Pharmacotherapy for mild hypertension

Abstract

Rationale

This is an update of a Cochrane review published in 2012 of initiation of antihypertensive monotherapy or step‐up therapy in people with untreated mild hypertension (systolic blood pressure 140 to 159 mmHg or diastolic blood pressure 90 to 99 mmHg, or both) and no pre‐existing cardiovascular disease. The original review demonstrated no difference in the incidence of all‐cause mortality, total cardiovascular events (stroke, myocardial infarction, and congestive heart failure), stroke incidence, coronary heart disease, or withdrawal due to adverse effects (WDAEs). Evidence for antihypertensive pharmacotherapy in people with mild hypertension for primary prevention remains uncertain in the literature with conflicting studies. We therefore performed an update of the original Cochrane review to reassess whether initiation of antihypertensive pharmacotherapy compared to placebo or no treatment in people with untreated mild hypertension and no pre‐existing cardiovascular disease reduces the risk of all‐cause mortality, total cardiovascular events, stroke, coronary heart disease, or WDAEs.

Objectives

To reassess the efficacy and risks of initiating antihypertensive pharmacotherapy in adults with untreated mild hypertension and no pre‐existing cardiovascular disease. The primary objective was to reassess the risk of all‐cause mortality and total cardiovascular events (defined as fatal and non‐fatal strokes, myocardial infarction, and congestive heart failure). The secondary objectives were to reassess the risk of stroke (fatal and non‐fatal), coronary heart disease (fatal and non‐fatal myocardial infarction and sudden cardiac death), and WDAEs.

Search methods

We searched the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to June 2024.

Eligibility criteria

We included randomized controlled trials (RCTs) of at least one‐year duration comparing initiation on antihypertensive monotherapy or step‐up therapy, or both, versus placebo or no treatment in participants with mild hypertension and no pre‐existing cardiovascular disease.

Outcomes

Our critical outcomes were all‐cause mortality and total cardiovascular events. Important outcomes were stroke, coronary heart disease (fatal and non‐fatal myocardial infarction and sudden cardiac death), and WDAEs.

Risk of bias

Two review authors assessed risk of bias independently and in duplicate using Cochrane's RoB 1 tool.

Synthesis methods

Two review authors performed title and abstract screening, full‐text review, and data extraction independently and in duplicate. We calculated risk ratio (RR) along with 95% confidence interval (CI) for all‐cause mortality, total cardiovascular events, stroke events, coronary heart disease events, and WDAEs with the Mantel‐Haenszel test and a fixed‐effect model. We assessed the certainty of the evidence using the GRADE approach.

Included studies

We included five trials involving a total of 9124 participants, of whom 4593 received antihypertensives and 4531 received placebo or no treatment. All five trials reported all‐cause mortality; four trials reported total cardiovascular events and strokes; three trials reported coronary heart disease; and one trial reported WDAEs.

Synthesis of results

There may be little to no reduction in all‐cause mortality (RR 0.85, 95% CI 0.64 to 1.14; 5 trials, 9124 participants; low‐certainty evidence), total cardiovascular events (RR 0.93, 95% CI 0.69 to 1.24; 4 trials, 7292 participants; low‐certainty evidence), or coronary heart disease (RR 1.12, 95% CI 0.80 to 1.57; 3 trials, 7080 participants; low‐certainty evidence). There may be a decreased risk of stroke (RR 0.41, 95% CI 0.20 to 0.84; 4 trials, 7292 participants; low‐certainty evidence) and an increase in WDAEs (RR 4.80, 95% CI 4.14 to 5.57; 1 trial, 17,354 participants; low‐certainty evidence) with antihypertensives. We downgraded the certainty of evidence for all outcomes due to imprecision, indirectness, and risk of bias.

Authors' conclusions

In people with untreated mild hypertension and no pre‐existing cardiovascular disease, initiation of antihypertensive monotherapy or step‐up therapy may not reduce all‐cause mortality, total cardiovascular events, or coronary heart disease compared to those who received placebo or no treatment. There may be a reduction in stroke, but possibly also an increase in WDAEs.

Funding

CIHR Grant to the Hypertension Review Group and British Columbia Ministry of Health Grant to the Therapeutics Initiative.

Registration

Protocol (2007): doi.org/10.1002/14651858.CD006742.

Original review (2012): doi.org/10.1002/14651858.CD006742.pub2.

Plain language summary

What are the benefits and harms of medications used to treat mildly elevated blood pressure?

Key messages

• In people who have mildly elevated blood pressure but do not have cardiovascular disease (e.g. heart attacks) or other related health risks (e.g. diabetes), blood pressure‐lowering medications may not reduce the risk of death or the risk of developing major cardiovascular (heart and blood vessel) disease.

• Blood pressure‐lowering medications may lower the risk of stroke, but may also increase the risk of unwanted effects that result in study withdrawal.

• Additional research is needed to understand the effects of blood pressure‐lowering medications in people with mildly elevated blood pressure without cardiovascular disease or other health‐related risks (e.g. diabetes).

What is hypertension?

Hypertension is consistently high blood pressure.

How is hypertension treated?

Depending on the severity of an individual's hypertension and other medical conditions they may have, hypertension can be treated with a healthy lifestyle including diet and regular physical activity. Medications are also commonly prescribed.

What did we want to find out?

We wanted to know the benefits and risks of medications that lower blood pressure prescribed in people who have mild hypertension (systolic blood pressure 140 to 159 mmHg, diastolic blood pressure 90 to 99 mmHg) and did not have major cardiovascular (heart and blood vessel) diseases or other related health risks.

What did we do?

We searched for studies of blood pressure‐lowering medications in people with mild hypertension to find out if they lower the risk of death and major cardiovascular diseases (including stroke and heart attacks). We also looked at the risk of unwanted effects. We compared and summarized the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We included five studies involving a total of 9124 people, 4593 who received blood pressure‐lowering medications and 4531 who received placebo (dummy treatment) or no treatment. We found that medications may not lower the risk of death or major cardiovascular diseases. Blood pressure‐lowering medications may lower the risk of stroke, but may also increase the risk of unwanted effects that result in study withdrawal.

Main results

The benefit of a lower risk of stroke with blood pressure medications for people with mild hypertension and no other heart conditions or conditions that increase their risk of cardiovascular disease needs to be weighed against the unwanted effects of these medications.

What are the limitations of the evidence?

We have little confidence in the evidence because the studies did not cover all the people we were interested in; the studies were very small; and there were not enough studies to be certain about the results. One of the studies that showed a reduced risk of stroke looked at people with kidney disease, so it may not be applicable to all people with mild hypertension. Only one study reported on unwanted effects of the medications.

How up‐to‐date is the evidence?

The evidence is current to June 2024.

Summary of findings

Summary of findings 1. Antihypertensive monotherapy/step‐up therapy versus placebo or no treatment for mild hypertension.

Antihypertensive monotherapy/step‐up therapy versus placebo or no treatment for mild hypertension
Patient or population: People with mild untreated hypertension and no history of pre‐existing cardiovascular disease Settings: Ambulatory Intervention: Antihypertensive monotherapy or step‐up therapy Comparison: Placebo or no treatment
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo/no treatment	Antihypertensive pharmacotherapy
All‐cause mortality 2 to 5 years	Study population		RR 0.85 (0.64 to 1.14)	9124 (5 studies)	⊕⊕⊝⊝ low1,2
	21 per 1000	18 per 1000 (13 to 24)
Total cardiovascular events 2 to 5 years	Study population		RR 0.93 (0.69 to 1.24)	7292 (4 studies)	⊕⊕⊝⊝ low1,2
	25 per 1000	23 per 1000 (17 to 31)
Stroke 2 to 5 years	Study population		RR 0.41 (0.20 to 0.84)	7292 (4 studies)	⊕⊕⊝⊝ low1,2	There were few stroke events (35 total). In addition, most of the events occurred in a trial that recruited people with microalbuminuria.
	7 per 1000	3 per 1000 (1 to 6)
Coronary heart disease 2 to 5 years	Study population		RR 1.12 (0.80 to 1.57)	7080 (3 studies)	⊕⊕⊝⊝ low1,2
	18 per 1000	20 per 1000 (14 to 28)
Withdrawal due to adverse effects 5 years	Study population		RR 4.80 (4.14 to 5.57)	17,354 (1 study)	⊕⊕⊝⊝ low1,2,3	Certainty of evidence was also downgraded since individual patient data were not accessible, and therefore includes people with pre‐existing cardiovascular disease.
	23 per 1000	110 per 1000 (95 to 128)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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.

The assumed control group risk was derived from the event rate in the control group (i.e. 20 per 1000 mortality, 25 per 1000 total cardiovascular events, etc.).

¹Downgraded one level due to unclear or high risk of bias in at least one risk of bias domain.
²Downgraded one level due to imprecision with low number of events and corresponding wide CIs.
³Downgraded one level due to indirectness with inclusion of people with pre‐existing cardiovascular disease.

Background

The decision to initiate people with mild hypertension without pre‐existing cardiovascular disease on pharmacotherapy is a clinically pertinent one. The HOPE‐3 trial, which demonstrated no benefit from antihypertensive therapy in healthy patients with a mean blood pressure (BP) of 138/82, emphasizes the importance of determining the BP threshold where the benefits of antihypertensive drug therapy outweigh the harms [1].

Description of the condition

Hypertension is a leading risk factor for global disease burden [2]. Elevated BP is associated with increased all‐cause mortality and cardiovascular morbidity [3]. Worldwide, around 20% of people diagnosed with hypertension are untreated [4].

Description of the intervention and how it might work

There are more than 120 antihypertensive medications from eight drug classes available. Their primary mechanisms to lower BP are vasodilation, decreased intravascular volume, reduced cardiac contractility, renin‐angiotensin‐aldosterone system inhibition, and decreased sympathetic nervous system stimulation [5].

Why it is important to do this review

Previous meta‐analyses have demonstrated that antihypertensive pharmacotherapy reduces the risk of all‐cause mortality and cardiovascular events compared to placebo or no treatment in many patient populations [6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. Most trials included people with both mild hypertension (i.e. stage 1, defined as systolic blood pressure [SBP] 140 to 159 mmHg and/or diastolic blood pressure [DBP] 90 to 99 mmHg) and moderate to severe hypertension (i.e. stage 2 to 3, SBP ≥ 160 and/or DBP ≥ 100 mmHg).

Recent guidelines recommend a low threshold to initiate antihypertensive pharmacotherapy for primary prevention [16, 17, 18, 19, 20, 21, 22]. Currently, approximately half of all patients from the general population who are prescribed antihypertensive drugs are initiated for primary prevention [23]. Evidence for antihypertensive pharmacotherapy in people with mild hypertension for primary prevention is conflicting, and yet most people with hypertension do not have a pre‐existing history of cardiovascular disease [24, 25, 26]. It is critical that we use data from high‐quality randomized controlled trials (RCTs) to make decisions around initiation of pharmacotherapy in people with mild hypertension without pre‐existing cardiovascular disease, rather than relying on extrapolations from indirect data.

In 2012, we published a Cochrane review of RCTs investigating the initiation of antihypertensive monotherapy or step‐up therapy, or both, in people with untreated mild hypertension and no pre‐existing cardiovascular disease (defined as coronary heart disease, stroke/transient ischemic attack (TIA), peripheral vascular disease, or renal disease with elevated creatinine). There was no difference in the risk of all‐cause mortality, total cardiovascular events, or stroke [27]. A subsequent meta‐analysis published in 2015 by Sundström and colleagues added individual patient data of participants from Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) trials and demonstrated a reduced risk of all‐cause mortality, stroke, and cardiovascular death [28, 29]. However, many participants from the BPLTTC trials were treated with step‐up therapy, since many were receiving antihypertensive pharmacotherapy at baseline.

We have updated the original Cochrane review to reassess whether initiation of antihypertensive pharmacotherapy compared to placebo or no treatment in people with untreated mild hypertension and no pre‐existing cardiovascular disease reduces the risk of all‐cause mortality, total cardiovascular events, and stroke.

Objectives

To reassess the efficacy and risks of initiating antihypertensive pharmacotherapy in adults with untreated mild hypertension and no pre‐existing cardiovascular disease. The primary objective was to reassess the risk of all‐cause mortality and total cardiovascular events (defined as fatal and non‐fatal strokes, myocardial infarction, and congestive heart failure). The secondary objectives were to reassess the risk of stroke (fatal and non‐fatal), coronary heart disease (fatal and non‐fatal myocardial infarction and sudden cardiac death), and withdrawals due to adverse drug events (WDAEs).

Methods

All methods are consistent between the original protocol registration, original meta‐analysis, and the present study.

Criteria for considering studies for this review

Types of studies

We considered all RCTs of at least one‐year duration evaluating antihypertensive pharmacotherapy compared to placebo or no treatment in people without pre‐existing cardiovascular disease. We excluded observational studies, cross‐sectional studies, case series, and case reports. There were no language restrictions.

Types of participants

We included adult (≥ 18 years old) males and non‐pregnant females with mild hypertension. Mild hypertension is defined as SBP of 140 to 159 mmHg or DBP of 90 to 99 mmHg, or both. We excluded people receiving antihypertensive pharmacotherapy at baseline. We also excluded people with evidence of pre‐existing cardiovascular disease, defined as a history of myocardial infarction, angina pectoris, coronary angioplasty, coronary bypass graft surgery, stroke or TIA, carotid endarterectomy, intermittent claudication, surgery for peripheral vascular disease, or renal disease (defined as creatinine > 1.5 times the upper limit of normal).

We contacted authors of trials that may have had individual patient data that met the criteria. If we could not obtain access, we included publicly available aggregate data from trials if greater than 80% of participants had either an SBP 140 to 159 mmHg or DBP 90 to 99 mmHg.

Types of interventions

We included trials that initiated antihypertensive pharmacotherapy as monotherapy or in a step‐up approach, or both. We only included trials that used placebo or no treatment as their control groups. All treatment arms for each study are listed in Supplementary material 2 and Table 2.

1. Overview of syntheses and included studies.

Study name (year) country of conduct	Study design	Other key detail of intervention	Population sample size: Treatment by sex Placebo by sex	Specific outcome measure	Follow‐up time	Methods of synthesis
ANBP 1980 Australia	Randomized controlled trial	Single‐blind placebo‐controlled	Population sample size: 3427 Treatment: 1721 Placebo: 1706 Treatment: 1085 males and 636 females Placebo: 1085 males and 621 females	All‐cause mortality	4 years	Risk ratio
MRC 1985 UK	Randomized controlled trial	Single‐blind placebo‐controlled	Population sample size: 17354 Bendrofluazide: 4297 Propranolol: 4403 Placebo: 8654 Bendrofluazide: 2238 were male and 2059 were female Propranolol: 2285 were male and 2118 were female Placebo: 4525 were male and 4129 were female	1. All‐cause mortality 2. Total cardiovascular events 3. Stroke 4. Coronary heart disease 5. Withdrawals due to adverse effects	5 years	1. Risk ratio 2. Risk ratio 3.Risk ratio 4.Risk ratio 5.Risk ratio
PREVEND IT 2004 Netherlands	Randomized controlled trial	Double‐blind placebo‐controlled	Population sample size: 864 Fosinopril: 431 Placebo: 433 Fosinopril: 285 were male and 146 were female Placebo: 276 were male and 157 were female	1. All‐cause mortality 2. Total cardiovascular events 3. Stroke	46 months	1.Risk ratio 2.Risk ratio 3.Risk ratio
SHEP 1991 USA	Randomized controlled trial	Double‐blind placebo‐controlled	Population sample size: 4736 Treatment: 2365 Placebo: 2371 Treatment: 1034 were male and 1331 were female Placebo: 1011 were male and 1360 were female	1. All cause mortality 2. Total cardiovascular events 3. Stroke 4. Coronary heart disease	4.5 years	1.Risk ratio 2.Risk ratio 3.Risk ratio 4.Risk ratio
VA‐NHLBI 1978 USA	Randomized controlled trial	Double‐blind placebo‐controlled	Population sample size: 1012 Treatment: 508 Placebo: 504 All participants were male.	1. All‐cause mortality 2. Total cardiovascular events 3. Stroke 4. Coronary heart disease	2 years	1.Risk ratio 2.Risk ratio 3.Risk ratio 4.Risk ratio

Outcome measures

Critical outcomes

• All‐cause mortality

• Total cardiovascular events (fatal and non‐fatal strokes, myocardial infarction, and congestive heart failure)

Important outcomes

• Stroke (fatal and non‐fatal)

• Coronary heart disease (fatal and non‐fatal myocardial infarction and sudden cardiac death)

• Withdrawal due to adverse drug events (WDAEs)

Search methods for identification of studies

All search methods and search strategies are presented in Supplementary material 1. This review includes searches up to 10 June 2024.

Electronic searches

The Cochrane Hypertension Information Specialist searched the following databases without language or publication status restrictions:

• Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (to 10 June 2024);

• Cochrane Central Register of Controlled Trials (CENTRAL; 2024, Issue 6) via the Cochrane Register of Studies (to 10 June 2024);

• MEDLINE(R) ALL Ovid (1946 to 9 June 2024);

• Embase Ovid (1974 to 9 June 2024).

The Information Specialist modeled search strategies for databases on the search strategy designed for MEDLINE. The MEDLINE strategy was peer‐reviewed by another Cochrane Information Specialist and was combined with subject strategy adaptations as designed by Cochrane to identify RCTs as described in the Cochrane Handbook for Systematic Reviews of Interventions [30]. The search strategy for this review is identical to the strategies developed for a recent Cochrane review [31]. Results were de‐duplicated against search results from a systematic review published in 2018 that also examined first‐line drug classes for hypertension [15]. Thus, search dates were limited from 2017 to June 2024.

Results from the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (trialsearch.who.int) were retrieved as part of the search of CENTRAL.

The search strategies are presented in Supplementary material 1.

Searching other resources

The Cochrane Hypertension Information Specialist searched the Hypertension Specialised Register segment to retrieve existing reviews relevant to this systematic review in order to scan their reference lists for additional trials. We searched Epistemonikos (www.epistemonikos.org) for related systematic reviews. We checked the bibliographies of the included studies and any relevant systematic reviews identified for further references to relevant trials. We checked the included studies for retractions and errata via PubMed (pubmed.ncbi.nlm.nih.gov) and the Retraction Watch Database (retractiondatabase.org). We included publicly available individual patient data from Sundström and colleagues after evaluation based on the inclusion criteria described above [29].

Data collection and analysis

Selection of studies

We screened all abstracts of trials identified by electronic searching or bibliographic scanning for potential relevance. We obtained the full‐text reports of those studies deemed potentially relevant, and assessed the full texts for inclusion in the review and listed the reasons for exclusion of excluded studies. Two review authors independently assessed the eligibility of the trials, with any discrepancies resolved by a third review author.

Data extraction and management

Two review authors independently extracted data from the included trials using standardized data collection forms, which were piloted by team authors prior to use. We checked for disagreements before data entry into RevMan [32]. We contacted study authors for clarification and further data if required. Characteristics of the included studies are available in Supplementary material 2. If information was not reported in a format that could be entered directly, we converted it to the required format as described in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions [33].

We extracted the following data.

• Methods: study design (antihypertensive pharmacotherapy arm, placebo arm), additional methods data

• Population: inclusion criteria baseline characteristics (number, gender, age, SBP/DBP, comorbidities)

• Interventions and comparisons: antihypertensive pharmacotherapy as monotherapy or in a step‐up approach, or both, and placebo or no treatment as control

• Outcomes: all‐cause mortality, total cardiovascular events (fatal and non‐fatal strokes, myocardial infarction, and congestive heart failure), stroke (fatal and non‐fatal), coronary heart disease (fatal and non‐fatal myocardial infarction and sudden cardiac death), and WDAEs

For trials with individual patient data, we extracted data for participants that met all inclusion criteria only (see Types of participants).

Risk of bias assessment in included studies

Two review authors independently assessed risk of bias in the included studies using Cochrane's RoB 1 tool. We assessed risk of bias for the following domains.

• Random sequence generation

• Allocation concealment

• Blinding of participants and personnel

• Blinding of outcome assessors

• Incomplete outcome data

• Selective outcome reporting

• Other bias

We categorized each domain as low risk of bias, high risk of bias, or unclear risk of bias [34]. Any disagreements between review authors were resolved by a third review author.

Measures of treatment effect

We calculated risk ratio (RR) along with 95% confidence interval (CI) using the Mantel‐Haenszel test and a fixed‐effect model.

Unit of analysis issues

The unit of analysis was the number of participants in whom the event occurred. For multi‐arm studies, we divided the placebo group equally across intervention arms to avoid duplicates.

Dealing with missing data

We contacted hypertension experts to identify potentially relevant trials missed in the search. We contacted study authors for unpublished data from ongoing trials if possible. If a trial may have included a subgroup of participants that met our inclusion criteria, we contacted the authors of the trial for individual patient data.

Reporting bias assessment

We assessed reporting bias with RoB 1.

Synthesis methods

We performed statistical analysis using RevMan [32]. We calculated the RR with 95% CI, using the Mantel‐Haenszel test and a fixed‐effect model. The Chi² test to identify heterogeneity is not appropriate, as it has low power when there are few studies but excessive power to detect clinically unimportant heterogeneity when there are many studies. I² is a more appropriate statistic, as it measures the proportion of total variation in the estimate of the treatment effect that is due to heterogeneity between studies. This statistic is also independent of the number of studies in the analysis [35].

We interpreted the I² value with reference to the Cochrane Handbook for Systematic Reviews of Interventions, using the following thresholds [36]:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

Investigation of heterogeneity and subgroup analysis

We used the I² statistic to assess for heterogeneity between studies [35]. Due to the limited number of events, a priori subgroup analyses by sex, ethnicity, and comorbidities were not conducted.

Equity‐related assessment

Equity‐related assessments could not be performed due to limited available data per the PROGRESS‐Plus framework. As mentioned above, we could not conduct equity‐based assessment comparisons by traits such as sex, ethnicity, lifestyle, or comorbidities due to the limited number of events.

Sensitivity analysis

We planned sensitivity analyses excluding studies at high risk of bias in any domain, as well as excluding studies at high risk of publication bias. However, these could not be performed due to the limited number of trials.

Certainty of the evidence assessment

We assessed the certainty of evidence for each outcome using the GRADE framework [37]. We categorized the certainty of evidence as high, moderate, low, or very low. All‐cause mortality, total cardiovascular events, coronary heart disease, and stroke occurred at two to five years. WDAEs were measured for up to five years. All outcomes were assessed from the last available time point reported in the trial.

Consumer involvement

Consumers were not directly involved in the review. We targeted the plain language summary for consumers.

Results

Description of studies

The full data package is available in Supplementary material 5, and a complete record of all comparisons and analyses is provided in Table 2.

Results of the search

For this update, we identified 25,590 references through database searching and 292 records through other sources. After removal of duplicates, 16,336 references remained. We assessed 16,336 papers based on title and abstract, of which 16,299 records were excluded. We assessed 37 full‐text reports, of which 24 trials (35 reports) were excluded with reasons, and 1 new trial (2 reports) was included in this update. In total, 5 trials (55 reports) were included, of which 4 studies (53 reports) were from the previous version of the review and 1 study (2 reports) was newly included (Figure 1; Supplementary material 3; Supplementary material 4; Supplementary material 2).

1.

Study flow diagram.

Included studies

We included four studies in the original version of this review (ANBP 1980 [38, 39, 40, 41, 42, 43, 44, 45, 46, 47]; MRC 1985 [48, 49, 50, 51, 52, 53, 54, 55, 56]; SHEP 1991 [57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88]; VA‐NHLBI 1978 [89, 90]). We obtained individual patient data for ANBP 1980, MRC 1985, and SHEP 1991. In VA‐NHLBI 1978, less than 20% of participants had DBP ≥ 100 mmHg. The newly included study was individual patient data from PREVEND IT 2004 [91, 92].

Methods

All studies included were single‐blinded (participants were blinded) or double‐blinded (investigators and participants were blinded) RCTs. All studies were conducted in parallel, except PREVEND IT 2004, which was a 2 x 2 factorial. Trials enrolled participants from sites in North America, Europe, and Australia. The mean weighted follow‐up was 4.4 years.

Participants

The five trials included a total of 9124 participants, of whom 4593 received antihypertensives and 4531 received placebo or no treatment (Table 3). The weighted mean age at baseline was 50 years.

2. Number of participants included in the present study versus total from the original trial populations.

Trials	Present study		Original trials
	Treatment	Placebo	Treatment	Placebo
ANBP	958	874	1721	1706
MRC	3012	3049	8700	8854
PREVEND IT	112	100	431	433
SHEP	3	4	2365	2371
VA‐NHLBI	508	504	508	504
Total	4593	4531	13725	13868

PREVEND IT 2004 analyzed people with microalbuminuria. Additional details on study participants are provided in Supplementary material 2.

Interventions

In ANBP 1980, participants received chlorothiazide 500 mg once as first‐line treatment, chlorothiazide 500 mg twice daily or add‐on methyldopa, propranolol, or pindolol as second‐line treatment, and add‐on hydralazine or clonidine as third‐line treatment.

In MRC 1985, participants received step‐up therapy with bendrofluazide 10 mg daily or propranolol 80 to 240 mg daily as first‐line treatment and methyldopa as second‐line treatment.

In VA‐NHLBI 1978, participants received step‐up therapy with chlorothalidone 50 mg or 100 mg as first‐line treatment and reserpine 0.25 mg as second‐line treatment.

In SHEP 1991, participants received chlorthalidone 12.5 to 25 mg as first‐line treatment, and atenolol 25 to 50 mg (23%) or reserpine 0.05 to 0.1 mg as second‐line treatment.

In PREVEND IT 2004, participants received monotherapy with fosinopril 20 mg only.

The control groups in all trials received either placebo or no treatment.

Outcomes

The primary outcomes of the four trials included in the original version of this review were mortality, stroke, and cardiovascular events.

The primary outcome of PREVEND IT 2004 was a composite of cardiovascular mortality and hospitalization due to cardiovascular disease. Secondary outcomes included all‐cause mortality and stroke.

Excluded studies

In 12 trials, participants received antihypertensive pharmacotherapy at baseline (ABCD 1998 [93, 94, 95]; ADVANCE 2007 [96, 97, 98, 99]; BENEDICT 2006 [100]; DEMAND 2011 [101, 102]; DIABHYCAR 2004 [103]; ESAX‐DN 2020 [104, 105]; EVALUATE 2014 [106, 107]; FEVER 2005 [108, 109]; HDFP 1982 [110, 111, 112, 113, 114]; MRFIT 1982 [115, 116]; SCAT 2000 [117]; UKPDS 1998 [118, 119]).

In seven trials, participants had moderate to severe hypertension (COOPE 1986 [120]; Hu 2020 [121]; HYVET 2008 [122, 123]; IDNT 2001 [124, 125, 126, 127]; MRC2 1992 [128, 129]; Oslo Study 1980 [130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140]; USPHSHC 1977 [141]).

In three trials, participants had pre‐existing cardiovascular disease (HOPE 2000 [142, 143]; PART‐2 2000 [144]; PROGRESS 2001 [145, 146]).

In two trials, participants in the control group received an intervention (Alam 2020 [147, 148]; ANBP2 2003 [149, 150, 151]).

Additional details are listed in Supplementary material 3.

Risk of bias in included studies

We assessed risk of bias in the included trials using RoB 1 (Figure 2).

2.

Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

Random sequence generation, allocation concealment (selection bias)

Risk of bias related to random sequence generation was low in one trial and unclear in four trials. Risk of bias related to allocation concealment was low in three trials and unclear in two trials.

Blinding of participants and personnel (performance bias) and blinding of outcome assessors (detection bias)

Risk of performance bias was low in three trials, unclear in one trial, and high in one trial. Risk of detection bias was low in all trials.

Incomplete outcome data (attrition bias)

Risk of attrition bias was low in one trial, unclear in one trial, and high in three trials.

Selective reporting (reporting bias)

Risk of reporting bias was low in one trial and unclear in four trials.

Other bias

Risk of other potential sources of bias was low in two trials, unclear in two trials, and high in one trial due to potential conflicts of interest and funding sources.

Synthesis of results

All findings are summarized in Table 1.

1.1 All‐cause mortality

There may be little to no difference between antihypertensive monotherapy or step‐up therapy, or both, and placebo or no treatment in the risk of all‐cause mortality (RR 0.85, 95% CI 0.64 to 1.14; 5 trials, 9124 participants; low‐certainty evidence).

1.2 Total cardiovascular events

There may be little to no difference between antihypertensive monotherapy or step‐up therapy, or both, and placebo or no treatment in the risk of total cardiovascular events (RR 0.93, 95% CI 0.69 to 1.24; 4 trials, 7292 participants; low‐certainty evidence).

1.3 Stroke

Participants who received antihypertensive monotherapy or step‐up therapy, or both, may have a reduced risk of stroke compared to those who received placebo or no treatment (RR 0.41, 95% CI 0.20 to 0.84; 4 trials, 7292 participants; low‐certainty evidence).

1.4 Coronary heart disease

There may be little to no difference between antihypertensive monotherapy or step‐up therapy, or both, and placebo or no treatment in the risk of coronary heart disease (RR 1.12, 95% CI 0.80 to 1.57; 3 trials, 7080 participants; low‐certainty evidence).

1.5 Withdrawal due to adverse drug events

Participants who received antihypertensive monotherapy or step‐up therapy, or both, may have an increased risk of WDAEs compared to those who received placebo or no treatment (RR 4.80, 95% CI 4.14 to 5.57; 1 trial, 17,354 participants; low‐certainty evidence).

Equity assessment

Equity‐related assessment could not be performed in this review.

Reporting biases

An assessment of reporting bias could not be conducted due to the limited number of studies included in this review.

Discussion

Only one additional trial was added to our review since the last update in 2012. Recent trials have recruited patients receiving antihypertensives at baseline or those with additional cardiovascular risk factors. Extracting relevant individual patient data for inclusion in individual meta‐analyses is increasingly challenging given the complexity and heterogeneity of current trials.

Summary of main results

This updated Cochrane review of antihypertensive monotherapy or step‐up therapy, or both, initiated in people with untreated mild hypertension and no pre‐existing cardiovascular disease demonstrated little to no difference in the incidence of all‐cause mortality, total cardiovascular events, or coronary heart disease compared to placebo or no treatment. There may be a decrease in the incidence of stroke, and a possible increase in the incidence of WDAEs. The certainty of evidence for all outcomes was low, primarily due to risk of bias, imprecision, and indirectness of the included studies.

Limitations of the evidence included in the review

The BPLTTC group published an update to our original meta‐analysis in 2015 with the addition of individual patient data from their trials in Sundström and colleagues [29]. Unfortunately, we were only able to add individual patient data from one trial (PREVEND IT 2004). These key differences in our study populations re‐illustrate the uncertainty about the risks‐benefits of pharmacotherapy in people with mild hypertension and no prior cardiovascular disease.

Two of our inclusion criteria excluded most potentially relevant trials. First, many trials enrolled individuals already receiving antihypertensive pharmacotherapy (ADVANCE 2007; BENEDICT 2006; DIABHYCAR 2004; ESAX‐DN 2020; FEVER 2005; SCAT 2000; UKPDS 1998). Therefore, these trials may have enrolled people with moderate‐severe hypertension at baseline, given that there is no consensus on the exact incremental BP reduction achieved per antihypertensive agent, and we cannot extrapolate an estimated BP. Second, some trials compared lower versus higher BP thresholds to initiate pharmacotherapy (i.e. 'conservative' lower threshold versus 'liberal' higher threshold) (ABCD 1998; ANBP2 2003; HDFP 1982), and were therefore designed to answer a different question than our objective.

In this update, we also conducted a comprehensive search of all trials from 2012 until June 2024. We did not find any new trials meeting our inclusion criteria. Of the excluded trials, the most common reason was because participants were on antihypertensives at baseline. Finally, recent trials test antihypertensive pharmacotherapy in combination (i.e. dual or triple therapy) rather than monotherapy or step‐up therapy, or both [1]. Our study population specifically addresses the efficacy of initiation of antihypertensive monotherapy and step‐up therapy in untreated mild hypertension. Given the limited number of trials in the context of recent hypertension meta‐analyses, we downgraded the certainty of evidence for all outcomes to low.

The risk reduction for stroke must be interpreted with caution. Only a total of 35 events occurred. Furthermore, PREVEND IT 2004 enrolled people with microalbuminuria. Chronic kidney disease, particularly in those with proteinuria, is a well‐recognized independent risk factor for cardiovascular events [152]. Antihypertensive pharmacotherapy with angiotensin‐converting enzyme inhibitors is strongly associated with a reduced risk of cardiovascular events, and is partially independent of BP change [153, 154]. We therefore cannot determine if this benefit can be extrapolated to people without microalbuminuria.

Our study characterizes the efficacy of antihypertensive pharmacotherapy in people without pre‐existing cardiovascular disease. The participants included in our study had mean ages of 40 to 50 (except for SHEP 1991), no diabetes, and no chronic kidney disease (except for PREVEND IT 2004). The benefit of initiation of pharmacotherapy in people with mild hypertension and no pre‐existing cardiovascular disease is uncertain. In a subgroup analysis of the HOPE‐3 trial, participants with an average Atherosclerotic Cardiovascular Disease score of 3.8% who received candesartan and hydrochlorothiazide demonstrated no difference in the incidence of major adverse cardiovascular events compared to placebo [1].

This uncertainty regarding the initiation of antihypertensive pharmacotherapy in people with lower cardiovascular risk is reflected in current guidelines. Some guidelines suggest a three‐ to six‐month trial of non‐pharmacologic intervention prior to initiation of pharmacotherapy [18], while others suggest non‐pharmacotherapeutic intervention only [19, 20]. Our study re‐illustrates the existing uncertainty on initiating pharmacotherapy in people without pre‐existing cardiovascular disease.

Limitations of the review processes

Some of the excluded trials may have included individual participants that met our study inclusion criteria. Unfortunately, we could not obtain access to individual patient data despite attempts to contact study authors (Oslo Study 1980; USPHSHC 1977).

In future reviews, we will incorporate consumers in the review process.

Agreements and disagreements with other studies or reviews

This updated study remains in conflict with the results of Sundström and colleagues [29]. Many of the trials included in the Sundström and colleagues' meta‐analysis studied participants who were receiving antihypertensive pharmacotherapy at baseline [29].

This conflict is likely related to our study population's lower baseline risk for cardiovascular disease. The mean age of participants included in the BPLTTC trials is approximately 10 years greater than our study population (average age 64 compared to average ages of 40 to 50). A recent large meta‐analysis of observational studies demonstrated that people with SBP at the highest decile of their age group had a similar risk of cardiovascular death as those 20 years older with BP levels at the lowest decile of their age group [3]. Moreover, most trials in our meta‐analysis excluded people with diabetes, whereas 96% of participants from the BPLTTC trials had type 2 diabetes. Individuals with type 2 diabetes have an increased cardiovascular risk [155]. Overall, our study reflects the uncertain benefit in people with lower baseline cardiovascular risk, while Sundström and colleagues' study supports a benefit in those with a higher cardiovascular risk, including diabetes.

We are also cautious to recommend antihypertensive pharmacotherapy due to the risk of adverse drug events. This conclusion has significant limitations, since it was based on one study (due to lack of access to individual patient data for this outcome), a significant proportion of withdrawals were due to headaches (a controversial adverse effect), and the medications used are either no longer administered as first‐line therapy, or are no longer prescribed [156]. However, this concern has been reflected in a recent large meta‐analysis, which demonstrated a significant association between antihypertensive pharmacotherapy and severe adverse events including syncope and acute kidney injury [157]. In addition, some classes of antihypertensives have been associated with an increased risk of fall and an increased risk of major fractures, including hip fractures [158, 159].

Authors' conclusions

Implications for practice

There may be little to no difference in the risk of all‐cause mortality, total cardiovascular events, and coronary heart disease between participants who received antihypertensive monotherapy or step‐up therapy, or both, and those who received placebo or no treatment.

There may be a decreased risk of stroke in participants who received antihypertensive monotherapy or step‐up therapy, or both, compared to those who received placebo or no treatment. There may be an increased risk of withdrawal due to adverse drug events in participants who received antihypertensive monotherapy or step‐up therapy, or both, compared to those who received placebo or no treatment.

The certainty of evidence for all outcomes was low due to imprecision, indirectness, and risk of bias.

Equity‐related implications for practice

The included trials involved both males and females, therefore our conclusions are relevant to both.

Implications for research

The optimal blood pressure threshold to initiate antihypertensive pharmacotherapy in people with no pre‐existing cardiovascular disease remains uncertain.

We suggest consideration of initiation of antihypertensive pharmacotherapy in patients with mild, untreated hypertension, and no pre‐existing cardiovascular disease, diabetes, or chronic kidney disease on an individual basis.

Future meta‐analyses may help establish the optimal blood pressure threshold to initiate antihypertensive pharmacotherapy in people with untreated mild hypertension and no pre‐existing cardiovascular disease if additional trials limited to this population are conducted, and by identifying large trials that included participants with no pre‐existing cardiovascular disease and collecting individual patient data.

Equity‐related implications for research

Trials should report data for males and females separately. Trials should include participants with diverse ethnicities, lifestyles, and comorbidities.

Supporting Information

Supplementary materials are available with the online version of this article: 10.1002/14651858.CD006742.pub3.

Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.

Supplementary material 1 Search strategies

Supplementary material 2 Characteristics of included studies

Supplementary material 3 Characteristics of excluded studies

Supplementary material 4 Analyses

Supplementary material 5 Data package

New search for studies and content updated (conclusions changed)

Additional information

Contributions of authors

SA, AA, DW, and JW determined trial eligibility. DW contributed substantially to study design, data collection, and data analysis. All authors contributed to study interpretation and writing and editing of the final draft.

Declarations of interest

Guillaume Grenet has received funding from the Association Française pour la Recherche Thermale. Guillaume Grenet is currently employed by the University of British Columbia. Guillaume Grenet has no financial interests that could appear to influence the work reported in this review.

Anshula Ambasta has received funding for research projects from the Canadian Institutes of Health Research, Canadian Society of Internal Medicine, University of Calgary, University of Alberta, and Choosing Wisely Alberta. Anshula Ambasta is currently employed by the University of British Columbia. She has no financial interests that could appear to influence the work reported in this review.

Dominic Wang, James Wright, Stephen Adams, David Cundiff, and Francois Gueyffier report no conflicts of interest relevant to this review.

Sources of support

Internal sources

• BIMBO project, SYSCOMM 2008 Nr 002, ANR‐ www.agence‐nationale‐recherche.fr, France

  BIMBO project, SYSCOMM 2008 Nr 002, ANR‐ www.agence‐nationale‐recherche.fr, France

• Claude Bernard University Lyon I, France

  Claude Bernard University Lyon I, France

• UMR5558, CNRS, France

  UMR5558, CNRS, France

• Clinical Pharmacology Department, Hospices Civils de Lyon, France

  Clinical Pharmacology Department, Hospices Civils de Lyon, France

• Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Canada

  Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Canada

External sources

• British Columbia Ministry of Health Grant to the Therapeutics Initiative, Canada

  British Columbia Ministry of Health Grant to the Therapeutics Initiative, Canada

• CIHR Grant to the Hypertension Review Group, Canada

  The Canadian Institutes of Health Research is a federal agency responsible for funding health and medical research in Canada.

Registration and protocol

Protocol (2007) [160].

Original review (2012) [27].

Data, code and other materials

As part of the published Cochrane Review, the following are made available for download for users of the Cochrane Library: full search strategies for each database; full citations of each unique report for all studies included, ongoing or awaiting classification, or excluded at the full‐text screen, in the final review; study data, including study information, study arms, and study results or test data; consensus risk of bias assessments; and analysis data, including overall estimates and settings, subgroup estimates, and individual data rows. Appropriate permissions have been obtained for such use. Analyses and data management were conducted within Cochrane’s authoring tool, Review Manager Web, using the inbuilt computation methods. Template data extraction forms from Covidence are available from the authors on reasonable request.

What's new

Date	Event	Description
24 September 2025	New citation required and conclusions have changed	Review updated and conclusions changed.
24 September 2025	New search has been performed	New search was performed and one new trial identified for inclusion.

History

Protocol first published: Issue 3, 2007
Review first published: Issue 8, 2012

Date	Event	Description
6 December 2013	Feedback has been incorporated	Comment: Should mild hypertension be treated?
6 December 2013	Feedback has been incorporated	Comment: The results of this review should be interpreted (appropriately) as subgroup analyses