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. 2019 Sep 17;2019(9):CD012039. doi: 10.1002/14651858.CD012039.pub2

Pharmacotherapy for hypertension‐induced left ventricular hypertrophy

Rosa M Finizola 1,✉, Elizabeth Infante 2, Bartolome Finizola 3, Jordi Pardo Pardo 4, Yris Flores 5, Ricardo Granero 6, Kaduo J Arai 7, Leire Leache 8
PMCID: PMC6746669

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effect of antihypertensive pharmacotherapy on adults with hypertension‐induced left ventricular hypertrophy.

Background

Description of the condition

Hypertension is one of the most important contributors to heart disease and stroke, which together are one of the leading causes of premature morbidity and mortality (NICE 2016). Estimates of the overall prevalence of hypertension in adults are greatly influenced by the cutpoint established to categorize it, varying from 30% to 46% (ESC/ESH 2018; ACC‐AHA 2017). Hypertension is commonly defined as values greater than or equal to 140 mmHg systolic blood pressure, or greater than or equal to 90 mmHg diastolic blood pressure, or both (ESC/ESH 2018).

An increase of 20 mmHg in systolic blood pressure or 10 mmHg in diastolic blood pressure is associated with a two‐fold difference in the mortality rate for stroke, ischaemic heart disease, and other vascular causes (Lewington 2002; ACC‐AHA 2017). One of the clinical effects of hypertension is left ventricular hypertrophy (LVH) (ESC/ESH 2018), which describes the changes in the heart ventricular myocardium in response to increased demand for energy. These changes are called cardiac remodeling which, in addition to achieving greater functionality, can also lead to clinical cardiopathy (Berdensky 2002; de Suárez 1998; Devereux 1986; Zipes 2006). When left untreated, LVH evolves over time as a chronic condition, which can result in a clinically relevant heart failure in the medium‐ or long‐term. LVH can be diagnosed by electrocardiography criteria (Ang 2008; Bauml 2010; Fisch 1993; Giuliani 1996; González‐Juanatey 2007; Malmqvist 2001; Romhilt 1968; Romhilt 1969), echocardiography criteria (Lang 2005), or cardiac magnetic resonance imaging criteria (Dweck 2012; Khouri 2010).

LVH prevalence in people with hypertension varies between 36% according to more restrictive diagnostic criteria and 41% according to less conservative ones (Cuspidi 2012). Factors influencing left ventricular geometry in people with hypertension include among others: a) severity, duration and rapidity of onset of the increased pressure load; b) the volume load; c) age, ethnicity and sex; d) comorbidities such as coronary artery disease, diabetes mellitus, obesity and valvular heart disease; and e) genetic factors (Aronow 2017). Black people with hypertension are more likely than whites 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 to a higher prevalence of cardiovascular disease (González‐Juanatey 2007). Mortality of individuals with LVH is three to four times higher than of those without LVH (Águila‐Marín 2013).

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

See Appendix 1 for the medical glossary.

See Appendix 2 for the LVH diagnostic criteria.

Description of the intervention

A large number of drugs are currently available for lowering blood pressure (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).

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 in the myocyte an increase in force‐generating units (sarcomeres). 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 only one of many structural alterations in hypertensive heart disease. Fibroblasts undergo hyperplasia and conversion to myofibroblasts, along with hypertrophy of vascular smooth muscle cells. Noncellular elements related to myocardial remodeling include expansion of interstitial and perivascular collagen that make up the extracellular matrix. Changes in intramyocardial capillary density and arteriolar thickening compound ischaemia in the hearts of people with hypertension. These remodeling events are orchestrated via effects of biomechanical stress on the extracellular matrix that, in turn, signals 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 normalize myocardial stress. However, long‐term outcomes clearly worsen with progressive hypertrophy, with increasing left ventricular mass index 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). If the findings of this Cochrane Review suggest differences between different drug classes, we will discuss the possible explanation for the differences.

Why it is important to do this review

Reviews comparing different antihypertensive drug classess in LVH regression are inconsistent and they do not analyse the repercusion on cardiovascular events or mortality (Fagard 2009; Rousch 2018; Soliman 2017). A systematic review and meta‐analysis published in 2010 obtained that regression of echocardiographic LVH in hypertension was associated with a reduction of cardiovascular events (Pierdomenico 2010). However, since then management of LVH has changed and to date, no systematic review assessing the effect of antihypertensive pharmacotherapy in hypertension‐induced LVH has been undertaken using Cochrane methodology.

Objectives

To assess the effect of antihypertensive pharmacotherapy on adults with hypertension‐induced left ventricular hypertrophy.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials with at least 12 months' follow‐up that analyse at least one primary outcome (all‐cause mortality, cardiovascular events, or total serious adverse events)

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 include patients in whom the cause of the LVH is 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 will select and include subgroups of patients with both LVH and hypertension without other alternative causes of LVH.

We will identify these specific subgroups of patients through individual patient data of the studies. If we cannot obtain individual patient data, we will include the studies if greater than or equal to 80% of the participants have LVH and hypertension without other possible causes of LVH. In the case of studies that do not explicitly provide data regarding the cause of the LVH or when this can not be inferred from the participants´ baseline characteristics, we will include these studies. We will perform a sensitivity analysis by excluding studies with no specific information regarding the cause of the LVH.

Types of interventions

Intervention

Antihypertensive pharmacological therapy (monotherapy or in combination):

  • Antihipertensives.

  • Diuretics.

  • Beta‐blocking agents.

  • Calcium channel blockers.

  • Agents acting on Renin‐Angiotensin system.

Control

Placebo or no treatment.

Types of outcome measures

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 are defined according to the International Conference on Harmonisation (ICH) Guidelines as any event that at any dose results in death, is life‐threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability, or is a congenital anomaly/birth defect, and any important medical event that may have jeopardized the participant or requires intervention to prevent it (ICH‐GCP 1997). These events do not necessarily need to have a causal relationship with the antihypertensive treatment.

Secondary outcomes

  • Hospitalization for heart failure.

  • Reduction of the index of left ventricular mass.

  • Total adverse events.

  • Withdrawal due to adverse events.

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist will search the following databases without language, publication year, or publication status restrictions.

  • The Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web).

  • The Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web).

  • MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations.

  • Embase Ovid (from 1974 onwards).

  • ClinicalTrials.gov (www.clinicaltrials.gov).

  • World Health Organization International Clinical Trials Registry Platform (ICTRP) (www.who.it.trialsearch).

The Cochrane Hypertension Information Specialist will model the subject strategies for databases on the search strategy designed for MEDLINE in Appendix 3. Where appropriate, these will be combined 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, Box 6.4.d (Higgins 2011)).

Searching other resources

  • The Cochrane Hypertension Information Specialist will search the Hypertension Specialised Register segment (which includes searches of MEDLINE, Embase, the Cochrane Library, and Epistemonikos for systematic reviews) to retrieve published systematic reviews related to this review title, so that we can scan their reference lists to identify additional relevant trials. The Cochrane Hypertension Specialised Register also includes searches of the CAB Abstracts & Global Health, CINAHL, LILACS, ProQuest Dissertations & Theses, and Web of Science.

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

  • We will contact experts/organizations in the field to obtain additional information on relevant trials.

  • We may contact original study authors for clarification and further data if trial reports are unclear.

  • In addition to the above electronic databases, we will search LILACS (1982 to present), Epistemonikos (www.epistemonikos.org), and we will search ISI Web of Science for papers that cite studies included in the review.

Data collection and analysis

Selection of studies

We will summarize data using standard Cochrane methodologies (Higgins 2011). We will not apply any language restrictions.

Two review authors (RF and YF) will screen the search results for potentially relevant trials and independently assess them for inclusion or exclusion, using a predesigned eligibility form based on the inclusion criteria. We will resolve disagreements through discussion until consensus be reached. One review author (KA) will act as referee.

We will select the studies for inclusion in this review following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

  • Merge search results using Covidence (Covidence), removing duplicate records of the same report.

  • Examine titles and abstracts to remove obviously irrelevant reports.

  • Retrieve the full text of the potentially relevant reports.

  • Link together multiple reports of the same study.

  • Examine full‐text reports to determine if the studies meet the inclusion criteria.

  • Correspond with investigators, where appropriate, to clarify study eligibility (it may be appropriate to request further information, such as missing results, at the same time).

  • Make a final decision on study inclusion and proceed to data collection.

We will illustrate the study selection process in a PRISMA diagram.

Data extraction and management

Two review authors will extract data from the included trials using a spreadsheet data extraction form, and one review author (YF) will check the data entered.

We will extract 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.

  • Outcome data (all‐cause mortality, cardiovascular events, total serious adverse events, hospitalization for heart failure, reduction of the index of left ventricular mass, total adverse events, withdrawal due to adverse events).

  • Intervention data: type and regimens.

In case of discrepancies, one review author (KA) will act as referee to achieve a final consensus.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias for each included trial using the domain‐based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will discuss discrepancies and achieve consensus. One review author (RG) will act as referee during discussions.

We will assess 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)

We will describe for each included trial the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as follows.

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

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

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

Allocation concealment (checking for possible selection bias)

We will describe for each included trial 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 will assess the methods as follows.

  • Low risk (e.g. telephone or central randomization; 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 described as randomized but the method used to conceal the allocation was not described.

Blinding or masking (checking for possible performance bias)

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

We will assess 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.

A sensitivity analysis will be performed 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 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 not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes 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 likely to be related to the true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes 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 randomization; potentially inappropriate application of simple imputation.

  • Unclear risk (any one of the following): insufficient reporting of attrition or exclusions to permit judgment for ‘low risk' or ‘high risk' (e.g. number randomized not stated, no reasons for missing data provided); the study did not address this outcome.

Selective reporting bias (reporting bias due to selective outcome reporting)

For each included trial we will describe how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as follows.

  • Low risk (any one of the following): the trial protocol is available and all of the trial’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way, or the trial protocol is unavailable but it is clear that the published reports include 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 have been reported; one or more primary outcomes are 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 is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so they cannot be entered in a meta‐analysis; the trial report fails to include results for a key outcome that would be expected to have been reported for such a trial.

  • Unclear: insufficient information to permit judgment for ‘low risk' or ‘high risk'.

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

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

  • Low risk of bias: the trial appears to be free from other components that could put it at risk of bias.

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

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

Overall risk of bias

We will make explicit judgments about whether trials were at high risk of bias, according to criteria provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess the likely magnitude and direction of bias, and whether we consider it likely to impact our findings.

For trials that we assess as at ‘low risk of bias' in all of the above specified individual domains, we will consider as ‘trials at low risk of bias'. For trials that we assess as being at ‘unclear risk of bias' or ‘high risk of bias' in one or more of the above specified individual domains, we will consider these as ‘trials at high risk of bias'.

Measures of treatment effect

We will perform the meta‐analyses according to the Cochrane guidance (Higgins 2011). We will use Review Manager 5 to analyse the data (RevMan 2014).

For binary outcomes, such as all‐cause mortality, cardiovascular events, total serious adverse events, hospitalization by heart failure, total adverse events, and withdrawals by adverse events, we will calculate the risk ratio with 95% confidence intervals (CIs) for each.

For continuous outcomes (reduction of the index of left ventricular mass), we will calculate mean difference with 95% CI.

Dealing with missing data

We will contact the corresponding author of included randomized trial(s) to obtain information on missing data. If they do not provide any further information, we will carry out an available participant information analysis as our main analysis; that is, the denominator for each outcome in each trial will be the number randomized minus the number of participants whose outcomes were known to be missing.

We will assess the percentage of dropouts for each included trial and for each study group. We will consider an intention‐to‐treat analysis for all the trials that either report this analysis or provide enough information to perform it. Otherwise, we will assume the analysis done and conduct a sensitivity analysis including only results derived from an intention‐to‐treat analysis.

Assessment of heterogeneity

We will use the I2 statistic and the Q test to measure statistical heterogeneity between the trials. The I2 statistic describes the percentage of total variation between trials due to heterogeneity rather than sampling error (Higgins 2003).  

Assessment of reporting biases

We will assess publication bias and other bias by a funnel plot only if 10 or more trials meet the inclusion criteria (Sterne 2011).

Data synthesis

We will use both fixed‐effect and random‐effects models to analyse the data. We will report only the results from the random‐effects model when the CIs are wider than those from the fixed‐effect model.

Trial sequential analysis

Meta‐analysis of cumulative data may run 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 2011; Wetterslev 2008; Wetterslev 2009). To assess the risk of random errors in our cumulative meta‐analyses, we will 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 2011). We will conduct sensitivity analysis of the trial sequential analysis to estimate the need for further trials.

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity (> 60%) in a primary outcome (all‐cause mortality, cardiovascular events, and total serious adverse events), we will explore potential causes by conducting subgroup analyses, if possible, according to the following aspects.

  • Risk of bias of included trials.

  • Participants´ gender.

  • Participants' ethnicity.

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

  • Drug group.

Sensitivity analysis

We will test the robustness of the results using several sensitivity analyses, and will restrict 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 it is unlikely that we will find many trials at low risk of bias in all items, we plan to choose three core domains instead of all domains: generation of random sequence and allocation concealment, incomplete outcome data, and selective reporting bias.

‘Summary of findings' tables

We will use the GRADE approach to assess the quality of the body of evidence associated with specific outcomes where possible (all‐cause mortality, cardiovascular events, total serious adverse events, hospitalization for heart failure, and withdrawal due to adverse drug effects) (Guyatt 2011a). We will create a ‘Summary of findings' table using GRADEpro software (GRADEpro GDT). The GRADE approach appraises the quality 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 quality of evidence considers within‐study risk of bias (methodological quality), the 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).

Acknowledgements

We acknowledge the assistance provided by the Cochrane Hypertension Group.

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. It does not include accidental or intentional poisoning, for which specific headings are available PubMed – MeSH terms
Atrial fibrillation Abnormal cardiac rhythm characterized 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 by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its 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 greater than 140 mmHg or when diastolic pressure is consistently 90 mmHg or more Cochrane Library – MeSH terms
Hypertension‐induced left ventricular hypertrophy An increase in left ventricular mass resulting from elevated pressure load
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 characterized 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, etiology, age of the affected individual, and haemorrhagic vs non‐haemorrhagic nature (Adams 1996) 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
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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

  1. Voltage criteria = 3 points

  2. ST‐T abnormalities without digital = 3, with digital = 1

  3. Electrical axis deviation > ‐15 degrees = 2

  4. QRS duration > 0.09 second = 1

  5. Intrinsicoid deflection > 0.04 second = 1


SCORE ROMHILT:
4 point: probable LVH
≥ 5 point: LVH diagnosed

  1. 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

  2. ST segment changes with or without digital = 1 or 2 points, respectively

  3. Left atrial enlargement = 3 points

  4. Left axis deviation > 30 degrees = 2 points

  5. 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

  1. Voltage criteria (3 points):

    1. Any S or R in limb leads ≥ 20 mm

    2. SV1, SV2, RV5, or RV6 ≥ 30 mm

  2. ST‐T wave changes of LVH (3 points, 1 point on digitalis)

  3. Left atrial abnormality (3 points):

    1. Terminal component of the P wave in V1 ≥ 1 mm and ≥ 40 ms

  4. Left axis deviation (2 points):

    1. QRS axis of –30 degrees or more negative

  5. Prolonged QRS duration (1 point): ≥ 90 ms

  6. 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

  1. R AVL > 7 mm

  2. R V5 or V6 plus S V1 or V2 > 35 mm

  3. R V6 > R V4

  4. R V6 > R V5

  5. S V2 > 24 mm

  6. R D1 plus S D3 > 25 mm

  7. 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:

  1. SV3 + RaVL > 2.4 mV

  2. Left ventricular strain pattern

  3. Romhilt–Estes point score ≥ 5

 Ang 2008
Framingham Score
RI + SIII > 2.5 mV, SV1/2 + RV5/6 > 3.5mV,
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 remodeling: 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
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.
Remodeling 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.

  1. Increased concentricity without increased LVEDV (“thick hypertrophy”).

  2. Increased LVEDV without increased concentricity (“dilated hypertrophy”).

  3. Increased concentricity with increased LVEDV (“both thick and dilated hypertrophy”).

  4. Neither increased concentricity nor increased LVEDV (“indeterminate hypertrophy”).

 Dweck 2012
Khouri 2010
LVED: left ventricular end‐diastolic volume; LVH: left ventricular hypertrophy
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Appendix 3. Search strategy

Database: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) <January 25, 2019> Search strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 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 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 pressure or bp)).tw,kf. 49 or/45‐48 50 randomized controlled trial.pt. 51 controlled clinical trial.pt. 52 randomized.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

What's new

Date Event Description
5 September 2019 New citation required and major changes 1. Background:
1.1. Description of the condition: References have been updated.
1.2. Description of the intervention: Classification of blood pressure lowering drugs has been replaced by the current Anatomical, Therapeutic, Chemical (ATC) classification of the WHO.
2. Methods:
2.1. Types of studies: Potentially elegible randomized controlled trials have been limited to those with at least 12 months´ follow‐up that analyse at least one primary outcome (all‐cause mortality, cardiovascular events, or total serious adverse events).
2.2. Types of participants: exclusion criterion regarding people with high blood pressure and with left ventricular hypertrophy‐associated conditions has been deleted. Additional specifications related to the management of individual patient data and selection of specific subgroups of participants from trials have been added.
2.3. Types of interventions: classification of blood pressure lowering drugs has been replaced by the current Anatomical, Therapeutic, Chemical (ATC) classification of the WHO in accordance to the "Background" section.
2.4. Types of outcome measures:
2.4.1. Primary outcomes: "Myocardial infarction" endpoint has been replaced by "cardiovascular events" (myocardial infarction, stroke or atrial fibrillation). "Adverse events" variable has been replaced by "total serious adverse events".
2.4.2. Secondary outcomes: "stroke" and "atrial fibrillation" endpoints have been deleted and included in the composite primary endpoint. "Total adverse events" variable has been added. "Withdrawal due to adverse drug effects" has been replaced by "withdrawal due to adverse events".
2.5. Assessment of risk of bias in included studies. Blinding or masking (checking for possible performance bias): inclusion of a sensitivity analysis to analyse results from blinded studies separately.
2.6. Subgroup analysis and investigation of heterogeneity: a subgroup analysis regarding risk of bias of included trials has been included,
2.7. Sensitivity analysis: the analysis comparing trials with comparable baseline characteristics versus non‐comparable characteristics has been removed. We have included a sensitivity analysis cited in section 2.5 regarding blinded trials.
3. Contributions of authors: contributions have been replaced and limited to those activities related to the development of the protocol.
4. Declarations of interest: have been updated.
5. Appendices:
5.1. Appendix 1. Medical Glossary: inclusion of the term "Hypertension‐induced left ventricular hypertrophy".
5.2.. Appendix 3. Pharmacotherapy adverse events: this section has been removed.
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Contributions of authors

Bartolome Finizola and Yris Flores formulated the main idea for the protocol. Jordi Pardo provided methodological expertise in the development of the protocol. The rest of the authors (Rosa M Finizola, Elizabeth Infante, Ricardo Granero, Kadui J Arai and Leire Leache) contributed to the protocol design and/or writing. All the authors read and approved the final protocol draft.

Sources of support

Internal sources

  • Adherent unit to the Iberoamerican Cochrane Centre – ASCARDIO, Barquisimeto, Venezuela.

External sources

  • No sources of support supplied

Declarations of interest

Rosa M Finizola: no conflict of interest to declare.

Elizabeth Infante: no conflict of interest to declare.

Bartolome Finizola: no conflict of interest to declare.

Jordi Pardo Pardo: no conflict of interest to declare.

Yris Flores: no conflict of interest to declare.

Ricardo Granero: no conflict of interest to declare.

Kaduo J Arai: no conflict of interest to declare.

Leire Leache: attendance at the 22nd Congress of the European Association of Hospital Pharmacist (EAHP) in 2017 was financed by MSD.

Amended to reflect a change in scope (see 'What's new')

References

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