. Outcomes for the specific subgroup of participants with hypertension and LVH were not published. We contacted the trial investigators several times to obtain data for this subgroup, but have not yet received a response.

HYVET 2001.

Methods	The Hypertension in the Very Elderly Trial (HYVET) was an international, double‐blind, randomised trial that assessed the benefits and risk of antihypertensive treatment in hypertensive patients aged 80 years or older.
Participants	Patients 80 years of age or older with persistent hypertension (defined as a sustained systolic blood pressure of 160 mmHg)
Interventions	Indapamide 1.5 mg daily or matching placebo. Perindopril (2 or 4 mg) or matching placebo was added if needed to achieve the target blood pressure of 150/80 mmHg.
Outcomes	The primary endpoint was the incidence of stroke (fatal or non‐fatal). Secondary endpoints included death from any cause, death from cardiovascular causes, death from cardiac causes, and death from stroke.
Notes	A total of 3845 participants were included in the trial. The median follow‐up duration was 1.8 years. A further substudy that analysed the prevalence of LVH in the HYVET population included 2993 participants that had technically codable ECGs available. In this population, the prevalence of LVH varied from 2.4% to 17.5% depending on sex, race, and ECG criterion. Data for the outcomes of interest for the population with hypertension and LVH were not published. We contacted the trial investigators and received a response from Dr Peters. However, the investigators have not yet responded as to whether they can provide data for the subgroup of interest.

PROFESS 2007.

Methods	The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) was a multicentre, randomised, double‐blind trial with a 2‐by‐2 factorial design aimed at evaluating whether acetylsalicylic acid and extended‐release dypyridamole compared to clopidogrel, and whether telmisartan in addition to usual care compared to placebo, reduced the risk of further strokes in individuals who had recently had an ischaemic stroke.
Participants	Patients 55 years of age or older who had had an ischaemic stroke fewer than 90 days before randomisation and whose condition was stable. After about 6000 participants had been enrolled, the protocol was modified to allow the inclusion of younger patients (50 to 54 years) and those who had had less recent strokes (within 90 to 120 days) if they also had at least 2 additional risk factors.
Interventions	Twice‐daily fixed‐dose combination of aspirin (25 mg) plus extended‐release dipyridamole (200 mg) or once‐daily clopidogrel (75 mg) and either once‐daily telmisartan (80 mg) or placebo
Outcomes	The primary outcome was recurrent stroke of any type. The 2 secondary outcomes were major cardiovascular events (death from cardiovascular causes, myocardial infarction, recurrent stroke, or worsening or new heart failure) and new‐onset diabetes.
Notes	A total of 20,332 participants took part in the trial. The mean follow‐up was 2.5 years. 74% of trial participants had hypertension, and 15.6% had LVH. Outcomes for the specific population with hypertension and LVH were not published. The trial was supported by Boehringer Ingelheim, and in selected countries also by Bayer Schering Pharma and GlaxoSmithKline. We contacted the first author of the main publication (Dr Yusuf) to request individual participant‐level data, who referred us to Boehringer Ingelheim. Trial data were available upon request in Vivli repository (vivli.org/). The request has been approved and trial data are expected to be obtained.

RALES 1999.

Methods	The Randomized Aldactone Evaluation Study (RALES) was a randomised, double‐blind, placebo‐controlled trial that analysed the effect of spironolactone on mortality in patients with severe heart failure and an LVEF of no more than 35% and who were being treated with an angiotensin‐converting‐enzyme (ACE) inhibitor, a loop diuretic, and in most cases digoxin.
Participants	Patients were eligible for enrolment if they had had NYHA class IV heart failure within the 6 months before enrolment and were in NYHA class III or IV at the time of enrolment; had been given a diagnosis of heart failure at least 6 weeks before enrolment; were being treated with an ACE inhibitor (if tolerated) and a loop diuretic; and had an LVEF of no more than 35% within the 6 months before enrolment (with no clinically significant intercurrent event).
Interventions	Spironolactone (25 mg/day) or matching placebo
Outcomes	The primary endpoint of the study was death from any cause. Secondary endpoints included death from cardiac causes, hospitalisation for cardiac causes, the combined incidence of death from cardiac causes or hospitalisation for cardiac causes, and a change in NYHA class. The effect of spironolactone was also assessed with the use of 6 pre‐randomisation variables: LVEF, the cause of heart failure, serum creatinine concentration, age, use of ACE inhibitors, and use of digitalis.
Notes	A total of 1663 participants were included in the trial. The mean (standard deviation) LVEF was 25.6% ± 6.7% in the spironolactone group and 25.2 ± 6.8 in the placebo group. The main publication did not provide data for participants who also had LVH. We contacted the authors to obtain individual participant‐level data, but have not yet received a response.

Syst‐Eur 1991.

Methods	The Systolic Hypertension in Europe (Syst‐Eur) trial was a randomised, double‐blind, placebo‐controlled trial that analysed the effect of nitrendipine, with the possible addition of enalapril and hydrochlorotiazide, on the morbidity and mortality of individuals at least 60 years old with isolated systolic hypertension.
Participants	Newly diagnosed and patients with known isolated systolic hypertension who were at least 60 years old. Patients were eligible if during masked placebo at the run‐in phase they presented an average sitting systolic blood pressure of 160 to 219 mmHg, a sitting diastolic blood pressure below 95 mmHg, and a standing systolic blood pressure of at least 140 mmHg. Blood pressure measurements for entry were based on the averages of 6 sitting and 6 standing readings, 2 in each position at 3 baseline visits, 1 month apart.
Interventions	Active treatment was started with nitrendipine; if needed this was combined with or replaced by enalapril, hydrochlorothiazide, or both. The aim was to reduce sitting systolic blood pressure by at least 20 mmHg to less than 150 mmHg. The dosage steps for nitrendipine were 10 mg in the evening, then 10 mg twice daily, then 20 mg twice daily; for enalapril 5 mg, then 10 mg, then 20 mg in the evening; and for hydrochlorothiazide 12.5 mg, then 25 mg in the morning. Placebo tablets were identical to the study drugs, with a similar schedule.
Outcomes	The main endpoints were death, stroke, retinal haemorrhage or exudates, myocardial infarction, congestive heart failure, dissecting aortic aneurysm, and renal insufficiency. Other analysed events were transient ischaemic attack, angina pectoris, need for coronary revascularisation, non‐fatal non‐cardiovascular disorders leading to hospital admission, or withdrawal of double‐blind treatment or supervised open follow‐up.
Notes	LVH was present in 614 of the 4695 randomised participants. Data for this specific subgroup were not presented. We contacted the authors of the publication (Drs Staessen and Lutgarde) to obtain data for these participants, but have not yet received a response.

TRANSCEND 2004.

Methods	The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) was a randomised, double‐blind, parallel, placebo‐controlled trial that analysed whether telmisartan was superior to placebo in reducing cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure in individuals with cardiovascular disease or high‐risk diabetes and without heart failure, who were intolerant to angiotensin‐converting enzyme (ACE) inhibitors.
Participants	Patients intolerant to ACE inhibitors with established coronary artery, peripheral vascular, or cerebrovascular disease, or high‐risk diabetes with end‐organ damage
Interventions	Telmisartan (80 mg/day) or placebo
Outcomes	The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure. Secondary outcomes included: the composite outcome of cardiovascular death, myocardial infarction, or stroke; new heart failure; development of diabetes mellitus; atrial fibrillation; cognitive decline or dementia; nephropathy; and revascularisation. Other outcomes were total mortality, angina, transient ischaemic attack, development of LVH, microvascular complications of diabetes, changes in blood pressure, changes in ankle‐to‐arm blood pressure ratios, and new cancers. A combined outcome of macrovascular and microvascular disease was also analysed.
Notes	76% of trial participants had hypertension, and 13% had LVH. Outcomes for the specific population with hypertension and LVH were not published. The trial was supported by Boehringer Ingelheim. We contacted the corresponding author of the main publication (Dr Yusuf) to request individual participant‐level data, who referred us to Boehringer Ingelheim. Trial data were available upon request in Vivli repository (vivli.org/). The request has been approved and trial data are expected to be obtained.

VAL‐HeFT 2001.

Methods	The Valsartan Heart Failure Trial (Val‐HeFT) was an international, multicentre, randomised, placebo‐controlled, double‐blind, parallel‐group trial that analysed the effect of the addition of valsartan to standard therapy on morbidity and mortality in patients with heart failure.
Participants	Adult patients with heart failure (NYHA class II, III, or IV) who were clinically stable
Interventions	Valsartan 160 mg or placebo twice daily
Outcomes	The primary outcomes were mortality and the combined endpoint of mortality and morbidity, which was defined as cardiac arrest with resuscitation, hospitalisation for heart failure, or administration of intravenous inotropic or vasodilator drugs for 4 hours or more without hospitalisation. Secondary cardiovascular outcomes included changes in ejection fraction, NYHA functional class, quality of life scores, and signs and symptoms of heart failure.
Notes	A total of 5010 participants were included, of which 6.7% had hypertension. The mean ejection fraction of participants was 27%. It is unknown whether there were participants with hypertension and LVH in the trial, and outcomes for these individuals were not published. We contacted the authors of the main publications, but have not yet obtained individual participant‐level data.

ECG: electrocardiogram
LVEF: left ventricular ejection fraction
LVH: left ventricular hypertrophy
NYHA: New York Heart Association

Characteristics of ongoing studies [ordered by study ID]

ChiCTR‐INR‐16008079.

Study name	Aldosterone antagonist delays the progression of heart failure with preserved ejection fraction: a randomised controlled clinical trial
Methods	Randomised study with a parallel design that aims to evaluate the effect of spironolactone and the specific role of galectin‐3
Participants	Patients in a pre‐clinical stage of heart failure with preserved ejection fraction. Inclusion criteria: Patients with essential hypertension aged 50 to 80 years old Echocardiographic signs of LVH (LVMI > 125 g/m2 for men and > 110 g/m2 for women) LVEF ≥ 50% Voluntarily participate and sign the informed consent form Exclusion criteria: Heart failure with reduced ejection fraction and stage C or D of heart failure with preserved ejection fraction Organic heart disease (coronary artery disease, valvular heart disease, cardiomyopathy, congenital heart disease) Secondary hypertension Documented contraindication or allergy to aldosterone antagonist therapy Patients receiving aldosterone antagonist therapy in the previous 3 months Electrolyte disturbances Severe kidney dysfunction: eGFR < 30 mL/min/1.73 m2 Severe liver dysfunction
Interventions	Spironolactone versus placebo
Outcomes	Primary outcome variable: left ventricular diastolic function Secondary outcome variables: clinical composite endpoint (stage C or D of heart failure with preserved heart failure, hospitalisation due to heart failure and cardiac death), LVMI, LVEF
Starting date	March 2016
Contact information	Jun Gu (forrestgu@126.com), Chang‐qian Wang (changqianwang@hotmail.com). Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 639 Zhizaoju Road, Shanghai Trial registry:www.chictr.org.cn/showprojen.aspx?proj=13650
Notes	The study has the "Prospective registration" status registered.

ChiCTR‐IPR‐16009507.

Study name	Aldosterone antagonist delays the progression of diastolic dysfunction in patients with hypertension and myocardial hypertrophy: a randomised controlled clinical trial
Methods	Randomised controlled phase IV trial with a parallel design that aims to evaluate the effect of spironolactone and the specific role of galectin‐3
Participants	Patients in a pre‐clinical stage of heart failure with preserved ejection fraction. Inclusion criteria: Patient with essential hypertension aged 50 to 80 years old Echocardiographic signs of LVH (LVMI > 125 g/m2 for men and > 110 g/m2 for women) Suspected left ventricular diastolic dysfunction E/E: 8 to 15 LVEF ≥ 50% Voluntarily participate and sign the informed consent form Exclusion criteria: Heart failure with reduced ejection fraction and stage C or D of heart failure with preserved ejection fraction Organic heart disease (coronary artery disease, valvular heart disease, cardiomyopathy, congenital heart disease) Secondary hypertension Documented contraindication or allergy to aldosterone antagonist therapy Patient receiving aldosterone antagonist therapy in previous 3 months Electrolyte disturbance Severe kidney dysfunction: eGFR < 30 mL/min/1.73 m2 Severe liver dysfunction
Interventions	Spironolactone versus placebo
Outcomes	Primary outcome variable: left ventricular diastolic function (TDI: E/E’) Secondary outcome variables: clinical composite endpoint (stage C or D of heart failure with preserved heart failure, hospitalisation due to heart failure, and cardiac death), LVMI, LVEF
Starting date	October 2016
Contact information	Jun Gu (forrestgu@126.com, forrestgu@sina.com), Changqian Wang. Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 639 Zhizaoju Road, Shanghai Trial registry:www.chictr.org.cn/showprojen.aspx?proj=16311
Notes	The study has the "Prospective registration" status registered. We contacted the trial investigators in June 2020 and they indicated the trial was still ongoing.

NCT02893358.

Study name	Antihypertensive Treatment in Masked Hypertension for Target Organ Protection (ANTI‐MASK)
Methods	Double‐blinded randomised controlled phase IV trial with a parallel design. Primary objective: to estimate the target organ protection after 12 months of antihypertensive treatment Secondary objectives: blood pressure‐lowering effect, target organ damage parameters improvement, and incidence rate of all‐cause death and cardiovascular events (stroke and myocardial infarction)
Participants	Adults between 30 and 70 years old with masked hypertension and at least 1 kind of target organ damage (LVH, large arterial stiffness, and microalbuminuria)). Inclusion criteria: Age 30 to 70 years old Masked hypertension patients, defined as clinic BP < 140/90 mmHg, whilst 24‐hour ambulatory BP ≥ 130/80 mmHg and/or daytime BP ≥ 135/85 mmHg and/or nighttime BP ≥ 120/70 mmHg Combined with at least 1 kind of target organ damage: LVH (Cornell voltage combination ≥ 2440 mm·ms or Sokolow‐Lyon index ≥ 4.0 mV for males and 3.5 mV for females), large arterial stiffness (brachial‐ankle pulse wave velocity ≥ 1400 cm/s), and microalbuminuria (twice random urine microalbuminuria/creatinine ratio ≥ 2.5 mg/mmol for males and 3.5 mg/mmol for females) Had not used any antihypertension drugs within 2 weeks Willing to participate in the trials and able to finish clinic visits Exclusion criteria: Under antihypertensive treatment Secondary hypertension Taking other medications that may influence BP Sleep apnoea syndrome Diabetes combined with microalbuminuria Renal parenchymal disease, such as chronic nephritis, polycystic kidney Occurrence of coronary heart disease, myocardial infraction, or stroke within 6 months Structural heart disease, such as hypertrophic cardiomyopathy, dilated cardiomyopathy Alanine transaminase, aspartate transaminase, total bilirubin upper twice of normal range, serum creatinine ≥ 2.0 mg/dL, plasma hypokalaemia ≥ 5.5 mmol/L Patients with contraindications to angiotensin receptor blockers
Interventions	Allisartan versus placebo
Outcomes	Primary outcome variable: improvement rate of target organ damage (LVH, large arterial stiffness, and microalbuminuria) at 1 year Secondary outcome variables: 24‐hour ambulatory blood pressure at 1 year Change in Cornell voltage and Sokolow‐Lyon index at 1 year Microalbuminuria/creatinine ratio at 1 year Brachial‐ankle pulse wave velocity at 1 year Incidence rate of all‐cause death and cardiovascular events (stroke and myocardial infarction) at 1 year
Starting date	February 2017
Contact information	Yan Li (liyanshcn@yahoo.com). Ruijin Hospital, Shanghai, China, 200025. Trial registry:clinicaltrials.gov/ct2/show/NCT02893358
Notes	The trial has "Recruiting" status registered. We contacted the trial investigators in January 2020 and they indicated that the trial was in the recruitment phase. We contacted them again in May 2021 and they indicated that the recruitment phase had been completed in October 2020, therefore the 1‐year follow‐up will end in October 2021.

NCT03315832.

Study name	Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi‐cEntric Double‐blind Phase II Study (ARISTOTE)
Methods	Multicentre, prospective, phase II, randomised, double‐blind study with a follow‐up of 12 to 13 months
Participants	Adults with severe aortic stenosis and indication for valve intervention
Interventions	Valsartan versus placebo
Outcomes	Primary outcome variable: change in indexed left ventricular mass at 1 year Many secondary outcome variables were established, such as change in different cardiac parameters and in LVEF, and incidence of adverse events and serious adverse events.
Starting date	March 2021
Contact information	Victor Aboyans (victor.aboyans@chu‐limoges.fr), Julien Magne (julien.magne@chu‐limoges.fr). Limoges University Hospital, Limoges, France, 87042 Trial registry:clinicaltrials.gov/ct2/show/NCT03315832
Notes	The trial has the "Not yet recruiting" status registered. We contacted the trial investigators in November 2019 and they indicated that the trial was scheduled to initiate in 2020. We contacted the trial investigators again in May 2021 and they indicated that the trial was ongoing.

BP: blood pressure
eGFR: estimated glomerular filtration rate
LVEF: left ventricular ejection fraction
LVH: left ventricular hypertrophy
LVMI: left ventricular mass index
TDI: tissue Doppler imaging

Differences between protocol and review

We established that trials with multidimensional interventions would be excluded, as in such cases it would not be possible to isolate the specific effect of the antihypertensive therapy.

Contributions of authors

BF and YF formulated the main idea for the protocol. JP provided methodological expertise in the development of the protocol. RMF, EI, RG, KJA, and LL contributed to the protocol design or writing, or both. We carried out screening of the studies by pairs (RMF, EI, MGV, and LL). Any discrepancies were resolved by consensus amongst all the review authors. LL contacted the authors and funders of the identified studies and made the necessary actions to obtain individual‐participant data of the trials. LL and MGV carried out data extraction and analyses. LL and MGV assessed the risk of bias of the trials and the overall quality of the evidence. All review authors interpreted the obtained results. LL and MGV wrote the first draft of the review. All review authors critically revised and approved the final version of the review.

Sources of support

Internal sources

• Navarre Cochrane Associate Centre, Navarre Health Service, Spain

  Salary and infrastructure support for Leire Leache and Marta Gutiérrez‐Valencia as part of their ongoing employment in the Navarre Health Service

• The Centroccidental Cardiovascular Association (ASCARDIO), Venezuela

  Salary and infrastructure support for Rosa M Finizola, Elizabeth Infante, Bartolome Finizola, Yris Flores, Ricardo Granero, and Kaduo J Arai as part of their ongoing employment in The Centroccidental Cardiovascular Association (ASCARDIO)

External sources

• Biomedical Research Institute Sant Pau (IIB Sant Pau), Spain

  Support to the project

Declarations of interest

Leire Leache has no conflicts to declare.

Marta Gutiérrez‐Valencia has no conflicts to declare.

Rosa M Finizola has no conflicts to declare.

Elizabeth Infante has no conflicts to declare.

Bartolome Finizola has no conflicts to declare.

Jordi Pardo Pardo has no conflicts to declare.

Yris Flores has no conflicts to declare.

Ricardo Granero has no conflicts to declare.

Kaduo J Arai has no conflicts to declare.

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