Which patient finding would cause the nurse to hold the 8 a.m. dose of verapamil

Cochrane Database Syst Rev. 2018; 2018(4): CD001841.

Monitoring Editor: James M Wright,

University of British Columbia, Department of Anesthesiology, Pharmacology and Therapeutics, 2176 Health Sciences Mall, VancouverBCCanada, V6T 1Z3

Manipal University, Department of Pharmacology, ManipalIndia

Abstract

Background

This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical question: What class of drug to use first‐line? This review attempted to answer that question.

Objectives

To quantify the mortality and morbidity effects from different first‐line antihypertensive drug classes: thiazides (low‐dose and high‐dose), beta‐blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers (ARB), and alpha‐blockers, compared to placebo or no treatment.

Secondary objectives: when different antihypertensive drug classes are used as the first‐line drug, to quantify the blood pressure lowering effect and the rate of withdrawal due to adverse drug effects, compared to placebo or no treatment.

Search methods

The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work.

Selection criteria

Randomized trials (RCT) of at least one year duration, comparing one of six major drug classes with a placebo or no treatment, in adult patients with blood pressure over 140/90 mmHg at baseline. The majority (over 70%) of the patients in the treatment group were taking the drug class of interest after one year. We included trials with both hypertensive and normotensive patients in this review if the majority (over 70%) of patients had elevated blood pressure, or the trial separately reported outcome data on patients with elevated blood pressure.

Data collection and analysis

The outcomes assessed were mortality, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. We used a fixed‐effect model to to combine dichotomous outcomes across trials and calculate risk ratio (RR) with 95% confidence interval (CI). We presented blood pressure data as mean difference (MD) with 99% CI.

Main results

The 2017 updated search failed to identify any new trials. The original review identified 24 trials with 28 active treatment arms, including 58,040 patients. We found no RCTs for ARBs or alpha‐blockers. These results are mostly applicable to adult patients with moderate to severe primary hypertension. The mean age of participants was 56 years, and mean duration of follow‐up was three to five years.

High‐quality evidence showed that first‐line low‐dose thiazides reduced mortality (11.0% with control versus 9.8% with treatment; RR 0.89, 95% CI 0.82 to 0.97); total CVS (12.9% with control versus 9.0% with treatment; RR 0.70, 95% CI 0.64 to 0.76), stroke (6.2% with control versus 4.2% with treatment; RR 0.68, 95% CI 0.60 to 0.77), and coronary heart disease (3.9% with control versus 2.8% with treatment; RR 0.72, 95% CI 0.61 to 0.84).

Low‐ to moderate‐quality evidence showed that first‐line high‐dose thiazides reduced stroke (1.9% with control versus 0.9% with treatment; RR 0.47, 95% CI 0.37 to 0.61) and total CVS (5.1% with control versus 3.7% with treatment; RR 0.72, 95% CI 0.63 to 0.82), but did not reduce mortality (3.1% with control versus 2.8% with treatment; RR 0.90, 95% CI 0.76 to 1.05), or coronary heart disease (2.7% with control versus 2.7% with treatment; RR 1.01, 95% CI 0.85 to 1.20).

Low‐ to moderate‐quality evidence showed that first‐line beta‐blockers did not reduce mortality (6.2% with control versus 6.0% with treatment; RR 0.96, 95% CI 0.86 to 1.07) or coronary heart disease (4.4% with control versus 3.9% with treatment; RR 0.90, 95% CI 0.78 to 1.03), but reduced stroke (3.4% with control versus 2.8% with treatment; RR 0.83, 95% CI 0.72 to 0.97) and total CVS (7.6% with control versus 6.8% with treatment; RR 0.89, 95% CI 0.81 to 0.98).

Low‐ to moderate‐quality evidence showed that first‐line ACE inhibitors reduced mortality (13.6% with control versus 11.3% with treatment; RR 0.83, 95% CI 0.72 to 0.95), stroke (6.0% with control versus 3.9% with treatment; RR 0.65, 95% CI 0.52 to 0.82), coronary heart disease (13.5% with control versus 11.0% with treatment; RR 0.81, 95% CI 0.70 to 0.94), and total CVS (20.1% with control versus 15.3% with treatment; RR 0.76, 95% CI 0.67 to 0.85).

Low‐quality evidence showed that first‐line calcium channel blockers reduced stroke (3.4% with control versus 1.9% with treatment; RR 0.58, 95% CI 0.41 to 0.84) and total CVS (8.0% with control versus 5.7% with treatment; RR 0.71, 95% CI 0.57 to 0.87), but not coronary heart disease (3.1% with control versus 2.4% with treatment; RR 0.77, 95% CI 0.55 to 1.09), or mortality (6.0% with control versus 5.1% with treatment; RR 0.86, 95% CI 0.68 to 1.09).

There was low‐quality evidence that withdrawals due to adverse effects were increased with first‐line low‐dose thiazides (5.0% with control versus 11.3% with treatment; RR 2.38, 95% CI 2.06 to 2.75), high‐dose thiazides (2.2% with control versus 9.8% with treatment; RR 4.48, 95% CI 3.83 to 5.24), and beta‐blockers (3.1% with control versus 14.4% with treatment; RR 4.59, 95% CI 4.11 to 5.13). No data for these outcomes were available for first‐line ACE inhibitors or calcium channel blockers. The blood pressure data were not used to assess the effect of the different classes of drugs as the data were heterogeneous, and the number of drugs used in the trials differed.

Authors' conclusions

First‐line low‐dose thiazides reduced all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. First‐line ACE inhibitors and calcium channel blockers may be similarly effective, but the evidence was of lower quality. First‐line high‐dose thiazides and first‐line beta‐blockers were inferior to first‐line low‐dose thiazides.

Plain language summary

Thiazides best first choice for hypertension

Review Question(s)

In this first update of a review published in 2009, we wanted to determine which drug class was the best first‐line choice in treating adult patients with raised blood pressure.

We searched the available medical literature to find all the trials that compared the drugs to placebo or no treatment to assess this question. The data included in this review are up to date as of November 2017.

Background

High blood pressure or hypertension can increase the risk of heart attacks and stroke. One of the most important decisions in treating people with elevated blood pressure is what drug class to use first. This decision has important consequences in terms of health outcomes and cost.

Study characteristics

We found no new trials in this updated search. In the original review, we found 24 studies that randomly assigned 58,040 adult people (mean age 62 years) with high blood pressure, to four different drug classes or placebo. Duration of these studies ranged from three to five years. Drug classes studied included thiazide diuretics, beta‐blockers, ACE inhibitors, and calcium channel blockers.

Key Results

We concluded that most of the evidence demonstrated that first‐line low‐dose thiazides reduced mortality, stroke, and heart attack. No other drug class improved health outcomes better than low‐dose thiazides. Beta‐blockers and high‐dose thiazides were inferior.

Conclusions

High‐quality evidence supported that low‐dose thiazides should be used first for most patients with elevated blood pressure. Fortunately, thiazides are also very inexpensive.

Quality of evidence

The evidence for first‐line low dose thiazides was high quality. For the other classes, we judged the evidence to be moderate or low quality.

Summary of findings

Background

Elevated blood pressure (hypertension) is a chronic condition in which the blood pressure in the arteries is persistently elevated. It has been divided into three categories, based on resting blood pressures, measured in a standard way: mild hypertension (140 to 159/90‐99 mmHg), moderate hypertension (160 to 179/100 to 109 mmHg), and severe hypertension (180/110 mmHg or higher). Most people with high blood pressure have no signs or symptoms, even if blood pressure readings are very high. For most adults with primary or essential hypertension, there is no identifiable cause for the high blood pressure. Some people have high blood pressure, called secondary hypertension, caused by underlying conditions such as adrenal gland tumours, kidney problems, thyroid problems, excessive alcohol intake, or use of certain medications, such as birth control pills. Isolated systolic hypertension is a condition in which the diastolic pressure is normal (less than 90 mmHg), but systolic pressure is high (160 mmHg or greater). This is a common type of high blood pressure among older people.

Blood pressure tends to increase with age. High blood pressure is more common in men in early middle age, more common in women after age 65, and more common in Blacks compared to Caucasians. The risk of high blood pressure is increased when there is a family history of high blood pressure, in the presence of obesity, or when physically inactive. High blood pressure is associated with smoking, too much salt in the diet, drinking excessive amounts of alcohol, high levels of stress, and chronic conditions such as diabetes, kidney disease, and sleep apnea.

Uncontrolled persistent resting high blood pressure increases the risk of stroke, heart attack, heart failure, kidney damage, and vision loss.

Description of the condition

When drug treatment is indicated in the management of patients with elevated blood pressure, an important decision is which drug to choose first. The decision should be informed by the best available evidence on reduction of the outcomes that are important to the patient, i.e. the ability of the drug to reduce the adverse health outcomes associated with elevated blood pressure (disabling stroke, myocardial infarction, heart failure, and mortality).

Description of the intervention

High blood pressure should initially be managed with changing life style — eating a healthy diet with less salt, exercising regularly, quitting smoking, and maintaining a healthy weight. When these life‐style changes are not enough, treatment with antihypertensive drugs is recommended. Several different classes of medications are available to reduce blood pressure. The six main drug classes, included in this review, are thiazide diuretics, beta‐blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, calcium channel blockers, and alpha blockers.

How the intervention might work

Different classes of antihypertensive drugs have different mechanisms of action.

Thiazide and thiazide‐like diuretics: The mechanism of action by which thiazide diuretics lower blood pressure in the long term is not fully understood (Zhu 2005). After chronic use, thiazides lower peripheral resistance. The mechanism of these effects is uncertain, as it may involve effects on the whole body, renal autoregulation, or direct vasodilator actions (Hughes 2004). Thiazides act on the kidney to inhibit reabsorption of sodium (Na+) and chloride (Cl‐) ions from the distal convoluted tubules in the kidneys, by blocking the thiazide‐sensitive sodium‐chloride symporter (Duarte 2010). They also increase calcium reabsorption at the distal tubule, and increase the reabsorption of calcium ions (Ca2+), by a mechanism involving the reabsorption of sodium and calcium in the proximal tubule in response to sodium depletion.

Beta‐blockers: Beta‐blockers are competitive antagonists that block the receptor sites for epinephrine (adrenaline) and norepinephrine on adrenergic beta‐receptors. Some block activation of all types of beta‐adrenergic receptors (β1, β2, and β3), and others are selective for one of the three types of beta receptors (Frishman 2005).

Angiotensin converting enzyme (ACE) inhibitors: ACE inhibitors block the conversion of angiotensin I (AI) to angiotensin II (AII), and thus decrease the actions of angiotensin II. The end result is to lower arteriolar resistance and increase venous capacity; decrease cardiac output, cardiac index, stroke work, and volume; lower resistance in blood vessels in the kidneys; and increase excretion of sodium in the urine. Renin and AI increases in concentration in the blood as a result of negative feedback of the conversion of AI to AII. AII and aldosterone levels decrease. Bradykinin increases, because ACE is also responsible for inactivation of bradykinin.

Angiotensin receptor blockers (ARBs): ARBs block the activation of angiotensin II AT1 receptors. Blockage of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces the production and secretion of aldosterone.

Calcium channel blockers (CCBs): CCBs block calcium channel and inhibit calcium ion influx into vascular smooth muscle and myocardial cells. They reduce blood pressure through various mechanisms: by vasodilation, by reducing the force of contraction of the heart, by slowing the heart rate, and by directly reducing aldosterone production.

Alpha blockers: α1 adrenergic receptor blockers inhibit the binding of norepinephrine (noradrenaline) to the α1 receptors on vascular smooth muscle cells. The primary effect of this inhibition is vasodilation, which decreases peripheral vascular resistance, leading to decreased blood pressure.

Why it is important to do this review

There have been a number of reviews of the effectiveness of antihypertensive therapy, but most have emphasized effectiveness of all drug classes (Collins 1990; Gueyffier 1996), or effectiveness of all drug classes in special populations, such the elderly (Insua 1994; MacMahon 1993; Mulrow 1994; Mulrow 1998; Thijs 1992). When all drug therapies are included in one review, there is an underlying assumption that the benefits of lowering blood pressure are independent of the mechanism by which it is achieved. This assumption has not been proven, and it is likely that different classes of drugs will have different blood pressure lowering effects, and will have effects that are independent of the blood pressure lowering effect. A drug that lowers blood pressure could have pharmacological and physiological actions independent of blood pressure lowering, and these other actions (both known and unknown) could enhance or negate the effects on health outcomes associated with the decrease in blood pressure. This possibility is supported by a recent analysis that suggested that blood pressure lowering only explains about 50% of the treatment effect in antihypertensive trials (Boissel 2005).

This review update aims to 1) document the best available evidence of effectiveness for different classes of drugs and doses used as first‐line therapy, compared to placebo or no treatment, and 2) present the outcome data in a way that best assists clinicians in the choice of a first‐line drug.

Objectives

Primary objective

1. To quantify the mortality and morbidity effects from different first‐line anti‐hypertensive drug classes: thiazides (low dose and high dose), beta‐blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers, and alpha‐blockers, compared to placebo or no treatment.

Secondary objectives

1. To quantify the blood pressure lowering effect of antihypertensive treatment when different drug classes are used as the first‐line drug.

2. To quantify the rate of withdrawal due to adverse drug effects of different first‐line antihypertensive class drugs, compared to placebo or no treatme

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCT) of at least one year duration. The comparative group was a placebo, or an untreated control. We required the following data from the trial: baseline patient characteristics, clearly defined morbidity and mortality endpoints, and outcome data presented using the intention‐to‐treat principle.

We excluded trials using other than randomized allocation methods, such as alternate allocation, week of presentation, or retrospective controls. We also excluded trials that compared two specific antihypertensive first‐line therapies without a placebo or untreated control.

Types of participants

Blood pressure was measured using proper technique at least two times, with the patient resting for at least five minutes. All patients must have had a baseline resting blood pressure of at least 140 mmHg systolic or a diastolic blood pressure of at least 90 mmHg. Trials that included both hypertensive and normotensive patients were acceptable if the majority (> 70%) of patients had elevated blood pressure, or the trial separately reported outcome data on patients with elevated blood pressure. Trials were not limited by any other factor or baseline risk. It was assumed that age and comorbidities did not affect the risk ratio of outcomes associated with drug treatment.

Types of interventions

Treatment was to be clearly defined as a specific class of first‐line antihypertensive therapy in one of the following classes: thiazide diuretics, beta blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or alpha adrenergic blockers. The majority (> 70%) of the patients in the treatment group were to be taking the drug class of interest after one year. We allowed initial combined therapies with drug classes not in the defined categories. We also allowed supplemental drugs from other drug classes of interest as stepped therapy, but only as long as they were not taken by over 50% of the patients. We assumed that these supplemental drugs did not systematically interact to affect the occurrence of the outcomes studied.
We also stratified the analysis by the thiazide dose. We classified thiazide doses as high‐dose and low‐dose by selecting hydrochlorothiazide as the standard, and translating the doses of other drugs in the class into hydrochlorothiazide equivalents. We assumed that each thiazide had a similar dose‐response curve, and the usual prescription dose range represented a similar range on the dose‐response curve.

We classified groups according to the starting dose in the trial:

High‐dose thiazide group: starting dose

• hydrochlorothiazide ≥ 50 mg per day

• chlorothiazide ≥ 500 mg per day

• chlorthalidone ≥ 50 mg per day

• bendrofluazide ≥ 5 mg per day

• methylclothiazide ≥ 5 mg per day

• trichlormethiazide ≥ 2 mg per day

• indapamide ≥ 5 mg per day

Low‐dose thiazide group: starting dose

• hydrochlorothiazide < 50 mg per day

• chlorthiazide < 500 mg per day

• chlorthalidone < 50 mg per day

• bendrofluazide < 5 mg per day

• methylclothiazide < 5 mg per day

• trichlormethiazide < 2 mg per day

• indapamide < 5 mg per day

We calculated the average dose in the high‐dose and low‐dose group as a weighted average from the trials in which the average dose was reported, or could be estimated.

Types of outcome measures

Primary outcomes

1. Total mortality (death from all causes)

2. Total stroke (fatal and non‐fatal strokes)

3. Total coronary heart disease (CHD; fatal and non‐fatal myocardial infarction, and sudden or rapid cardiac death).

4. Total cardiovascular events (total stroke, total CHD, hospitalization or death from congestive heart failure and other significant vascular deaths, such as ruptured aneurysms. It does not include angina, transient ischemic attacks, surgical or other procedures, or accelerated hypertension).

When the primary trials did not report outcomes that fit the above definitions, we based our decisions on maximizing the inclusion of the data and maintaining concordance, with how the data were classified in previous reviews. We assumed that the effect of antihypertensive treatment on outcomes was independent of whether elevated blood pressure was defined in terms of systolic or diastolic pressure.

Secondary outcomes

1. Reduction in systolic and diastolic blood pressure during the first year

2. Patient withdrawal due to adverse drug effects

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist (DS) conducted systematic searches in the following databases for RCTs without language, publication year, or publication status restrictions:

• the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web; searched 24 November 2017);

• the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web; searched 24 November 2017);

• MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 24 November 2017);

• Embase Ovid (searched 24 November 2017);

• ClinicalTrials.gov (www.clinicaltrials.gov; searched 24 November 2017);

• World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch; searched 24 November 2017).

The Cochrane Hypertension Information Specialist (DS) modelled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomized controlled (as described in the Cochrane Handbook for Systematic Reviews of Interventions (Box 6.4.b; Higgins 2011a). The MEDLINE search strategy was translated into the other databases using the appropriate controlled vocabulary, as applicable (Appendix 1).

Data collection and analysis

Selection of studies

We rejected articles on the initial screening if we could determine from the title or the abstract that the article was not a report of a randomized controlled trial, or that there was no possibility that the trial would fit the requirements of this review. Of the articles selected for further review, two reviewers (JMW and VM) independently assessed whether they would be included or excluded.

Data extraction and management

The data abstraction form included details of study design, randomization, blinding, duration of treatment, baseline characteristics, number of patients lost to follow‐up, outcomes, intervention, statistical analysis, and reporting. Two reviewers (JMW and VM) independently extracted the data, cross‐checked, and compared, whenever possible, to data from previously published meta‐analyses. We detailed trial characteristics in the 'Characteristics of included studies' table. We detailed trials that were excluded in the 'Characteristics of excluded studies' table.

Assessment of risk of bias in included studies

Two review authors (VM and RG) independently assessed risk of bias of each included trial; a third review author (JMW) sorted any disagreements. We assessed risk of bias according to Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We assessed seven domains: randomization and allocation concealment to assess selection bias; blinding of the participants and physician to assess performance bias; blinding of the outcome assessor to assess detection bias; incomplete outcome reporting to assess attrition bias; selective reporting of outcomes to assess selective reporting bias; and we added an additional category ‐ other bias, to assess whether the study was funded by the manufacturer and conflict of interest was present, which we assessed as high risk of bias, since it has been shown to overestimate treatment effect.

'Summary of findings' table

We used GRADEpro GDT software to present the 'Summary of findings' table (GRADEpro GDT). We decided to include all clinically relevant primary and secondary outcomes: total mortality, total stroke, total coronary heart disease, total cardiovascular events, and withdrawal due to adverse events. We did not include the magnitude of systolic and diastolic blood pressure reduction.

We considered five factors in grading the overall quality of evidence: limitations in study design and implementation, indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision in results, and high probability of publication bias. This approach specifies four levels of quality: high‐, moderate‐, low‐, and very low‐quality evidence. The highest quality rating is for randomized trial evidence. Quality rating is downgraded by one level for each factor, up to a maximum of three levels for all factors. If there are severe problems for any one factor (when assessing limitations in study design and implementation, in concealment of allocation, loss of blinding, or attrition over 50% of participants during follow‐up), randomized trial evidence may fall by two levels due to that factor alone.

Measures of treatment effect

We used Review Manager 5 for data synthesis and analyses (RevMan 2014). We based quantitative analyses of outcomes on intention‐to‐treat results. We used risk ratios (RR) with 95% confidence intervals (CI) to combine outcomes across trials. If there was a significant difference in any outcome measure, we presented an absolute risk reduction (ARR), and number needed to treat for an additional beneficial (NNTB) or harmful (NNTH) outcome in the 'Summary of findings' table. This estimate, with 95% confidence intervals (CI), is considered the best estimate of the average benefit and the range of that benefit in populations with different baseline risks.

For continuous outcomes (systolic and diastolic blood pressure), we calculated the mean difference (MD) with 99% CI to combine outcomes across studies. Systolic and diastolic blood pressure readings were taken at one year, or the earliest time after one year, to include the data from the maximum number of randomized patients. Mean blood pressure values only reflected data for patients in whom blood pressure was measured. We used standard deviation of the change (SD) at one year if available.

Unit of analysis issues

For all outcomes measures reported, we used data from each trial at the end of the follow‐up period mentioned in each trial, which varied from 1.1 to 10 years.

Dealing with missing data

When participants were lost to follow‐up, we used data as reported for participants who were followed until the end of the study, in the analyses. We outlined how data were accounted for and included in each study under assessment of attrition bias in the 'Risk of bias in included studies' table.

For example, in the MRC‐TMH 1985 study, for events such as non‐fatal stroke or myocardial infarction, which terminated participation in the study, the investigators did not follow‐up these participants to the end of the study. In such instances, investigators included data available up to the time point during which participants were followed in the analyses.

If the SD value for reduction in systolic and diastolic blood pressure was not reported at one year, we imputed the SD of the change at other time points during treatment. If the SD of the change was not available at all, we imputed the SD of the endpoint systolic or diastolic blood pressure. In cases where these values were also missing, we imputed the mean weighted SD of the change from other trials. This imputation is a limitation, and to reduce the impact of this limitation, we used a 99% level of significance for the blood pressure measurements, instead of the standard 95%.

Assessment of heterogeneity

We tested heterogeneity of treatment effect between the trials using a standard Chi² statistic for heterogeneity. We used the fixed‐effect model to obtain summary statistics of pooled trials, unless there was significant between‐study heterogeneity, in which case we used the random‐effects model to test statistical significance.

Assessment of reporting biases

For each study, we evaluated whether selective reporting of outcomes was suspected. In the case of suspected reporting bias, we contacted study authors for clarification.

We had planned to use a funnel plot to assess the possibility of publication bias for outcomes that were reported in 10 or more studies. A test for funnel plot asymmetry (small study effects) formally examines whether the association between estimated intervention effects and a measure of study size is greater than might be expected to occur by chance.

Data synthesis

We used Review Manager 5 to perform data synthesis and analyses (RevMan 2014). We presented dichotomous outcomes as RR with 95% CI using a fixed‐effect model, and continuous outcomes (systolic and diastolic blood pressure) as MD with 99% CI.

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses: different race: Black versus Caucasian versus Asian; and baseline severity of hypertension: mild, moderate, severe. Unfortunately, it was not possible to do any subgroup analyses, because there were a lack of data specific to race, and most trial participants had moderate to severe hypertension, but data were not available separately.

When heterogeneity was significant (I² greater than 50%), we attempted to identify trials that would contribute to heterogeneity, and explore their population characteristics, baseline blood pressure, blinded or open‐label study design, use of antihypertensive drugs as fixed dose or stepped‐up therapy, or response to placebo that would possibly explain the reason for heterogeneity. As the decrease in systolic and diastolic blood pressure showed significant heterogeneity, we present results as MD with 99% CI using both a fixed‐effect as well as random effect model.

Sensitivity analysis

To test for robustness of results, we conducted several sensitivity analyses. This was done by deselecting trials in the following categories: trials that were not placebo‐controlled and blinded, trials restricted to patients with isolated systolic hypertension, trials that enrolled more than 80% of patients with previous stroke, and myocardial infarction of peripheral vascular disease (secondary prevention), trials using combined starting drugs, and trials using supplemental drugs from other defined classes.

Results

Description of studies

Results of the search

The initial search up to 2009 resulted in 6232 citations, 5985 of which we excluded on reading titles and abstracts. We retrieved 247 citations for more detailed evaluation, 13 of which were review articles. We further evaluated 234 reports; we included 127 reports of 24 trials, and excluded 107 reports.

The updated search in November 2017 resulted in 11,855 citations. We screened the titles and abstracts of these citations, and found 11,500 to be irrelevant. We requested the full text of 355 citations, but none of them met the minimum inclusion criteria. We found 6 additional reports of previously included studies.

For this update of a total of 87 potential trials identified, we included 133 reports of 24 trials, (58,040 patients), and excluded 63 trials. Refer to Figure 1 for study flow diagram.

Included studies

We found 24 trials, with 28 active treatment arms, studying 58,040 patients, which met the inclusion criteria. Trials were only available to evaluate the effectiveness of four drug classes as first‐line drugs thiazides (19 trials in 39,713 patients), beta‐blockers (five trials in 19,313 patients), ACE inhibitors (three trials in 6002 patients), and calcium channel blockers (one trial in 4695 patients). Two trials evaluated thiazides as well as beta‐blockers versus placebo (MRC‐O 1992; MRC‐TMH 1985;); UKPDS 39 1998 evaluated beta‐blockers as well as ACE inhibitors versus placebo, and HYVET pilot 2003 evaluated thiazides as well as ACE inhibitors versus placebo, making 28 total comparisons from 24 trials. We did not identify any randomized controlled trials that compared first‐line alpha‐adrenergic blockers or angiotensin receptor blockers to placebo or untreated control group.

The average age of participants across all included trials was 62 years. Six trials were limited to patients over 60 years of age (EWPHE 1985; HYVET 2008; HYVET pilot 2003; Kuramoto 1981; MRC‐O 1992; SHEP 1991; SHEP‐P 1989; SYST‐EUR 1997). The age range in other trials was between 21 and 80 years. The mean age of patients from the four classes was: thiazide ‒ 61 years, beta‐blockers ‒ 56 years, ACE inhibitors ‒ 67 years, and calcium channel blockers ‒ 70 years.

Most participants were recruited from Western industrialized countries. Two trials did not report percentage of participants from different countries (HOPE HYP 2000; HYVET 2008). In 22 trials reporting recruitment of participants, 7750 (15.5%) were from USA, 32,907 (66%) from Europe; 3427 (6.9%) from Australia, and 91 (0.2%) from Japan. Females represented 45% of the population studied. Four trials included only men (OSLO 1986; VA‐I 1967; VA‐II 1970; VA‐NHLBI 1978) .

Fourteen trials did not report ethnicity (Barraclough 1973; Carter 1970; Dutch TIA 1993; EWPHE 1985; HOPE HYP 2000; HYVET 2008; HYVET pilot 2003; Kuramoto 1981; MRC‐TMH 1985; MRC‐O 1992; OSLO 1986; PATS 1996; SYST‐EUR 1997; TEST 1995). Ten trials reported ethnicity. African‐Americans comprised the following percentages in these trials: ATTMH 1980 (0%), HSCSG 1974 (80%), SHEP 1991 (13.8%), SHEP‐P 1989 (18%), UKPDS 39 1998 (7.6%), USPHSHCSG 1977 (28%), VA‐I 1967 ( 53.8%), VA‐II 1970 (42%), VA‐NHLBI 1978 (25%), and Wolff 1966 (89.6%).

The study population consisted of predominantly ambulatory patients recruited from the community, primary care centres, or hospital‐based clinics in 22 trials (57,982 patients, 99.7% of all patients included in this review). In the Kuramoto 1981 trial, 91 (0.2% of total) subjects were recruited from a home for the aged. Carter 1970 recruited 97 (0.3% of total) participants admitted to the hospital, who had survived an ischemic‐type major stroke.

In most trials, it was possible to determine whether the participants in the trials represented primary or secondary prevention. All trials excluded patients with angina and congestive heart failure, as these conditions would require use of antihypertensive drugs for reasons independent of their antihypertensive action. Some trials allowed patients with prior myocardial infarction or stroke, as long as they were not recent (e.g. within the previous three months). Thus, by determining the baseline prevalence of stroke and myocardial infarction, it was possible to calculate the percentage that represented secondary prevention. Three trials did not report prevalence of stroke or myocardial infarction, but it was likely low in these trials (Barraclough 1973; Kuramoto 1981; VA‐II 1970; 587 participants, (1.0% of total randomized participants). Six trials (11,157 patients) were primary prevention with less than 1% secondary prevention patients (ATTMH 1980 (0.4%); MRC‐O 1992 (0%); OSLO 1986 (0%); UKPDS 39 1998 (0%); USPHSHCSG 1977 (0%); and VA‐NHLBI 1978 (0%). Six trials (12,042 patients) were secondary prevention (Dutch TIA 1993 (100%); HOPE HYP 2000 (88%); HSCSG 1974 (96%); OSLO 1986 (0%); PATS 1996 (100%); and TEST 1995 (100%). Nine trials (34,041 patients) were mostly primary prevention patients (EWPHE 1985 (it was reported that the baseline prevalence of cardiovascular complications was 36% and these included conditions other than proven myocardial infarction and stroke); HYVET 2008 (12%); HYVET pilot 2003 (7%); MRC‐TMH 1985 (2.2%); SHEP 1991 (6.4%); SHEP‐P 1989 (5.5%); SYST‐EUR 1997 (reported as 30% patients with cardiovascular complications); VA‐I 1967 (7%);and Wolff 1966 (29%). The percentage of secondary patients in the 10 mostly primary prevention trials was 3212 (5.6%) of total randomized patients.

Thus, since 42,196 (72.7%) of total randomized people were primary prevention, the conclusions from this review are primarily relevant to the primary prevention setting.

Baseline prevalence of diabetes was reported in 8 trials as follows: HOPE HYP 2000 (38%); HYVET 2008 (7%); MRC‐O 1992 (0%); SHEP 1991 (10.1%); UKPDS 39 1998 (100%); USPHSHCSG 1977 (0%); VA‐I 1967 (9.1%); and Wolff 1966 (16.0%). Baseline prevalence of smoking was as follows: ATTMH 1980 (25.0%); EWPHE 1985 (16.0%); HYVET 2008 (6.5%); OSLO 1986 (41.7%); MRC‐TMH 1985 (28.5%); MRC‐O 1992 (36.0%); SHEP 1991 (13.0%); SHEP‐P 1989 (11.0%); SYST‐EUR 1997 (7.0%); UKPDS 39 1998 (22.3%); and USPHSHCSG 1977 (46.7%).

Recent trials defined stroke as the presence of neurological deficit lasting for more than 24 hours. It includes some patients with no disability. Older trials, like the HSCSG 1974, defined stroke as a neurological deficit lasting more than 24 hours, or a marked increase in transient ischemic attacks (twice the weekly pre‐randomization level of occurrence, more than four per week, or deterioration of more than eight points in neurological score). VA‐NHLBI 1978 defined stroke as typical weakness or paralysis. In some trials, stroke was not defined. In our opinion, lumping all strokes, including reversible ischemic neurological deficit (RIND), into one outcome is not optimal. More clinically relevant interpretations could be made if strokes were subdivided into three groups: strokes with no disability, strokes with mild disability, and strokes with severe disability. Myocardial infarction and sudden death were defined consistently across most trials. Myocardial infarction was defined as typical chest pain with ECG changes or increased cardiac enzymes; sudden death was defined as death within 24 hours of first evidence of acute cardiovascular disease, or unrelated to other known pre‐existing diseases.

Five trials restricted recruitment to persons with systolic hypertension; defined as systolic pressure 160 to 219 mmHg, and diastolic pressure less than 90 mmHg (SHEP 1991; SHEP‐P 1989), diastolic pressure less than 95 mmHg (SYST‐EUR 1997), or systolic pressure higher than 140 mmHg (TEST 1995), or higher than 160 mmHg (HYVET 2008). Six trials based entry on diastolic hypertension (Barraclough 1973; USPHSHCSG 1977; VA‐I 1967; VA‐II 1970; VA‐NHLBI 1978; Wolff 1966); and 10 trials based entry on either systolic or diastolic hypertension (ATTMH 1980; Carter 1970; EWPHE 1985; HSCSG 1974; HYVET pilot 2003; Kuramoto 1981; MRC‐TMH 1985; MRC‐O 1992; OSLO 1986; UKPDS 39 1998). HOPE HYP 2000 represented the subgroup of the HOPE trial that had a baseline blood pressure higher than 140 mmHg systolic, or higher than 90 mmHg diastolic. Two trials were included because more than 70% of patients at entry had a systolic BP higher than 140 mmHg (Dutch TIA 1993; PATS 1996).

Weighted mean baseline blood pressure for all the trials was 168/94 mmHg. When this was broken down into those that used systolic blood pressure as entry criteria, it was 173/84 mmHg; for those using diastolic pressure as entry criteria, it was 162/106 mmHg; and for those using both systolic and diastolic pressure as entry criteria, it was 167/97 mmHg. Two trials did not report baseline systolic pressure levels (Barraclough 1973;VA‐NHLBI 1978), and one trial did not report baseline diastolic pressure levels (VA‐NHLBI 1978).

For complete description of the blood pressure inclusion criteria for each study, see 'Participants' in the 'Characteristics of included studies' table.

A stepped approach to antihypertensive drug administration was used in 18 of the 24 trials. The exceptions were Dutch TIA 1993; HOPE HYP 2000; HSCSG 1974; PATS 1996; TEST 1995; and USPHSHCSG 1977, which used a standard dose of drug in the intervention arm. In 19 of the trials, a thiazide was the first‐line therapy in one of the arms of the trial. Because of a relatively large amount of data for thiazides, we were able to divide these 19 trials into those in which the thiazide starting dose was defined as low (8/19 trials, 874 patients) or high (11/19 trials, 19,839 patients), as explained in the methods. Three of the trials did not specify the thiazide dose, but were included in the high‐dose group because prescribing high doses of thiazides was common when those trials were conducted (Barraclough 1973; Carter 1970; OSLO 1986). The weighted mean dose of thiazide, in hydrochlorothiazide equivalents, was 90 mg for the high‐dose trials and 24 mg for the low‐dose trials. In five trials, a beta‐blocker was used as first‐line therapy in one of the arms of the trial (Dutch TIA 1993; MRC‐O 1992; MRC‐TMH 1985; TEST 1995; UKPDS 39 1998). Three trials used an angiotensin converting enzyme inhibitor, (HOPE HYP 2000; HYVET pilot 2003; UKPDS 39 1998). One trial used the calcium channel blocker nitrendipine (SYST‐EUR 1997). Second‐ and third‐line drugs included beta‐blockers, centrally‐acting drugs, peripherally‐acting anti‐adrenergic agents, vasodilators, thiazides, ACE inhibitors, alpha blockers, calcium channel blockers, and loop diuretics. See 'Interventions' in the 'Characteristics of included studies' table for a complete description of each study's drug treatment protocol.

Mean duration of follow‐up ranged from 1.1 years for the HYVET pilot 2003 trial to 10 years for the USPHSHCSG 1977 trial. The weighted average follow‐up was 4.1 years for the thiazide trials, 5.3 years for the beta‐blocker trials, 4.9 years for the ACE Inhibitor trials, and 2.5 years for the one calcium‐channel blocker trial.

Risk of bias in included studies

We assessed risk of bias for each included study using the Cochrane 'Risk of bias' tool for RCTs, described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). Potential parameters of methodological quality listed in the 'Risk of bias' table include: method used to randomize participants, whether randomization was completed in an appropriate and blinded manner; whether participants, providers, outcome assessors, or a combination of these, were blinded to assigned therapy; whether the control group received a placebo or no treatment; percent of participants who did not complete follow‐up (dropouts); percent of participants not on assigned active or placebo therapy at study completion; selective reporting of outcomes; and other bias, in terms of funding of the trial by the manufacturer.

Refer to Figure 2 for the 'Risk of bias' graph, which provides review authors' judgements about each risk of bias item, presented as percentages across all included studies. Refer to Figure 3 for the 'Risk of bias' summary, which provides review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5

Summary of findings for the main comparison

First‐line low‐dose thiazide compared to placebo for hypertension

Summary of findings 2

First‐line high‐dose thiazide compared to placebo for hypertension

Summary of findings 3

First‐line beta‐blocker compared to placebo for hypertension

Summary of findings 4

First‐line angiotensin converting enzyme inhibitor compared to placebo for hypertension

Summary of findings 5

First‐line calcium channel blocker compared to placebo for hypertension

Refer to five Summary of findings tables: Table 1; Table 2; Table 3; Table 4; Table 5.

Primary outcomes by drug class

Thiazides

Because of the large number of trials, and the high heterogeneity in the effect between low dose and high dose thiazides on coronary heart disease events, we presented data for the two subgroups only, and not overall results for all thiazides.

Low‐dose thiazides

First‐line low‐dose thiazide significantly reduced all the primary outcomes: mortality (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.82 to 0.97; N = 19874; RCTs = 8; I² = 0%; Analysis 1.1), stroke (RR 0.68, 95% CI 0.60 to 0.77; N = 19874; RCTs = 8; I² = 0%; Analysis 1.2), coronary heart disease (RR 0.72, 95% CI 0.61 to 0.84; N = 19,022; RCTs = 7; I² = 0%; Analysis 1.3), and total cardiovascular events (RR 0.70, 95% CI 0.64 to 0.76; N = 19,022; RCTs = 7; I² = 0%; Analysis 1.4). The SHEP 1991 trial was the only one that reported total hospitalizations, an acceptable measure of total serious adverse events. It showed a numerical reduction with treatment (RR 0.95, 95% CI 0.89 to 1.01, N = 4736; RCT = 1; Analysis 1.5).

Analysis

Comparison 1 First‐line thiazide vs placebo, Outcome 1 Total mortality.

Analysis

Comparison 1 First‐line thiazide vs placebo, Outcome 2 Total stroke.

Analysis

Comparison 1 First‐line thiazide vs placebo, Outcome 3 Total coronary heart disease.

Analysis

Comparison 1 First‐line thiazide vs placebo, Outcome 4 Total cardiovascular events.

Analysis

Comparison 1 First‐line thiazide vs placebo, Outcome 5 Total hospitalizations.

High‐dose thiazides

First‐line high‐dose thiazide, in contrast, significantly reduced stroke (RR 0.47, 95% CI 0.37 to 0.61; N = 19,839; RCTs = 11; I² = 46%; Analysis 1.2), and total cardiovascular events (RR 0.72, 95% CI 0.63 to 0.82; N = 19,839; RCTs = 11; I² = 35%; Analysis 1.4), but not mortality (RR 0.90, 95% CI 0.76 to 1.05; N = 19,839; RCTs = 11; I² = 21%; Analysis 1.1), or coronary heart disease (RR 1.01, 95% CI 0.85 to 1.20; N = 19,839; RCTs = 11; I² = 0%; Analysis 1.3).

Beta‐blockers

First‐line beta‐blockers reduced stroke (RR 0.83, 95% CI 0.72 to 0.97; N = 19313; RCTs = 5; I² = 7%; Analysis 2.2), and total cardiovascular events (RR 0.89, 95% CI 0.81 to 0.98; N = 19313; RCTs = 5; I² = 54%; Analysis 2.4), but not mortality (RR 0.96, 95% CI 0.86 to 1.07; N = 19313; RCTs = 5; I² = 25%; Analysis 2.1), or coronary heart disease (RR 0.90, 95% CI 0.78 to 1.03; N = 19313; RCTs = 5; I² = 4%; Analysis 2.3).

Analysis

Comparison 2 First‐line beta‐blocker vs placebo, Outcome 1 Total mortality.

Analysis

Comparison 2 First‐line beta‐blocker vs placebo, Outcome 2 Total stroke.

Analysis

Comparison 2 First‐line beta‐blocker vs placebo, Outcome 3 Total coronary heart disease.

Analysis

Comparison 2 First‐line beta‐blocker vs placebo, Outcome 4 Total cardiovascular events.

Angiotensin converting enzyme (ACE) inhibitors

First‐line ACE inhibitors reduced mortality (RR 0.83, 95% CI 0.72 to 0.95; N = 6002; RCTs = 3; I² = 0%; Analysis 3.1), stroke (RR 0.65, 95% CI 0.52 to 0.82; N = 6002; RCTs = 3; I² = 0%; Analysis 3.2), coronary heart disease (RR 0.81, 95% CI 0.70 to 0.94; N = 5145; RCTs = 2; I² = 0%; Analysis 3.3), and total cardiovascular events (RR 0.76, 95% CI 0.67 to 0.85; N = 5145; RCTs = 2; I² = 0%; Analysis 3.4).

Analysis

Comparison 3 First‐line ACE inhibitor vs Placebo, Outcome 1 Total mortality.

Analysis

Comparison 3 First‐line ACE inhibitor vs Placebo, Outcome 2 Total stroke.

Analysis

Comparison 3 First‐line ACE inhibitor vs Placebo, Outcome 3 Total coronary heart disease.

Analysis

Comparison 3 First‐line ACE inhibitor vs Placebo, Outcome 4 Total cardiovascular events.

Calcium channel blockers

First‐line calcium channel blockers reduced stroke (RR 0.58, 95% CI 0.41 to 0.84; N = 4695; RCT = 1; Analysis 4.2), and total cardiovascular events (RR 0.71, 95% CI 0.57 to 0.87; N = 4695; RCT = 1; Analysis 4.4), but not mortality (RR 0.86, 95% CI 0.68 to 1.09; N = 4695; RCT = 1; Analysis 4.1), or coronary heart disease (RR 0.77, 95% CI 0.55 to 1.09; N = 4695; RCT = 1; Analysis 4.3).

Analysis

Comparison 4 First‐line calcium channel blocker vs Placebo, Outcome 1 Total mortality.

Analysis

Comparison 4 First‐line calcium channel blocker vs Placebo, Outcome 2 Total stroke.

Analysis

Comparison 4 First‐line calcium channel blocker vs Placebo, Outcome 3 Total coronary heart disease.

Analysis

Comparison 4 First‐line calcium channel blocker vs Placebo, Outcome 4 Total cardiovascular event.

Secondary outcomes

Reduction in systolic and diastolic blood pressure

Antihypertensive drug therapy significantly lowered both systolic and diastolic blood pressure, compared to the control group. Please refer to Table 6 for details.

1

Blood pressure lowering efficacy with different drug classes

First‐line low‐dose thiazides, compared to placebo or no treatment, decreased systolic blood pressure (mean difference (MD) ‐12.56, 99% CI ‐13.22 to ‐11.91; N = 18,685; RCTs = 8; I² = 98%; Analysis 1.7), and diastolic blood pressure (MD ‐4.73, 99% CI ‐5.12 to ‐4.34; N = 18,685; RCTs = 8; I² = 98%; Analysis 1.8).

Analysis

Comparison 1 First‐line thiazide vs placebo, Outcome 7 Systolic blood pressure.

Analysis

Comparison 1 First‐line thiazide vs placebo, Outcome 8 Diastolic blood pressure.

First‐line high‐dose thiazides, compared to placebo or no treatment, decreased systolic blood pressure (MD ‐13.66, 99% CI ‐14.40 to ‐12.91; N = 14,906; RCTs = 6; I² = 98%; Analysis 1.7), and diastolic blood pressure (MD ‐6.82, 99% CI ‐7.24 to ‐6.41; N = 19,347; RCTs = 10; I² = 97%; Analysis 1.8).

First‐line beta‐blockers, compared to placebo or no treatment, reduced systolic blood pressure (MD ‐9.51, 99% CI ‐10.16 to ‐8.85; N = 18,833; RCTs = 5; I² = 92%; Analysis 2.6), and diastolic blood pressure (MD ‐5.64, 99% CI ‐6.06 to ‐5.22; N = 18,833; RCTs = 5; I² = 89%; Analysis 2.7).

Analysis

Comparison 2 First‐line beta‐blocker vs placebo, Outcome 6 Systolic blood pressure.

Analysis

Comparison 2 First‐line beta‐blocker vs placebo, Outcome 7 Diastolic blood pressure.

First‐line ACE Inhibitors, compared to placebo or no treatment, decreased systolic blood pressure (MD ‐21.14, 99% CI ‐23.13 to ‐19.15; N = 1071; RCTs = 2; I² = 98%; Analysis 3.5), and diastolic blood pressure (MD ‐9.64, 99% CI ‐10.70 to ‐8.58; N = 1071; RCTs = 2; I² = 98%; Analysis 3.6).

Analysis

Comparison 3 First‐line ACE inhibitor vs Placebo, Outcome 5 Systolic blood pressure.

Analysis

Comparison 3 First‐line ACE inhibitor vs Placebo, Outcome 6 Diastolic blood pressure.

First‐line calcium‐channel blockers, compared to placebo or no treatment, reduced systolic blood pressure (MD ‐8.90, 99% CI ‐10.14 to ‐7.66; N = 4695; RCT = 1; Analysis 4.6), and diastolic blood pressure (MD ‐4.50, 99% CI ‐5.10 to ‐3.90; N = 4695; RCT = 1; Analysis 4.7).

Analysis

Comparison 4 First‐line calcium channel blocker vs Placebo, Outcome 6 Systolic blood pressure.

Analysis

Comparison 4 First‐line calcium channel blocker vs Placebo, Outcome 7 Diastolic blood pressure.

For each class of drugs, the blood pressure data were heterogeneous, however the effects remained highly significant, using the random‐effects model. Because of the high heterogeneity, and the fact that in many trials, other drugs were allowed, we did not think this was an accurate reflection of the blood pressure lowering effect of the first‐line drug. For the same reason, we did not present these data in the 'Summary of findings' tables, and no attempt was made to indirectly compare the different drugs for blood pressure.

Withdrawal due to adverse effects

This outcome was not reported in most of the trials. Where it was reported, drug therapy increased withdrawals due to adverse effects, compared to placebo or no treatment: low‐dose thiazides (RR 2.38, 95% CI 2.06 to 2.75; N = 8870; RCTs = 3; I² = 96%; Analysis 1.6), high‐dose thiazides (RR 4.48, 95% CI 3.83 to 5.24; N = 15,170; RCTs = 7; I² = 31%; Analysis 1.6), and beta‐blockers (RR 4.59, 95% CI 4.11 to 5.13; N = 18,565; RCTs = 4; I² = 96%; Analysis 2.5).

Analysis

Comparison 1 First‐line thiazide vs placebo, Outcome 6 Withdrawal due to adverse effects.

Analysis

Comparison 2 First‐line beta‐blocker vs placebo, Outcome 5 Withdrawal due to adverse effects.

Because many of the trials did not report this outcome, and there was high heterogeneity between trials that did, we judged these data to have a high risk of bias. We could not calculate this information for the calcium channel blocker therapy, because withdrawals due to adverse drug effects were not reported in the SYST‐EUR 1997 trial, and authors declined to provide the information when requested. We could not use the data from the only ACE inhibitor trial that reported withdrawals due to adverse effects, as the untreated control group was not blinded (UKPDS 39 1998).

Discussion

Summary of main results

This review, with a large amount of thiazide trial data (19 randomized controlled trials (RCTs), 39,713 participants), demonstrates the benefits of starting with a low‐dose thiazide as first‐line therapy for elevated blood pressure. The pooled data showed a reduction in total mortality when using a thiazide as the first‐line choice, and suggested that as first‐line therapy, low‐dose thiazide, reduced coronary heart disease events, whereas high‐dose thiazide did not.

Five RCTs used a first‐line beta‐blocker (19,313 participants), and provided enough data to compare with first‐line thiazides. Analyses suggested that beta‐blockers reduced total stroke and total cardiovascular events less than all thiazides, and they reduced coronary heart disease less than a first‐line low‐dose thiazide. It is important to note that in four of the five beta‐blocker trials, atenolol was the beta‐blocker used. It is possible that the reduced effectiveness of first‐line beta blockers was limited to atenolol.

First‐line angiotensin converting enzyme (ACE) inhibitors, in three RCTs and a smaller population (6002 participants), were associated with similar benefits, but wider confidence intervals than first‐line low‐dose thiazides for all outcomes.

The amount of data for first‐line calcium channel blockers in one trial (4695 participants) was insufficient to make any meaningful comparisons; this can be appreciated by noting the wide confidence intervals associated with the treatment effects for this drug class (SYST‐EUR 1997).

Relative risk (risk ratio) is the best way to indirectly compare the effectiveness between different drug classes. When we compared risk ratios (RR), beta blockers (RR 0.89, 95% confidence interval (CI) 0.81 to 0.98) appeared to be less effective than low‐dose thiazides (RR 0.70, 95% CI 0.64 to 0.76) in reducing total cardiovascular events. First‐line ACE inhibitors (RR 0.76, 95% CI 0.67 to 0.85), and calcium channel blockers (RR 0.71, 95% CI 0.57 to 0.87), had less data, but could not be distinguished from low‐dose thiazides for the effect on total cardiovascular events, or other outcomes.

However, for the patient, it is more meaningful to have a measure of the absolute risk reduction (ARR) over a specified period of time. We calculated this summary measure for total cardiovascular events for the four drug classes in three clinical settings, where it was possible: secondary prevention, primary prevention (moderate to severe hypertension), and primary prevention (mild to moderate hypertension).

Secondary prevention: For the three secondary prevention trials using thiazides, and the one secondary trial using an ACE inhibitor, the average baseline blood pressure was approximately 155/94 mmHg. The average total cardiovascular event rate was 23.1% over five years in the control group, and the RR with treatment was 0.76. Therefore, the ARR over five years was 5.5% (23.1 X 0.24). For the two secondary prevention beta‐blocker trials, there was no clear reduction in total cardiovascular events (RR 1.01, 95% CI 0.84 to 1.21). There were no secondary prevention trials that used calcium channel blockers.

Primary prevention (moderate to severe hypertension): For the seven low‐dose thiazide trials in this category, the baseline systolic blood pressure was 175 mmHg, and the average total cardiovascular event rate over five years in the control groups was 16%. The RR with treatment was 0.68, for an ARR over five years of 5.1% (16 X 0.32). This is similar to the 5.5% calculated for secondary prevention. For the two beta‐blocker trials in this category, there was no significant reduction in total cardiovascular events (RR 0.88, 95% CI 0.71 to 1.02). In the one calcium channel blocker trial, the ARR over five years was 4.6% (16 X 0.29), and in the one ACE inhibitor trial, the estimated ARR over five years was 3.7% (16 X 0.23; UKPDS 39 1998).

Primary prevention (mild to moderate hypertension): There were five first‐line high‐dose thiazide trials in this category, with an average baseline systolic blood pressure of 160 mmHg. In these five trials, the average cardiovascular event rate in the control group over five years was 4.1%. The RR with first‐line high‐dose thiazide treatment was 0.80 (95% CI 0.69 to 0.94), and the ARR over five years was 0.82% (4.1 X 0.2). For the one beta‐blocker trial in this category, the RR with treatment was 0.82, and the ARR over five years was 0.74% (4.1 X 0.18).

This demonstrates that the absolute benefits are at least as good for first‐line low dose thiazides as the other classes of antihypertensives. The number needed to treat for an additional beneficial outcome (NNTB) for a low‐dose thiazide in moderate to severe hypertension (average systolic 175 mmHg) is about 20 over a five‐year duration. The NNTB was only a little lower in a secondary prevention setting, though the baseline blood pressures (average systolic 155 mmHg) were also lower.

Notably, the NNTB was much higher, about 120 over five years, for primary prevention patients with mild to moderate hypertension. The low absolute benefit in individuals with lower blood pressure at baseline reflected two differences: the lesser relative benefit of a RR of 0.8 versus a RR of 0.7, and the lower five‐year event rate in the control groups of 4%. One of the limitations of this analysis was that the first‐line drug used in this population was a high‐dose thiazide, which the evidence suggests is not as effective. It is possible that using a low‐dose thiazide in these trials would have improved the benefit to a RR of 0.7. However, even if that was true, the absolute benefit would still be small (ARR = 1.2%; NNTB 83 over five years). The low absolute benefit of antihypertensive therapy for mild to moderate elevations in blood pressure in primary prevention needs to be reflected by authors of hypertension guidelines.

Many of the patients in these trials also had co‐morbidities, such as diabetes mellitus. In this review, it was not possible to assess these patients separately, but SHEP 1991 analyzed their diabetes subgroup, and found the relative benefit was the same, and the absolute benefit was greater in diabetic patients than in non‐diabetic patients.

Overall completeness and applicability of evidence

Since 72.7% of participants in this review were primary prevention, the data are primarily relevant to a primary prevention population. Three of the included first‐line thiazide trials included participants with a prior stroke or transient ischemic attack (TIA; (Carter 1970; HSCSG 1974; PATS 1996)). When we deselected these trials from the thiazide analyses, the treatment effect estimates did not change. When we deselected all trials in which the baseline prevalence of myocardial infarction was either not reported (Barraclough 1973; Kuramoto 1981; MRC‐O 1992; VA‐II 1970), or was greater than 10% (Carter 1970; EWPHE 1985; HSCSG 1974; Wolff 1966), the treatment effect for total cardiovascular events was not different. For first‐line ACE inhibitors, HOPE HYP 2000 was predominantly secondary prevention, and the relative benefit with treatment was similar to the other two primary prevention trials (HYVET pilot 2003; UKPDS 39 1998).

For sensitivity analyses, we deselected trials that were not placebo controlled and blinded, trials that were restricted to patients with isolated systolic hypertension, small trials, and trials using supplemental drugs from other defined classes. In all of these instances, there was no clinically important change in the treatment effect estimate.

The data on withdrawals due to adverse effects were incomplete and heterogeneous. Therefore, it was difficult to compare the different drug classes for this outcome. However, there was nothing to suggest that other classes of drugs were better tolerated than first‐line low‐dose thiazides.

The blood pressure data in this systematic review were heterogeneous. This was because the number of drugs used in the trials differed, and only 16 of the 24 trials were double‐blinded. Blood pressure measurements are subject to bias if the observer and the patient know what is being administered. Because of these factors, it was not possible to use the blood pressure data to assess the blood pressure lowering efficacy of the different classes of drugs, or to compare low‐dose and high‐dose first‐line thiazides.

There is growing evidence that the surrogate marker ‐ the lowering of blood pressure ‐ is inadequate to predict health outcomes with antihypertensive therapy. Despite similar reductions in blood pressure, we found that first‐line low‐dose and high‐dose thiazide therapy had different impacts on the incidence of coronary heart disease.

In the 15 of the 24 trials where it could be assessed, despite dose titration and the addition of supplemental drugs, about 40% of the patients did not achieve the target blood pressure. Four trials reported that 34% of the patients did not achieve the target systolic pressure of less than 160 mm Hg (Kuramoto 1981; MRC‐O 1992; SHEP 1991; SHEP‐P 1989). In two trials, over 50% did not achieve the target systolic pressure of less than 150 mmHg (HYVET 2008; HYVET pilot 2003). The other nine trials reported that 40% of the patients did not achieve the target diastolic pressure of less than 90 mmHg (ATTMH 1980; EWPHE 1985; HSCSG 1974; MRC‐TMH 1985; OSLO 1986; USPHSHCSG 1977; VA‐I 1967; VA‐II 1970; Wolff 1966). This observation is extremely important clinically, as it means that physicians can only expect to achieve blood pressure targets in about 60% of the patients they treat. However, this does not mean that the patients who do not achieve the target will benefit less than those who do, as blood pressure reduction is only partly responsible for the risk reduction from antihypertensive treatment (Boissel 2005).

The evidence showed that starting with a low dose of thiazide, and only titrating up if necessary, significantly reduced the risk of coronary heart disease. In contrast, starting with a high dose (50 mg of hydrochlorothiazide or the equivalent) did not. Since the high‐dose therapy has no proven advantages, there is no justification for using high doses, or for comparing low‐dose and high‐dose thiazide therapies in a future trial. Therefore, the current recommendation for the use of thiazides in the management of hypertension is justifiable, based on the evidence presented here: start with a low dose (12.5 mg hydrochlorothiazide, or the equivalent), increase the dose if necessary, and do not exceed a dose of 50 mg of hydrochlorothiazide, or the equivalent.

The fact that thiazides are similarly, or more effective than other drug classes in reducing mortality and morbidity, and that the evidence is most robust for thiazides, is reason by itself to prescribe them first for most patients with hypertension. The value of this approach is further supported by the fact that of the drug classes studied, the thiazides are the least expensive drug class in most countries. If more than one thiazide or thiazide‐like drug is available, then the least expensive one is the most rational choice.

Additional information supporting the use of thiazides was recently published by Puttnam 2017. By using data from a national database, a post‐trial cohort surveillance study of the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack trial (ALLHAT) examined whether the use of thiazide diuretics for the treatment of hypertension was associated with reduced risk of fracture, compared with non‐use. ALLHAT was a large randomized clinical trial that compared the effect of first‐step therapy with different classes of antihypertensive drug therapy (chlorthalidone, amlodipine, and lisinopril) in preventing fatal coronary heart disease (CHD), nonfatal myocardial infarction (primary outcome), or other cardiovascular disease (CVD) events. Hospitalized hip and pelvic fractures were chosen as endpoints, because they are almost always associated with hospitalization. A total of 22,180 participants, with a mean age of 70.4 years, were followed for up to eight years (mean 4.9 years) during masked therapy. Participants randomized to receive chlorthalidone versus amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio (HR) 0.79, 95% CI 0.63 to 0.98; P = 0.04). The authors concluded that "findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide‐type diuretic therapy in reducing hip and pelvic fracture compared with treatment with other antihypertensive medications".

Quality of the evidence

We graded the overall quality of the evidence and developed 'Summary of findings' tables, using GRADEpro GDTsoftware (GRADEpro GDT).

We created five 'Summary of findings' tables to display the quality of evidence and summary of the effects on clinically important outcomes, for first‐line low‐dose thiazides (Table 1), high‐dose thiazides (Table 2), beta‐blockers (Table 3), ACE inhibitors (Table 4), and calcium channel blockers (Table 5).

We found high‐quality evidence that first‐line low‐dose thiazides reduced mortality, stroke, CHD, and total cardiovascular events more than placebo. We found moderate‐quality evidence that high‐dose thiazides reduced stroke, and CVS events more than placebo, and low‐quality evidence that first‐line high‐dose thiazides did not reduce CHD more than placebo.

We found low‐quality evidence that beta‐blockers reduced stroke, and total cardiovascular events more than placebo.

We found moderate‐quality evidence that ACE inhibitors reduced mortality and total CVS events, and low‐quality evidence that they reduced stroke and CHD more than placebo.

We found low‐quality evidence that calcium channel blockers reduced mortality, stroke, CHD, and CVS events more than placebo.

We found low‐quality evidence that thiazides and beta‐blockers caused more participants to withdraw from the trials due to adverse effects than those who took placebo.

We found low‐ to very low‐quality evidence that all four drug classes reduced systolic and diastolic blood pressure.

Potential biases in the review process

A potential limitation of attributing the benefit predominantly to the first‐line thiazide is the fact that in some of the thiazide trials, the first‐line therapy included the thiazide combined with another drug. In two trials, the first‐line therapy was a combination of a thiazide plus a potassium sparing diuretic (EWPHE 1985; MRC‐O 1992). Deselecting these two trials had no impact on the treatment effect. In five trials, a reserpine derivative was combined with the thiazide as first‐line therapy (HSCSG 1974; USPHSHCSG 1977; VA‐I 1967; VA‐II 1970; Wolff 1966. When these five trials were deselected, the treatment effect did not change either. Therefore, the data for first‐line thiazides appear robust, and the benefits achieved are most likely attributable to the first‐line thiazide therapy.

Agreements and disagreements with other studies or reviews

It is important in this type of analysis not to include trials in which there is significant contamination by drugs from other drug classes of interest. In our opinion, Psaty 1997 incorrectly included the trial by Coope 1986 and the STOP 1991 trial in their beta‐blocker group. In the trial by Coope 1986, 67% of patients in the active treatment group received bendrofluazide, and 70% received atenolol; in the STOP 1991 trial, more than 70% in the active treatment group received thiazides and more than 70% received beta‐blockers. Therefore, in those two trials, the treatment effect could not be attributed to first‐line thiazides or first‐line beta‐blockers. Other minor differences in the trials in this review and that by Psaty 1997 are as follows. We classified Kuramoto 1981 as a low‐dose trial, and they classified it as high‐dose trial. It fit into our low‐dose category, based on the starting dose of 1 mg of trichlormethiazide. Moving the trial from the low‐dose to the high‐dose group did not change our findings. Unlike Psaty 1997, we excluded the Hypertension Detection and Follow‐up Program trial because it did not have an untreated control group, and the intervention group was treated with life‐style therapies in addition to drug therapy (HDFP 1984). We included one small trial by Wolff 1966, not referenced by Psaty 1997. This trial was also included in the meta‐analysis in Collins 1990 and in Gueyffier 1996, The meta‐analysis by the blood pressure trialists group was incomplete and misleading because of their decision to exclude all trials prior to 1995 (BBLTTC 2005).

The network meta‐analysis included most of the trials comparing treatment versus placebo or no treatment that were included in this review (Psaty 2003). However, they again incorrectly included two trials in their beta‐blocker group (Coope 1986; STOP 1991), and in our opinion, inappropriately included PROGRESS 2001, IDM 2001, and Lewis 2001 as evidence for first‐line treatment in hypertension, when most patients did not have hypertension. Most importantly, this review includes four trials not included in the Psaty 2003 review (HOPE HYP 2000; HYVET pilot 2003; UKPDS 39 1998).

Our reasons for classifying UKPDS 39 1998 in this review deserve mention. First, in UKPDS 39 1998, the treatment target for the control group was over 200/105 mmHg for the first five years, after which it was lowered to over 180/105 mmHg. This was similar to the escape therapy in other trials that classified the control group as no treatment. For example, in the OSLO 1986 trial, drug treatment in the control group was started if blood pressure exceeded 179/109 mmHg and was sustained. Second, the UKPDS 39 1998 target in the intervention group (less than 150/85 mmHg) was very similar to the targets in the intervention groups of the included studies in this review (less than 140 to 160/less than 80 to 90 mmHg). Third, the difference in blood pressure achieved between the treatment and control group over the nine years of the trial (10 to 11/4 to 6 mmHg) is similar to the difference in BP for other included trials in this review (9 to 12/3 to 6 mmHg; (ATTMH 1980; Kuramoto 1981; MRC‐TMH 1985; SYST‐EUR 1997)).

Wiysonge 2017 also included UKPDS 39 1998 in their beta‐blocker review, published in 2007. In contrast to Wiysonge 2017, we did not include IPPPSH 1985 as representing first‐line beta blockers, as more than 65% of the patients also received a thiazide. We did include Dutch TIA 1993 and TEST 1995, which Wiysonge 2017 did not. Other reviews did not include HOPE HYP 2000, as the data separated for the hypertensive group had not been published. We are thankful to the authors of HOPE for providing these data. The HYVET pilot 2003 trial and the HYVET 2008 trial are more recent trials included in our review. Despite these differences, the conclusions and interpretation of the findings in this review are concordant with Psaty 2003, who concluded that thiazides were the first‐line drug of choice, and Wiysonge 2017, who concluded that beta‐blockers were not an appropriate first‐line drug choice. Refer to Table 7 for further details.

2

First‐line beta‐blocker compared to placebo. Comparison of this review with Wysonge 2017

The recent Taverny 2016 review assessed the effects of antihypertensive pharmacotherapy on three separate cardiac outcomes ‐ sudden cardiac death, fatal myocardial infarction, and nonfatal myocardial infarction in hypertensive individuals. In our review, these three outcomes were combined as total CHD events. In Taverny 2016, based on 15 randomized placebo‐controlled trials, in 39,908 patients, for a mean duration of 4.2 years, moderate‐quality evidence showed that antihypertensive therapy did not reduce sudden cardiac death (RR 0.96, 95% CI 0.81 to 1.15), but did reduce both nonfatal myocardial infarction (RR 0.85, 95% CI 0.74 to 0.98), and fatal myocardial infarction (RR 0.75, 95% CI 0.62 to 0.90). However, they did not report results separately for specific first‐line antihypertensive drug classes. Withdrawals due to adverse effects were increased in the drug treatment group to 12.8%, compared with 6.2% in the no treatment group. A Cochrane review, Pharmacotherapy for mild hypertension, has been published and is being updated (Diao 2012). A systematic review, Pharmacotherapy for hypertension in adults (18 to 59 years), has recently been published (Musini 2017). The Cochrane review, Pharmacotherapy for hypertension in the elderly (60 years or older), is being updated (Musini 2009).

Since more trials comparing drug therapy with a placebo or no treatment are unlikely to be forthcoming, future evidence of effectiveness of first‐line therapy will need to come from head‐to‐head comparisons. Two Cochrane reviews have compared first‐line calcium channel blockers (Chen 2010) and first‐line drugs inhibiting the renin angiotensin system (Xue 2015) with first‐line thiazides. These reviews confirm the likely morbidity benefits of first‐line thiazides. We are also currently working on a meta‐analysis of head‐to‐head trials in a separate systematic review. That review will focus on head‐to‐head trials comparing first‐line thiazides with other classes of drugs (Reinhart 2011).

Authors' conclusions

Implications for practice

Choice of first‐line treatment versus placebo or no treatment: the evidence for morbidity and mortality.

• Most of the available evidence justifying treatment of patients with elevated blood pressure used a thiazide as the first‐line drug.

• First‐line low‐dose thiazides were more effective than first‐line high‐dose thiazides and first‐line beta‐blockers.

• The treatment effect for first‐line ACE inhibitors was similar to low‐dose thiazides but less robust, and ACE inhibitors are more expensive than thiazides.

• Evidence for effectiveness of first‐line calcium channel blockers was insufficient.

• There were no RCTs comparing first‐line use of angiotensin receptor blockers or alpha blockers.

• Morbidity and mortality benefit with antihypertensive treatment depended on the drug class received, not the blood pressure achieved.

Blood pressure measurement.

• Blood pressure must be measured (average of multiple readings) using proper technique, with the patient non‐stimulated and resting for at least five minutes.

Population.

• Secondary prevention, survivors of transient ischemic attacks, stroke, or myocardial infarction, aged 55 to 80 years, with an average blood pressure of 155/94 mmHg (five‐year ARR 5.5%) (Moderate quality evidence).

• Primary prevention in adult patients with moderate to severe hypertension, with an average systolic blood pressure of 175 mmHg (five‐year ARR 5.1%) (High quality evidence).

• Primary prevention in adult patients with mild to moderate hypertension, with an average systolic blood pressure of 160 mmHg (five‐year ARR 0.8% to 1.2%) (Low quality evidence).

• Blood pressure targets are only achieved in about 60% of patients with mild, moderate, and severe hypertension treated with stepped‐care antihypertensive drugs.

Implications for research

At the present time, RCT data for antihypertensives as first‐line treatment versus placebo or no treatment are lacking for all classes other than thiazides. Since we have clear evidence of effectiveness of first‐line low‐dose thiazides in primary prevention, patients with blood pressure of 160/100 mmHg or higher, and in secondary prevention, in patients with lower blood pressures, it would be unethical to do further trials for this population compared to a placebo or untreated control group. Future RCTs in these populations should be done with low‐dose first‐line thiazides as the comparison group. The benefits and harms of primary prevention treatment of patients with lower blood pressures remains uncertain at the present time. Large trials recruiting primary prevention patients in lower blood pressure categories and using first‐line low‐dose thiazides compared to placebo are needed.

Feedback

Was Kuramoto study randomized?, 17 April 2014

Summary

In the table of included studies, the Cochrane review authors state that the included study by Kuramoto, a Japanese study is a randomised, double‐blind placebo‐controlled trial conducted in Japan. Internal validity, risk of bias for allocation is low risk.

It appears to me that the Kuramoto study may not have been randomized, but is a matched case control study.

I agree with the conflict of interest statement below:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

Thank you for your comment. Kuramoto 1981 study is a placebo‐controlled single site study conducted in ambulatory patients in home for the aged in Tokyo, Japan. This study was included as a randomised study in the "Pharmacotherapy for hypertension in the elderly" original review by Mulrow 1998 based on unpublished information as per personal conversation with study author. Mulrow 1998 review stated that "Allocation of individuals within matched pairs to treatment and control groups was made by a blinded statistical coordinator, thought to be randomised but not entirely clear. Both patients and providers were blinded." Based on this information from Mulrow 1998 review we have decided to include this study and reassessed the risk of bias for the two domains ‐ allocation concealment and blinding of patient and physician as "Low risk" of bias.

Contributors

Kirsty Loudon, PhD Student

Affiliation: University of Dundee

What's new

History

Protocol first published: Issue 4, 1999
Review first published: Issue 3, 2009

Acknowledgements

We would like to thank Stephen Adams for finding references and Ciprian Jauca for assistance with formatting and copy‐editing.

Appendices

Appendix 1. Search strategies

Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies (CRS‐Web)
Search Date: 24 November 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 (loop OR ceiling) NEXT (diuretic OR diuretics) AND INSEGMENT
#2 (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 or thiazides) AND INSEGMENT
#3 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide) AND INSEGMENT
#4 #1 OR #2 OR #3 AND INSEGMENT
#5 "angiotensin converting enzyme" NEXT inhibit* AND INSEGMENT
#6 ace NEAR3 inhibit* AND INSEGMENT
#7 acei AND INSEGMENT
#8 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril* or perindopril or pivopril or quinapril or ramipril or ramiprilat or rentiapril or saralasin or s nitrosocaptopril or spirapril or temocapril or teprotide or trandolapril or utibapril or zabicipril or zofenopril) AND INSEGMENT
#9 #5 OR #6 OR #7 OR #8 AND INSEGMENT
#10 angiotensin NEAR3 (receptor antagonist* OR receptor block*) AND INSEGMENT
#11 (arb OR arbs) AND INSEGMENT
#12 (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) AND INSEGMENT
#13 #10 OR #11 OR #12 AND INSEGMENT
#14 (amlodipine or amrinone or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil) AND INSEGMENT
#15 calcium NEAR2 (antagonist* OR block* OR inhibit*) AND INSEGMENT
#16 #14 OR #15 AND CENTRAL:TARGET
#17 (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):ti,ab,kw AND CENTRAL:TARGET
#18 (reserpine or serpentina or rauwolfia or serpasil):ti,ab,kw AND CENTRAL:TARGET
#19 (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) AND INSEGMENT
#20 (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) AND INSEGMENT
#21 #17 OR #18 OR #19 OR #20 AND INSEGMENT
#22 (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) AND INSEGMENT
#23 beta NEAR2 (adrenergic or antagonist or antagonists or blocker or blockers or blocking or receptor or receptors) AND INSEGMENT
#24 #22 OR #23 AND INSEGMENT
#25 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin) AND INSEGMENT
#26 adrenergic NEAR2 (alpha OR antagonist OR antagonists) AND INSEGMENT
#27 (adrenergic or alpha or receptor or receptors) NEAR2 (blocker or blockers or blocking) AND INSEGMENT
#28 #25 OR #26 OR #27 AND INSEGMENT
#29 #4 OR #9 OR #13 OR #16 OR #21 OR #24 OR #28 AND INSEGMENT
#30 hypertens* AND INSEGMENT
#31 (elevate* OR high* OR rais*) NEAR2 blood pressure AND INSEGMENT
#32 #30 OR #31 AND INSEGMENT
#33 RCT:DE AND INSEGMENT
#34 Review:MISC2 AND INSEGMENT
#35 #33 OR #34 AND INSEGMENT
#36 #29 AND #32 AND #35 AND INSEGMENT
#37 #36 AND (23/01/2017_TO_24/11/2017:CRSCREATED) AND INSEGMENT

***************************

Database: Cochrane Central Register of Controlled Trials via Cochrane Register of Studies (CRS‐Web)
Search Date: 24 November 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 MESH DESCRIPTOR Thiazides EXPLODE ALL AND CENTRAL:TARGET
#2 MeSH DESCRIPTOR Sodium Chloride Symporter Inhibitors EXPLODE ALL AND CENTRAL:TARGET
#3 MeSH DESCRIPTOR Sodium Potassium Chloride Symporter Inhibitors EXPLODE ALL AND CENTRAL:TARGET
#4 ((loop or ceiling) next (diuretic or diuretics)):ti,ab AND CENTRAL:TARGET
#5 (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 or thiazides):ti,ab AND CENTRAL:TARGET
#6 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide):ti,ab AND CENTRAL:TARGET
#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6 AND CENTRAL:TARGET
#8 MeSH DESCRIPTOR Angiotensin‐Converting Enzyme Inhibitors EXPLODE ALL AND CENTRAL:TARGET
#9 "angiotensin converting enzyme" next inhibit*:ti,ab AND CENTRAL:TARGET
#10 ace near3 inhibit*:ti,ab AND CENTRAL:TARGET
#11 acei:ti,ab AND CENTRAL:TARGET
#12 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril* or perindopril or pivopril or quinapril or ramipril or ramiprilat or rentiapril or saralasin or s nitrosocaptopril or spirapril or temocapril or teprotide or trandolapril or utibapril or zabicipril or zofenopril):ti,ab AND CENTRAL:TARGET
#13 #8 OR #9 OR #10 OR #11 OR #12 AND CENTRAL:TARGET
#14 MeSH DESCRIPTOR Angiotensin Receptor Antagonists EXPLODE ALL AND CENTRAL:TARGET
#15 angiotensin near3 (receptor antagonist* or receptor block*):ti,ab AND CENTRAL:TARGET
#16 (arb OR arbs):ti,ab AND CENTRAL:TARGET
#17 (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):ti,ab AND CENTRAL:TARGET
#18 #14 OR #15 OR #16 OR #17 AND CENTRAL:TARGET
#19 MeSH DESCRIPTOR Calcium Channel Blockers EXPLODE ALL AND CENTRAL:TARGET
#20 (amlodipine or amrinone or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil):ti,ab AND CENTRAL:TARGET
#21 calcium near2 (antagonist* or block* or inhibit*):ti,ab AND CENTRAL:TARGET
#22 #19 OR #20 OR #21 AND CENTRAL:TARGET
#23 (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):ti,ab,kw AND CENTRAL:TARGET
#24 (reserpine or serpentina or rauwolfia or serpasil):ti,ab,kw AND CENTRAL:TARGET
#25 (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):ti,ab,kw AND CENTRAL:TARGET
#26 MeSH DESCRIPTOR Hydralazine EXPLODE ALL AND CENTRAL:TARGET
#27 (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):ti,ab,kw AND CENTRAL:TARGET
#28 #23 OR #24 OR #25 OR #26 OR #27 AND CENTRAL:TARGET
#29 MeSH DESCRIPTOR Adrenergic beta‐Antagonists EXPLODE ALL AND CENTRAL:TARGET
#30 (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):ti,ab AND CENTRAL:TARGET
#31 beta near2 (adrenergic or antagonist or antagonists or blocker or blockers or blocking or receptor or receptors):ti,ab AND CENTRAL:TARGET
#32 #29 OR #30 OR #31 AND CENTRAL:TARGET
#33 MeSH DESCRIPTOR Adrenergic alpha‐Antagonists EXPLODE ALL AND CENTRAL:TARGET
#34 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin):ti,ab AND CENTRAL:TARGET
#35 adrenergic near2 (alpha or antagonist or antagonists):ti,ab AND CENTRAL:TARGET
#36 (adrenergic or alpha or receptor or receptors) near2 (blocker or blockers or blocking):ti,ab AND CENTRAL:TARGET
#37 #33 OR #34 OR #35 OR #36 AND CENTRAL:TARGET
#38 MeSH DESCRIPTOR Hypertension AND CENTRAL:TARGET
#39 hypertens*:ti,ab AND CENTRAL:TARGET
#40 (elevate* OR high* OR raise*) NEAR2 blood pressure:ti,ab AND CENTRAL:TARGET
#41 #38 OR #39 OR #40 AND CENTRAL:TARGET
#42 #7 OR #13 OR #18 OR #22 OR #28 OR #32 OR #37 AND CENTRAL:TARGET
#43 #41 AND #42 AND CENTRAL:TARGET
#44 #43 AND (23/01/2017_TO_24/11/2017:CRSCREATED) AND CENTRAL:TARGET

*****************************************************

Database: Ovid MEDLINE(R) 1946 to Present with Daily Update
Search Date: 24 November 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 exp thiazides/
2 exp sodium chloride symporter inhibitors/
3 exp sodium potassium chloride symporter inhibitors/
4 ((ceiling or loop) adj diuretic?).tw.
5 (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.
6 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide).tw.
7 or/1‐6
8 exp angiotensin‐converting enzyme inhibitors/
9 angiotensin converting enzyme inhibit$.tw.
10 (ace adj2 inhibit$).tw.
11 acei.tw.
12 (alacepril or altiopril or ancovenin or benazepril$ or captopril or ceranapril or ceronapril or cilazapril$ or deacetylalacepril or delapril or derapril or enalapril$ or epicaptopril or fasidotril$ or foroxymithine or fosinopril$ or gemopatrilat or idapril or imidapril$ or indolapril or libenzapril or lisinopril or moexipril$ or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw.
13 or/8‐12
14 exp Angiotensin Receptor Antagonists/
15 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw.
16 arb?.tw.
17 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten).tw.
18 or/14‐17
19 exp calcium channel blockers/
20 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM).tw.
21 (calcium adj2 (antagonist? or block$ or inhibit$)).tw.
22 or/19‐21
23 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or methyl dopa or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp.
24 (reserpine or serpentina or rauwolfia or serpasil).mp.
25 (clonidine or adesipress or arkamin or caprysin or catapres$ 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.
26 exp hydralazine/
27 (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.
28 or/23‐27
29 exp adrenergic beta‐antagonists/
30 (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.
31 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw.
32 or/29‐31
33 exp adrenergic alpha antagonists/
34 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).tw.
35 (adrenergic adj2 (alpha or antagonist?)).tw.
36 ((adrenergic or alpha or receptor?) adj2 block$).tw.
37 or/33‐36
38 hypertension/
39 hypertens$.tw.
40 ((high or elevat$ or rais$) adj2 blood pressure).tw.
41 or/38‐40
42 randomized controlled trial.pt.
43 controlled clinical trial.pt.
44 randomized.ab.
45 placebo.ab.
46 clinical trials as topic/
47 randomly.ab. )
48 trial.ti.
49 or/42‐48
50 animals/ not (humans/ and animals/)
51 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/
52 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti.
53 49 not (50 or 51 or 52)
54 (7 or 13 or 18 or 22 or 28 or 32 or 37) and 41 and 53
55 54 and (2016$ or 2017$).ed.
56 remove duplicates from 55

***************************

Database: Embase <1974 to 2017 November 22>
Search Date: 24 November 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 exp thiazide diuretic agent/
2 exp loop diuretic agent/ )
3 ((loop or ceiling) adj diuretic?).tw.
4 (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.
5 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide).tw.
6 or/1‐5
7 exp dipeptidyl carboxypeptidase inhibitor/
8 angiotensin converting enzyme inhibit$.tw.
9 (ace adj2 inhibit$).tw.
10 acei.tw.
11 (alacepril or altiopril or ancovenin or benazepril$ or captopril or ceranapril or ceronapril or cilazapril$ or deacetylalacepril or delapril or derapril or enalapril$ or epicaptopril or fasidotril$ or foroxymithine or fosinopril$ or gemopatrilat or idapril or imidapril$ or indolapril or libenzapril or lisinopril or moexipril$ or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw.
12 or/7‐11
13 exp angiotensin receptor antagonist/
14 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw.
15 arb?.tw.
16 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten).tw.
17 or/13‐16
18 calcium channel blocking agent/
19 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM).tw.
20 (calcium adj2 (antagonist? or block$ or inhibit$)).tw.
21 or/18‐20
22 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or methyl dopa or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp.
23 (reserpine or serpentina or rauwolfia or serpasil).mp.
24 (clonidine or adesipress or arkamin or caprysin or catapres$ 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.
25 hydralazine/
26 (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.
27 or/22‐26
28 exp beta adrenergic receptor blocking agent/
29 (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.
30 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw.
31 or/28‐30
32 exp alpha adrenergic receptor blocking agent/
33 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).tw.
34 (adrenergic adj2 (alpha or antagonist?)).tw.
35 ((adrenergic or alpha or receptor?) adj2 block$).tw.
36 or/32‐35
37 exp hypertension/
38 (hypertens$ or antihypertens$).tw.
39 ((high or elevat$ or rais$) adj2 blood pressure).tw.
40 or/37‐39
41 double blind$.mp.
42 placebo$.tw.
43 blind$.tw.
44 or/41‐43
45 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)
46 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/
47 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti.
48 44 not (45 or 46 or 47)
49 (6 or 12 or 17 or 21 or 27 or 31 or 36) and 40 and 48
50 49 and (2016$ or 2017$).dc.
51 remove duplicates from 50

***************************

Database: ClinicalTrials.gov
Search Date: 24 November 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Other Terms: randomized
Study Type: Interventional Studies
Condition / Disease: hypertension
Intervention / Treatment: Antihypertensive Agents
First Received: From 01/23/2017 to 11/24/2017

***************************

Database: WHO International Clinical Trials Registry Platform (ICTRP)
Search Date: 24 November 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
antihypertens* AND hypertens* AND randomized
antihypertens* AND high blood pressure AND randomized

Notes

New search for studies and content updated (no change to conclusions)

Data and analyses

Comparison 1

First‐line thiazide vs placebo

Comparison 2

First‐line beta‐blocker vs placebo

Comparison 3

First‐line ACE inhibitor vs Placebo

Comparison 4

First‐line calcium channel blocker vs Placebo

Analysis

Comparison 4 First‐line calcium channel blocker vs Placebo, Outcome 5 Heart Failure.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Differences between protocol and review

As the original version of this review did not include 'Risk of bias' assessment of all included studies, according to chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions, the protocol was updated to include it, using standard Cochrane methodology. Also, this update meets MECIR standards, including the addition of five 'Summary of findings' tables.

A third author, Rupam Gill has been added to the updated review. RG independently assessed risk of bias of the 24 included studies as a second reviewer.

Although the protocol did not specify primary and secondary outcome measures separately, we have categorized total mortality, total cardiovascular events, total stroke, and total CHD as the primary outcome measures. Reduction in systolic and diastolic blood pressure and withdrawal due to adverse effects are secondary outcome measures.

Contributions of authors

Jim Wright (JMW) was responsible for the design of the protocol, assessed all trials for inclusion or exclusion, checked the data entry, and contributed to the data analysis and to the interpretation and final draft of the review.

Vijaya Musini (VM) assessed all trials for inclusion or exclusion, extracted data, checked data entry, assessed risk of bias of all included studies, contributed to data analysis, interpretation and final draft of the review. Summary of Findings table was also prepared by VM.

Rupam Gill (RG) was the second reviewer who assessed risk of bias of all included studies.

Sources of support

Internal sources

• Faculty of Medicine, University of British Columbia, Canada.

  Salary, space and infrastructure

External sources

• CIHR grant to the Hypertension Review Group, Canada.

  Infrastructure support to the Cochrane Hypertension Group

Declarations of interest

JMW: none.

VM: none.

RG: none.

References

References to studies included in this review

ATTMH 1980 {published data only}

• Abernethy JD. The Australian therapeutic trial in mild hypertension. Hypertension 1984;6(5):774‐6. [MEDLINE: ] [PubMed] [Google Scholar]
• Abernethy JD. The need to treat mild hypertension. Misinterpretation of results from the Australian trial. JAMA 1986;256(22):3134‐7. [MEDLINE: ] [PubMed] [Google Scholar]
• Doyle AE. Cardiovascular morbidity and mortality in mild hypertension: the Australian trial. Journal of Cardiovascular Pharmacology 1985;7(Suppl 2):S10‐3. [MEDLINE: ] [PubMed] [Google Scholar]
• Doyle AE. The Australian therapeutic trial in mild hypertension. Nephron 1987;47(Suppl 1):115‐9. [MEDLINE: ] [PubMed] [Google Scholar]
• Management Committee. Initial results of the Australian therapeutic trial in mild hypertension. Report by the Management Committee. Clinical Science 1979;57:449s‐52s. [MEDLINE: ] [PubMed] [Google Scholar]
• Management Committee. The Australian therapeutic trial in mild hypertension. Report by the Management Committee. Lancet 1980;1:1261‐7. [MEDLINE: ] [PubMed] [Google Scholar]
• Management Committee. Untreated mild hypertension. A report by the Management Committee of the Australian Therapeutic Trial in Mild Hypertension. Lancet 1982;1(8265):185‐91. [MEDLINE: ] [PubMed] [Google Scholar]
• National Heart Foundation of Australia. Treatment of mild hypertension in the elderly. A study initiated and administered by the National Heart Foundation of Australia. Medical Journal of Australia 1981;2:398‐402. [MEDLINE: ] [PubMed] [Google Scholar]
• Parry CA. Australian therapeutic trial in mild hypertension. Lancet 1980;2(8191):425. [MEDLINE: ; Letter] [PubMed] [Google Scholar]
• Reader R. Australian therapeutic trial in mild hypertension. Medical Journal of Australia 1984;140(13):752‐4. [MEDLINE: ] [PubMed] [Google Scholar]

Barraclough 1973 {published data only}

• Barraclough M, Joy MD, MacGregor GA, Foley TH, Lee MR, Rosendorff C, et al. Control of moderately raised blood pressure. Report of a co‐operative randomized controlled trial. British Medical Journal 1973;III:434‐6. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]

Carter 1970 {published data only}

• Carter A. Hypotensive therapy in stroke survivors. Lancet 1970;I:485‐9. [MEDLINE: ] [PubMed] [Google Scholar]

Dutch TIA 1993 {published data only}

• Dutch TIA Trial Study Group. Trial of secondary prevention with atenolol after transient ischemic attack or non‐disabling ischemic stroke. Stroke 1993;24:543‐8. [PubMed] [Google Scholar]

EWPHE 1985 {published data only}

• Amery A, Berthaux P, Birkenhäger W, Boel A, Brixko P, Bulpitt C, et al. Antihypertensive therapy in patients above age 60 years. Fourth interim report of the European Working Party on High Blood Pressure in the Elderly. Clinical Science and Molecular Medicine 1978;55:263s‐70s. [MEDLINE: ] [PubMed] [Google Scholar]
• Amery A, Berthaux P, Birkenhäger W, Boel A, Brixko P, Bulpitt C, et al. Antihypertensive therapy in patients above age 60. Third interim report of the European Working Party on High Blood Pressure in the Elderly. Acta Cardiologica 1978;33(2):113‐34. [MEDLINE: ] [PubMed] [Google Scholar]
• Amery A, Berthaux P, Birkenhäger W, Bulpitt C, Clement D, Schaepdryver A, et al. Antihypertensive therapy in elderly patients. Pilot trial of the European Working Party on High Blood Pressure in the Elderly. Gerontology 1977;23(6):426‐37. [MEDLINE: ] [PubMed] [Google Scholar]
• Amery A, Birkenhäger W, Brixko P, Bulpitt C, Clement D, Deruyttere M, et al. Glucose intolerance during diuretic therapy in elderly hypertensive patients. A second report from the European Working Party on High Blood Pressure in the Elderly. Postgraduate Medical Journal 1986;62(732):919‐24. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]
• Amery A, Birkenhäger W, Brixko P, Bulpitt C, Clement D, Deruyttere M, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985;1(8442):1349‐54. [MEDLINE: ] [PubMed] [Google Scholar]
• Amery A, Birkenhäger W, Brixko P, Bulpitt C, Clement D, Leeuw P, et al. Efficacy of antihypertensive drug treatment according to age, sex, blood pressure and previous cardiovascular disease in patients over age of 60. Lancet 1986;2(8507):589‐92. [MEDLINE: ] [PubMed] [Google Scholar]
• Amery A, Birkenhäger W, Brixko P, Bulpitt C, Clement D, Leeuw P, et al. Influence of antihypertensive drug treatment on morbidity and mortality in patients over the age of 60 years. European Working Party on High blood pressure in the Elderly (EWPHE) results: sub‐group analysis on entry stratification. Journal of Hypertension 1986;4(6):S642‐7. [MEDLINE: ] [PubMed] [Google Scholar]
• Amery A, Birkenhäger W, Brixko P, Bulpitt C, Clement D, Leeuw P, et al. Influence of hypotensive drug treatment in elderly hypertensives: study terminating events in the trial of the European Working Party on High Blood Pressure in the Elderly. Journal of Hypertension 1985;3(Suppl 3):S501‐8. [MEDLINE: ] [PubMed] [Google Scholar]
• Amery A, Schaepdrijver A. European Working Party on High Blood Pressure in the Elderly (EWPHE): organization of a double‐blind multicenter trial on antihypertensive therapy in elderly patients. Clinical Science and Molecular Medicine 1973;45(Suppl):71s‐3s. [MEDLINE: ] [PubMed] [Google Scholar]
• Amery A, Schaepdryver A. The European Working Party on High Blood Pressure in the Elderly. The American Journal of Medicine 1991;90(Suppl 3A):1S‐4S. [MEDLINE: ] [PubMed] [Google Scholar]
• Leeuw PW. Renal function in the elderly: results from the European Working Party on High Blood Pressure in the Elderly trial. The American Journal of Medicine 1991;90(Suppl 3A):45S‐9S. [MEDLINE: ] [PubMed] [Google Scholar]
• European Working Party on High Blood Pressure in the Elderly (EWPHE). An international trial of antihypertensive therapy in elderly patients. Objectives, protocol and organization. Archives internationales de pharmacodynamie et de thérapie 1985;275:300‐34. [MEDLINE: ] [PubMed] [Google Scholar]
• European Working Party on High Blood Pressure in the Elderly (EWPHE). Antihypertensive therapy in the elderly. Ninth interim report. Netherlands Journal of Medicine 1984;27:165‐70. [MEDLINE: ] [PubMed] [Google Scholar]
• European Working Party on high blood pressure in the elderly trial. Discussion after the presentation of the results of the European Working Party on High Blood Pressure in the Elderly trial (EWPHE). Journal of Hypertension 1985;3(Suppl 3):S509‐11. [MEDLINE: ] [PubMed] [Google Scholar]
• Fagard R. Serum cholesterol levels and survival in elderly hypertensive patients: analysis of data from the European Working Party on High Blood Pressure in the Elderly. The American Journal of Medicine 1991;90(Suppl 3A):62S‐3S. [MEDLINE: ] [PubMed] [Google Scholar]
• Fagard R, Staessen J, Amery A. Experience with diuretics in the study conducted by the European Working Party on High Blood Pressure in the Elderly (EWPHE). Progress in Pharmacology and Clinical Pharmacology 1992;9:463‐72. [Accession number 1992230803] [Google Scholar]
• Fletcher A, Amery A, Birkenhäger W, Bulpitt C, Clement D, Leeuw P, et al. Risks and benefits in the trial of the European Working Party on High Blood Pressure in the Elderly. Journal of Hypertension 1991;9:225‐30. [MEDLINE: ] [PubMed] [Google Scholar]
• Fletcher AE. Adverse treatment effects in the trial of the European Working Party on High Blood Pressure in the Elderly. The American Journal of Medicine 1991;90(Suppl 3A):42S‐4S. [MEDLINE: ] [PubMed] [Google Scholar]
• O'Malley K, Cox JP, O'Brien E. Further learnings from the European Working Party on High Blood Pressure in the Elderly (EWPHE) study: focus on systolic hypertension. Cardiovascular Drugs and Therapy. 1990;4:1249‐52. [MEDLINE: ] [PubMed] [Google Scholar]
• O'Malley KO, McCormack P, O'Brien ET. Isolated systolic hypertension: data from the European Working Party on High Blood Pressure in the Elderly. Journal of Hypertension 1988;6(suppl 1):S105‐8. [MEDLINE: ] [PubMed] [Google Scholar]
• Prisant LM, Carr AA. Overview of the findings of the European Party on High Blood Pressure in the Elderly. Geriatric Medicine Today 1990;9(5):35‐8. [Accession number 1990224411] [Google Scholar]
• Staeesen J. The determinants and prognostic significance of serum uric acid in elderly patients of the European Working Party on High Blood Pressure in the Elderly trial. The American Journal of Medicine 1991;90(Suppl 3A):50S‐4S. [MEDLINE: ] [PubMed] [Google Scholar]
• Staessen J. Mortality and treatment of blood pressure in patients of the European Working Party on High Blood Pressure in the Elderly. The American Journal of Medicine 1991;90(Suppl 3A):60S‐1S. [MEDLINE: ] [PubMed] [Google Scholar]
• Staessen J, Bulpitt C, Clement D, Leeuw P, Fagard R, Fletcher A, et al. Relation between mortality and treated blood pressure in elderly patients with hypertension: report of the European Working Party on High Blood Pressure in the Elderly. BMJ 1989;298:1552‐6. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]
• Thijs L. Age‐related hypotensive effect of placebo and active treatment in patients older than 60 years. The American Journal of Medicine 1991;90(Suppl 3A):24S‐6S. [MEDLINE: ] [PubMed] [Google Scholar]
• Tuomilehto J. Body mass index and prognosis in elderly hypertensive patients: a report from the European Working Party on High Blood Pressure in the Elderly. The American Journal of Medicine 1991;90(Suppl 3A):34S‐41S. [MEDLINE: ] [PubMed] [Google Scholar]
• Hoof R. Left ventricular hypertrophy in elderly hypertensive patients: a report from the European Working Party on High Blood Pressure in the Elderly trial. The American Journal of Medicine 1991;90(Suppl 3A):55s‐59s. [MEDLINE: ] [PubMed] [Google Scholar]
• Hoof R, Staessen J, Fagard R, Thijs L, Amery A. The effect of antihypertensive treatment on electrocardiogram voltages in the European Working Party on High Blood Pressure in the Elderly trial. Journal of Cardiovascular Pharmacology 1991;17(Suppl 2):S101‐4. [MEDLINE: ] [PubMed] [Google Scholar]

HOPE HYP 2000 {published data only}

• The HOPE Study Investigators. The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large, simple randomized trial of angiotensin‐converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Canadian Journal of Cardiology 1996;12:127‐37. [PubMed] [Google Scholar]
• Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin‐converting‐enzyme inhibitor, ramipril, on cardiovascular events in high‐risk patients. The Heart Outcomes Prevention Evaluation Outcomes Study Investigators. New England Journal of Medicine 2000;342(3):145‐53. [MEDLINE: ] [PubMed] [Google Scholar]

HSCSG 1974 {published data only}

• Hypertension‐Stroke Cooperative Study Group. Effect of antihypertensive treatment on stroke recurrence. JAMA 1974;229:409‐18. [MEDLINE: ] [PubMed] [Google Scholar]

HYVET 2008 {published data only}

• Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. New Egyptian Journal of Medicine 2008;358(18):1887‐98. [MEDLINE: ] [PubMed] [Google Scholar]
• Bulpitt CJ, Fletcher AE, Amery A, Coope J, Evans JG, Lightowlers S, et al. The Hypertension in the Very Elderly Trial (HYVET). Journal of Human Hypertension 1994;8(8):631‐2. [PubMed] [Google Scholar]
• Bulpitt CJ, Fletcher AE, Amery A, Coope J, Evans JG, Lightowlers S, et al. The Hypertension in the Very Elderly Trial (HYVET): rationale, methodology and comparison with previous trials. Drugs & Aging 1994;5(3):171‐83. [PubMed] [Google Scholar]
• Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C, et al. HYVET investigators. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET‐COG): a double‐blind, placebo controlled trial. Lancet 2008;7(8):683‐9. [PubMed] [Google Scholar]

HYVET pilot 2003 {published data only}

• Beckett NS, Connor M, Sadler JD, Fletcher AE, Bulpitt CJ. Orthostatic fall in blood pressure in the very elderly: results from the Hypertension in the Very Elderly trial (HYVET) ‐ pilot. Journal of Human Hypertension 1999;13(12):839‐40. [MEDLINE: ] [PubMed] [Google Scholar]
• Bulpitt CJ, Beckett NS, Cooke J, Dumitrascu DL, Gil‐Extremera B, Nachev C, et al. Results of the pilot study for the Hypertension in the Very Elderly Trial. Journal of Hypertension 2003;21:2409‐17. [PubMed] [Google Scholar]

Kuramoto 1981 {published data only}

• Kuramoto K, Matsushita S, Kuwajima I, Murakami M. Prospective study on the treatment of mild hypertension in the aged. Japanese Heart Journal 1981;22:75‐85. [MEDLINE: ] [PubMed] [Google Scholar]

MRC‐O 1992 {published data only}

• MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. British Medical Journal 1992;304:405‐12. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]

MRC‐TMH 1985 {published data only}

• Medical Research Council Working Party. Comparison of the antihypertensive efficacy and adverse reactions to two doses of bendrofluazide and hydrochlorothiazide and the effect of potassium supplementation on the hypotensive action of bendrofluazide: sub studies of the Medical Research Council's trials of treatment of hypertension: Medical Research Council Working Party. Journal of Clinical Pharmacology 1987;27(4):271‐7. [MEDLINE: ] [PubMed] [Google Scholar]
• Medical Research Council Working Party. Randomised controlled trial of treatment of mild hypertension: design and pilot trial. Report of the Medical Research Council Working party on Mild to Moderate Hypertension. British Medical Journal 1977;1(6074):1437‐40. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]
• Medical Research Council Working Party on Mild Hypertension. Adverse reactions to bendrofluazide and propanolol for the treatment of mild hypertension. Report of Medical Research Council Working Party on Mild to Moderate Hypertension. Lancet 1981;2(8246):539‐43. [MEDLINE: ] [PubMed] [Google Scholar]
• Medical Research Council Working Party on Mild Hypertension. Comparison of the antihypertensive efficacy and adverse reactions of two doses of bendrofluazide and hydrochlorothiazide and the effect of potassium supplementation on the hypotensive action of bendrofluazide: sub studies of the Medical Research Council's trials of treatment of mild hypertension. Journal of Clinical Pharmacology 1987;27(4):271‐7. [MEDLINE: ] [PubMed] [Google Scholar]
• Medical Research Council Working Party on Mild Hypertension. Coronary heart disease in Medical Research Council trial of mild hypertension. British Heart Journal 1988;59(3):364‐78. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]
• Medical Research Council Working Party on Mild Hypertension. Course of blood pressure in mild hypertension after withdrawal of long term antihypertensive treatment. British Medical Journal (Clinical Research Ed.) 1986;293(6553):988‐92. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]
• Medical Research Council Working Party on Mild Hypertension. MRC trial of treatment of mild hypertension: principal results. British Medical Journal 1985;291(6488):97‐104. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]
• Medical Research Council Working Party on Mild Hypertension. Stroke and coronary heart disease in mild hypertension: risk factors and the value of treatment. BMJ 1988;296(6636):1565‐70. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]
• Miall WE, Brennan PJ, Mann AH. Medical Research Council's Treatment Trial for mild hypertension: an interim report. Clinical Science and Molecular Medicine 1976;51:563s‐5s. [MEDLINE: ] [PubMed] [Google Scholar]
• Peart S. Results of the MRC (UK) trial of drug therapy for mild hypertension. Clinical and Investigative Medicine 1987;10(6):616‐20. [MEDLINE: ] [PubMed] [Google Scholar]

OSLO 1986 {published data only}

• Helgeland A. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. American Journal of Medicine 1980;69:725‐32. [MEDLINE: ] [PubMed] [Google Scholar]
• Helgeland A, Baksaas IA, Leren P. Mild hypertension ‐ early drug treatment or follow‐up only? the Oslo study. Acta Medica Scandinavica. Supplementum 1979;626:34‐6. [MEDLINE: ] [PubMed] [Google Scholar]
• Helgeland A, Hjermann I, Holme I, Liren P. Serum triglycerides and serum uric acid in untreated and thiazide‐treated patients with mild hypertension. American Journal of Medicine 1978;64:34‐8. [MEDLINE: ] [PubMed] [Google Scholar]
• Helgeland A, Leren P. Oslo study: treatment of mild hypertension. A five‐year controlled drug study. Nephron 1987;47(Suppl 1):108‐10. [MEDLINE: ] [PubMed] [Google Scholar]
• Helgeland A, Leren P, Foss OP, Hjermann I, Holme I, Lund‐Larsen PG. Serum glucose levels during long‐term observation of treated and untreated men with mild hypertension. American Journal of Medicine 1984;76:802‐5. [MEDLINE: ] [PubMed] [Google Scholar]
• Holme I. Coronary risk factors and their possible causal role in the development of coronary heart disease: the Oslo study. Journal of the Oslo City Hospitals 1982;32(7‐8):80‐105. [MEDLINE: ] [PubMed] [Google Scholar]
• Holme I1, Helgeland A, Hjermann I, Leren P, Mogensen SB. Correlates of blood pressure change in middle‐aged male mild hypertensives: results from the untreated control group in the Oslo hypertension trial. The Oslo Study. American Journal of Epidemiology 1988;127(4):742‐52. [MEDLINE: ] [PubMed] [Google Scholar]
• Leren P, Eide I, Foss OP, Helgeland A, Hjermann I, Holme I, et al. Blood lipids and antihypertensive drugs. The Oslo study. Journal de pharmacologie (Paris) 1983;14(Suppl II):217‐20. [MEDLINE: ] [PubMed] [Google Scholar]
• Leren P, Hegeland A, Hjermann I, Holme I. The Oslo study: CHD risk factors, socioeconomic influences, and interventions. American Heart Journal 1983;106:1200‐6. [MEDLINE: ] [PubMed] [Google Scholar]
• Leren P, Helgeland A. Coronary heart disease and treatment of hypertension. Some Oslo Study data. American Journal of Medicine 1986;80(Suppl 2A):3‐6. [MEDLINE: ] [PubMed] [Google Scholar]
• Leren P, Helgeland A. Oslo hypertension study. Drugs 1986;31(Suppl 1):41‐5. [MEDLINE: ] [PubMed] [Google Scholar]

PATS 1996 {published data only}

• PATS collaborating group. Post‐stroke antihypertensive treatment study. A preliminary result. Chinese Medical Journal 1995;108(9):710‐7. [MEDLINE: ] [PubMed] [Google Scholar]

SHEP 1991 {published data only}

• Applegate WB, Davis BR, Black HR, et al. Prevalence of postural hypotension at baseline in the systolic hypertension in the elderly program (SHEP) cohort. Journal of American Geriatric Society 1991;39:1057‐64. [MEDLINE: ] [PubMed] [Google Scholar]
• Bearden D. Allman R. McDonald R, et al. Age, race, and gender variation in the utilization of coronary artery bypass surgery and angioplasty in SHEP. Journal of the American Geriatric Society 1994;42:1143‐49. [MEDLINE: ] [PubMed] [Google Scholar]
• Black HR. Unger D. Burlando A, et al. Part 6: Baseline physical examination findings. Hypertension 1991;17(3 (Suppl II)):II‐77‐II‐101. [MEDLINE: ] [PubMed] [Google Scholar]
• Borhani NO. Applegate WB. Cutler JA, et al. Part 1: rationale and design. Hypertension 1991;17(3 (Suppl II)):II‐2‐II‐15. [MEDLINE: ] [PubMed] [Google Scholar]
• Brittain E. Palensky J. Blood J and Wittes J. Blinded subjective rankings as a method of assessing treatment effect: a large sample example from the systolic hypertension in the elderly program (SHEP). Statistics in Medicine 1997;16:681‐693. [MEDLINE: ] [PubMed] [Google Scholar]
• Curb JD. Lee M. Jensen J, Applegate W. Part 4: baseline medical history findings. Hypertension 1991;17(3 (Suppl II)):II‐35‐II‐61. [MEDLINE: ] [PubMed] [Google Scholar]
• Curb JD. Pressel SL. Cutler JA, et al. Effect of diuretic based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886‐92. [MEDLINE: ] [PubMed] [Google Scholar]
• Davis BR. Wittes J. Pressel S, et al. Statistical considerations in monitoring the systolic hypertension in the elderly program (SHEP). Controlled Clinical Trials 1993;14:350‐361. [MEDLINE: ] [PubMed] [Google Scholar]
• Franse LV. Pahor M. Di Bari M, et al. serum uric acid, diuretic treatment and risk of cardiovascular events in the systolic hypertension in the elderly program. Journal of Hypertension 2000;18:1149‐54. [Accession number Current contents 343FE‐0021] [PubMed] [Google Scholar]
• Frost PH. Davis BR. Burlando AJ, et al. Serum lipids and incidence of coronary heart disease. Findings from the systolic hypertension in the elderly program. Circulation 1996;94:2381‐88. [MEDLINE: ] [PubMed] [Google Scholar]
• Hall WD. Davis BR. Frost P, et al. Part 7: Baseline laboratory characteristics. Hypertension 1991;17(3 (Suppl II)):II‐102‐II‐122. [MEDLINE: ] [PubMed] [Google Scholar]
• Hawkins CM. Isolated systolic hypertension, morbidity and mortality: The SHEP experience. American Journal of Geriatric Cardiology 1993;September/October:25‐27. [Accession number 1993303455] [PubMed] [Google Scholar]
• Kostis JB. Allen R. Berkson DM, et al. Correlates of ventricular ectopic activity in isolated systolic hypertension. American Heart Journal 1994;127:112‐21. [MEDLINE: ] [PubMed] [Google Scholar]
• Kostis JB. Davis BR. Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1997;278(3):212‐216. [MEDLINE: ] [PubMed] [Google Scholar]
• Kostis JB. Lacy CR. Hall D, et al. The effect of chlorthalidone on ventricular ectopic activity in patients with isolated systolic hypertension. American Journal of Cardiology 1994;74:464‐67. [MEDLINE: ] [PubMed] [Google Scholar]
• Kostis JB. Prineas R. Curb JD, et al. Part 8: Electrocardiographic characteristics. Hypertension 1991;17(3 (Suppl II)):II‐123‐II‐151. [MEDLINE: ] [PubMed] [Google Scholar]
• Menard J. Day M. Chatellier G, Laragh JH. Some lessons from systolic hypertension in the elderly program (SHEP). American Journal of Hypertension 1992;5:325‐30. [MEDLINE: ] [PubMed] [Google Scholar]
• Newman AB. Tyrrell KS, Kuller LH. Mortality over four years in SHEP participants with a low ankle‐arm index. Journal of American Geriatric Society 1997;45:1472‐78. [MEDLINE: ] [PubMed] [Google Scholar]
• Perry HM. Davis BR. Price TR, et al. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke. JAMA 2000;284(4):465‐471. [Accession number Current contents 335QB‐0033] [PubMed] [Google Scholar]
• Petrovich H. Byington R. Bailey G, et al. Part 2: screening and recruitment. Hypertension 1991;17 (Suppl II)(3):II‐17‐II‐23. [MEDLINE: ] [PubMed] [Google Scholar]
• Probstfield JL. Applegate WB. Borhani NO, et al. The systolic hypertension in the elderly program (SHEP): an intervention trial on isolated systolic hypertension. Clinc. and Exper. Hyper.‐Theory and Practice 1989;A11(5 & 6):973‐89. [MEDLINE: ] [PubMed] [Google Scholar]
• SHEP cooperative Research Group. Rationale and design of a randomized clinical trial on prevention of stroke in isolated systolic hypertension. Journal of Clinical Epidemiology 1988;41(12):1197‐1208. [Accession number 1989036523] [PubMed] [Google Scholar]
• SHEP cooperative research group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the SHEP. ACP Journal Club 1991;115(3):65. [Accession number 1992021057] [Google Scholar]
• SHEP cooperative research group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program. JAMA 1991;265:3255‐3264. [MEDLINE: ] [PubMed] [Google Scholar]
• Savage PJ. Pressel SL. Curb D, et al. Influence of long‐term, low‐dose, diuretic‐based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension. Archives of Internal Medicine 1998;158:741‐751. [MEDLINE: ] [PubMed] [Google Scholar]
• Vogt TM. Schron E. Pressel S, et al. Part 3: Sociodemographic characteristics. Hypertension 1991;17(3 (Suppl II)):II‐24‐II‐34. [MEDLINE: ] [PubMed] [Google Scholar]
• Wassertheil S. Applegate WB. Berge K, et al. Change in depression as a precursor of cardiovascular events. Archives of Internal Medicine 1996;156:553‐561. [MEDLINE: ] [PubMed] [Google Scholar]
• Wasserthell‐Smoller S. FannC. Allman RM, et al. Relation of low body mass to death and stroke in the systolic hypertension in the elderly program. Archives of Internal Medicine 2000;160:494‐500. [MEDLINE: ] [PubMed] [Google Scholar]
• Weiler PG. Camel GH. Chiappini M, et al. Part 9: Behavorial characteristics. Hypertension 1991;17(3 (Suppl II)):II‐152‐II‐161. [MEDLINE: ] [PubMed] [Google Scholar]
• Wittes J. Davis B. Berge K, et al. Part 10: Analysis. Hypertension 1991;17(3 (Suppl II)):II‐162‐II‐167. [MEDLINE: ] [PubMed] [Google Scholar]

SHEP‐P 1989 {published data only}

• Black DM. Brand RJ. Greenlick M, et al. Compliance to treatment for hypertension in elderly patients: The SHEP pilot study. Journal of Gerontology 1987;42(5):552‐57. [MEDLINE: ] [PubMed] [Google Scholar]
• Furberg CD. Black DM. for the SHEP research group. The systolic hypertension in the elderly program: Methodological issues. European Heart Journal 1988;9:223‐227. [MEDLINE: ] [PubMed] [Google Scholar]
• Hulley SB. Feigal D. Ireland C, et al. Systolic hypertension in the elderly program (SHEP). Journal of the American Geriatric Society 1986;34(2):101‐105. [MEDLINE: ] [PubMed] [Google Scholar]
• Hulley SB. Furberg CD. Gurland B. McDonald R, et al. Systolic Hypertension in the Elderly (SHEP): antihypertensive efficacy of chlorthalidone. The American Journal of cardiology 1985;56(15):913‐20. [MEDLINE: ] [PubMed] [Google Scholar]
• Perry HM, et al. Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) Pilot study. Stroke 1989;20:4‐13. [MEDLINE: ] [PubMed] [Google Scholar]
• Perry Jr HM. McDonald RH. Hulley SB, et al. Systolic hypertension in the elderly program, pilot study (SHEP‐PS): morbidity and mortality experience. Journal of Hypertension 1986;4(Suppl 6):S21‐S23. [MEDLINE: ] [PubMed] [Google Scholar]
• Vogt TM. Ireland CC. Black D, et al. Recruitment of elderly volunteers for a multicenter clinical trial: The SHEP pilot study. Controlled Clinical Trials 1986;7:118‐133. [MEDLINE: ] [PubMed] [Google Scholar]
• Vogt TM. Ireland CC. Greenlick MR, Hughes GH. Relation of life events to blood pressure control in the SHEP trial. American Journal of Preventive Medicine 1988;4:1‐4. [MEDLINE: ] [PubMed] [Google Scholar]

SYST‐EUR 1997 {published data only}

• Amery A. Birkenhager W. Bulpitt CJ, et al. Syst‐Eur. A multicenter trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol and organization. Aging 1991;3(3):287‐302. [MEDLINE: ] [PubMed] [Google Scholar]
• Birkenhager WH. Staessen J. Gasowski J, Leeuw PW. Effects of antihypertensive treatment on endpoints in the diabetic patients randomized in the systolic hypertension in Europe (Syst‐Eur) trial. Journal of Nephrology 2000;13:232‐237. [Accession number 331TE‐ 0011] [PubMed] [Google Scholar]
• Gasowski J. Birkenhager WH. Staessen J, Leeuw PW. Benefit of antihypertensive treatment in diabetic patients enrolled in the systolic hypertension in Europe (Sys‐Eur) trial. Cardiovascular Drugs and Therapy 2000;14:49‐53. [Accession number 281MJ‐ 0006] [PubMed] [Google Scholar]
• Girerd X, Amery A, Birkenhager W, Bulpitt C, Cox J, Leeuw P. SYST‐EUR: a multicenter trial of treatment of systolic hypertension in aged subjects. An initial report (French). Archives des Maladies du Coeur et des Vaisseaux 1992;85(8):1243‐7. [PubMed] [Google Scholar]
• Slovick D, Staessen J, Bert P, Bulpitt C, Cort P, Fagard R, et al. Nitrendipine in older patients with isolated systolic hypertension: second progress report on the Syst‐Eur trial. J Hum Hypertens 1993;7(4):411‐2. [PubMed] [Google Scholar]
• Slovick DI, Amery A, Birkenhager W, Bulpitt CJ, Cox J, Leeuw P, et al. Syst‐Eur multicenter trial on the treatment of isolated hypertension in the elderly: first interim report. J Hum Hypertens 1993;7(2):201‐3. [PubMed] [Google Scholar]
• Staessen J. Dekempeneer L. Fagard R, et al. Treatment of isolated systolic hypertension. Journal of Cardiovascular Pharmacology 1991;18(Suppl 1):S34‐S40. [MEDLINE: ] [PubMed] [Google Scholar]
• Staessen JA. Amery A. Birkenhager W, et al. Syst‐Eur‐ a multicenter trial on treatment of isolated systolic hypertension in the elderly: first interim report. Journal of Cardiovascular Pharmacology 1992;19:120‐125. [MEDLINE: ] [PubMed] [Google Scholar]
• Staessen JA. Fagard R. Thijs L. Celis H. Arabidze GG, et al. Randomised double‐blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757‐764. [MEDLINE: ] [PubMed] [Google Scholar]
• Staessen JA. Fagard R. Thijs L, et al. Subgroup and per protocol analysis of the randomized European trial on isolated systolic hypertension in the elderly. Archives of Internal medicine 1998;158:1681‐1691. [MEDLINE: ] [PubMed] [Google Scholar]

TEST 1995 {published data only}

• Eriksson S, Olofsson BO, Wesley PO, for the TEST study group. Atenolol for secondary prevention after stroke. Cerebrovasc Dis 1995;5:21‐25. [Google Scholar]

UKPDS 39 1998 {published data only}

• UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Brit Med J 1998;317:713‐720. [PMC free article] [PubMed] [Google Scholar]
• UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Brit Med J 1998;317:703‐713. [PMC free article] [PubMed] [Google Scholar]
• United Kingdom Prospective Diabetes Study Group. UK prospective diabetes study VIII: study design, progress and performance. Diabetologia 1991;34:877‐90. [PubMed] [Google Scholar]

USPHSHCSG 1977 {published data only}

• Smith WM, Bouchard RJ, Bromer L, et al. Morbidity and mortality in mild essential hypertension. Circ Res 1972;30/31(Suppl II):110‐20. [Google Scholar]
• Smith WM, Johnson WP, Bromer L. Intervention trial in mild hypertension,U.S. Public Health Service Hospitals Cooperative Study Group. Intervention trial in mild hypertension, U.S. Public Health Service Hospitals Cooperative Study Group. Miami, Symposia Specialists: In Epidemiology and Control of Hypertension, edited by OPaul, 1975:461‐83. [Google Scholar]
• US. public health service hospital cooperative study group (USPHSHCSG). Treatment of mild hypertension. Results of a ten‐year intervention trial. Circ Res 1977;40(Suppl 1):98‐105. [MEDLINE: ] [PubMed] [Google Scholar]

VA‐I 1967 {published data only}

• Freis ED. Antihypertensive Therapy; Principles and Practice, an International Symposium. In: Gross F editor(s). Antihypertensive Therapy; Principles and Practice, an International Symposium. New York: Springer‐Verlag, 1966:345‐54. [Google Scholar]
• Veterans Administration Cooperative Study Group on Antihypertensive Agents. A double‐blind control study of antihypertensive agents. III. Chlorothiazide alone and in combination with other agents: preliminary results. Arch Intern Med 1962;110:230‐5. [No unique identifier] [Google Scholar]
• Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967;202:1028‐1034. [MEDLINE: ] [PubMed] [Google Scholar]

VA‐II 1970 {published data only}

• Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970;213:1143‐1152. [MEDLINE: ] [PubMed] [Google Scholar]

VA‐NHLBI 1978 {published data only}

• Perry Jr HM, et al. Evaluation of drug treatment in mild hypertension: VA‐NHLBI feasibility trial. Ann N Y Acad Sci 1978;304:267‐288. [MEDLINE: ] [PubMed] [Google Scholar]
• Perry Jr HM, et al. Treatment of mild hypertension. Preliminary results of a two year feasibility trial. Circ Res 1977;40 suppl:1180‐187. [MEDLINE: ] [PubMed] [Google Scholar]

Wolff 1966 {published data only}

• Wolff FW, Lindeman RD. Effects of treatment in hypertension. Results of a controlled study. J Chron Dis 1966;19:227‐240. [MEDLINE: ] [PubMed] [Google Scholar]

References to studies excluded from this review

ACTIVE I 2011 {published data only}

• The Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE I)Investigators. Irbesartan in patients ACTIVE 1 with atrial fibrillation. N Engl J Med 2011;364:928‐33. [PubMed] [Google Scholar]

ADVANCE 2007 {published data only}

• Patel A, ADVANCE Collaborative Group, MacMahon S, Chalmers J, Neal B, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370:829‐40. [PubMed] [Google Scholar]

ALLHAT 2000 {published data only}

• ALLHAT Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000;283:1967‐75. [MEDLINE: ] [PubMed] [Google Scholar]
• Davis BR. Cutler JA. Gordon DJ. et al for the ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to prevent Heart Attack Trial (ALLHAT). Am J Hypertens 1996;9:342‐360. [MEDLINE: ] [PubMed] [Google Scholar]

BENEDICT 2004 {published data only}

• Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene‐Iordache B, Gaspari F, Perna A, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941‐51. [PubMed] [Google Scholar]

BENEDICT A 2006 {published data only}

• Parving H, Lehnert H, Brochner ‐ Mortensen J, Gomis R, et al. The effect of irbesartan on teh development of diabetic nephropathy in patients with type 2 diabetes. NEJM 2001;345:870‐8. [PubMed] [Google Scholar]

Berglund 1981 {published data only}

• Berglund G. Andersson O. Beta‐blockers of diuretics in hypertension? A six year follow‐up of blood pressure and metabolic side effects. Lancet 1981;I:744‐747. [MEDLINE: ] [PubMed] [Google Scholar]

CASTEL 1994 {published data only}

• Casigila E. Spolaore P. Mazza A. Ginocchio G, et al. Effect of two different therapeutic approaches on total and cardiovascular mortality in a Cardiovascular Study in the Elderly (CASTEL). Jpn Heart J 1994;35(5):589‐600. [MEDLINE: ] [PubMed] [Google Scholar]

Coope 1986 {published data only}

• Coope J. Randomised trial of treatment of hypertension in elderly patients in primary care. Brit Med J 1986;293:1145‐1151. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]

DIABHYCAR 2004 {published data only}

• Marre M, Lievre M, Chatellier G, Mann JF, Passa P, Ménard J, DIABHYCAR Study Investigators. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 2004;328:495‐502. [PMC free article] [PubMed] [Google Scholar]

DREAM 2006 {published data only}

• DREAM trial investigators. Effect of ramipril on the incidence of diabetes. The DREAM trial investigators. N Engl J Med 2006;355:1551‐62. [PubMed] [Google Scholar]

EUROPA 2003 {published data only}

• Fox KM, for the EURopean trial On reduction of‐cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of‐ cardiovascular events among patients with stable coronary artery disease: Randomised, double‐blind, placebo‐controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782‐8. [PubMed] [Google Scholar]

Fuchs 2011 {published data only}

• Fuchs FD, Fuchs SC, Moreira LB, Gus M, Nobrega AC, et al. Prevention of hypertension in patients with pre‐hypertension: protocol for the PREVER‐prevention trial. Trials 2011;12(65):1‐7. [DOI: 10.1186/1745‐6215‐12‐65] [PMC free article] [PubMed] [Google Scholar]

GENERIC 2010 {published data only}

• Punzi HA, Lewin AJ, Lukic T, Goodin T, Chen W. Efficacy and safety of nebivolol monotherapy in Hispanics with Stage I‐II Hypertension (Abstract). Journal of clinical hypertension 2010;12:536. [PubMed] [Google Scholar]

GENRES 2007 {published data only}

• Hitunen TP, Suonsyrja T, Hannila‐Handelberg T, Paavonen KJ, et al. Predictors of antihypertensive drug responses: initial data from a placebo‐controlled , randomized, cross over study with four antihypertensive drugs. Journal of Hypertension 2009;27:2001‐9. [PubMed] [Google Scholar]

GLANT 1995 {published data only}

• Study Group on Long‐term Antihypertensive Therapy. A 12‐month comparison of ACE inhibitor and CA antagonist therapy in mild to moderate essential hypertension‐ the GLANT study. Hypertens Res 1995;18:235‐244. [MEDLINE: ] [PubMed] [Google Scholar]

HAPPHY 1987 {published data only}

• Wilhelmsen L. Berglund B. Elmfeldt D. Fitzsimons T, et al. Beta‐blockers versus diuretics in hypertensive men: Main results from the HAPPHY trial. J Hypertens 1987;5:561‐572. [MEDLINE: ] [PubMed] [Google Scholar]

HDFP 1984 {published data only}

• HDFP. Effect of stepped care treatment on the incidence of myocardial infarction and angina pectoris. 5‐year findings of the hypertension detection and follow‐up program. Hypertension 1984;6(Suppl 1):198‐206. [MEDLINE: ] [PubMed] [Google Scholar]

Hood 2007 {published data only}

• Hood SJ, Taylor KP, Ashby MJ, Brown MJ. The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) Double‐Blind Crossover Trial in Patients With Low‐Renin Hypertension and Elevated Aldosterone‐Renin Ratio. Circulation 2007;116:268‐75. [PubMed] [Google Scholar]

HOPE 3 2016 {published data only}

• Lonn EM, Bosch J, Lopez‐ Jaramillo P, Zhu J, et al. Blood‐Pressure Lowering in Intermediate‐Risk Persons without Cardiovascular Disease. N Engl J Med 2016;374:2009‐20. [PubMed] [Google Scholar]

HOT 1995 {published data only}

• Hansson L, Zanchetti A. The Hypertension Optimal Treatment (HOT) Study: 12‐month Data on Blood Pressure and Tolerability. With Special Reference to Age and Gender. Blood Pressure 1995;4(5):313‐19. [PubMed] [Google Scholar]

IDM 2001 {published data only}

• Parving HH, Lehnert H, Brochner‐Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. NEJM 2001;345:870‐878. [PubMed] [Google Scholar]

IDNT 2003 {published data only}

• Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, Drury PL, Esmatjes E, Hricik D, Parikh CR, Raz I, Vanhille P, Wiegmann TB, Wolfe BM, Locatelli F, Goldhaber SZ, Lewis EJ, Irbesartan Diabetic Nephropathy Trial. Collaborative Study Group. Cardiovascular outcomes in the Irbesartan diabetic nephropathy trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med 2003;138:542‐9. [PubMed] [Google Scholar]

IMAGINE 2008 {published data only}

• Rouleau JL, Warnica WJ, Baillot R, Block PJ, Chocron S, Johnstone D, Myers MG, Calciu CD, Dalle‐Ave S, Martineau P, Mormont C, Gilst WH, IMAGINE (Ischemia Management with Accupril post‐bypass Graft via Inhibition of the coNverting Enzyme) Investigators. Effects of angiotensin converting enzyme inhibition in low‐risk patients early after coronary artery bypass surgery. Circulation 2008;117:24‐31. [PubMed] [Google Scholar]

Imai 2011 {published data only}

• Imai E, Chan J, Ito S, Yamasaki T, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo‐controlled study. Diabetologia 2011;54:2978‐86. [PMC free article] [PubMed] [Google Scholar]

INSIGHT 1996 {published data only}

• Brown MJ. Castaigne A. De Leeuw PW. Mancia G, et al. INSIGHT: International Nifedipine GITS study: Intervention as a goal in hypertension treatment. J Hum Hypertens 1996;10((Suppl3)):S157‐160. [MEDLINE: ] [PubMed] [Google Scholar]

IPPPSH 1985 {published data only}

• The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta‐blocker, oxprenolol: The international prospective primary prevention study in hypertension (IPPPSH). J Hypertens 1985;3:379‐392. [MEDLINE: ] [PubMed] [Google Scholar]

Kondo 2003 {published data only}

• Kondo J, Sone T, Tsuboi H, Mukawa H, Morishima I, Uesugi M, Kono T, Kosaka T, Yoshida T, Numaguchi Y, Matsui H, Murohara T, Okumura K. Effects of low‐dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease. Am Heart J 2003;146:E20‐25. [PubMed] [Google Scholar]

Kuramoto‐2 1994 {published data only}

• Kuramoto K. Treatment of the elderly hypertensives in Japan: National Intervention Cooperative Study in Elderly Hypertensives. The National Intervention Cooperative study Group. J Hypertens 1994;12(6):S35‐40. [MEDLINE: ] [PubMed] [Google Scholar]

Lewis 1993 {published data only}

• Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin‐converting‐enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456‐62. [PubMed] [Google Scholar]

Lewis 2001 {published data only}

• Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin‐receptor antagonist irbesartan in patients with nephropathy due to Type 2 Diabetes. NEJM 2001;345:851‐860. [PubMed] [Google Scholar]

MacMahon 2000 {published data only}

• MacMahon S, Sharpe N, Gamble G, Clague A, Mhurchu CN, Clark T, et al. PART‐2 Collaborative Research Group. Randomized, placebo‐controlled trial of the angiotensin‐converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. J Am Coll Cardiol 2000;36:438‐43. [PubMed] [Google Scholar]

MAPHY 1988 {published data only}

• Wikstrand J. Warnold I. Olsson G, et al. Primary prevention with metoprolol in patients with hypertension: mortality results from the MAPHY study. JAMA 1988;259:1976‐1982. [MEDLINE: ] [PubMed] [Google Scholar]
• Wikstrand J, et al. Metoprolol versus thiazide diuretics in hypertension. Morbidity results from the MAPHYstudy Hypertension 1991;17:579‐588. [MEDLINE: ] [PubMed] [Google Scholar]

Materson 1997 {published data only}

• Materson BJ. Reda DJ. Cushman WC. Massie BM, et al. Single‐drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. NEJM 1997;328:914‐921. [MEDLINE: ] [PubMed] [Google Scholar]

MIDAS 1996 {published data only}

• Borhani NO. Mercuri M. Borhani PA. Buckalew VM. Canossa‐Terris M, et al. Final outcome results of the multicenter isradipine diuretic atherosclerosis study (MIDAS) A randomised controlled trial. JAMA 1996;276:785‐791. [MEDLINE: ] [PubMed] [Google Scholar]

Morgan 1980 {published data only}

• Morgan TO. Adams WR. Hodgson M, Gibberd RW. Failure of therapy to improve prognosis in elderly males with hypertension. Med J Aust 1980;2(1):27‐31. [MEDLINE: ] [PubMed] [Google Scholar]

NAVIGATOR 2010 {published data only}

• McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362:1477‐90. [PubMed] [Google Scholar]

NICOLE 2003 {published data only}

• Dens JA, Desmet WJ, Coussement P, Scheerder KD, et al. Long term effects of nisoldipine on the progression of coronary atherosclerosis and the occurrence of clinical events: the NICOLE study. Heart 2003;89:887‐92. [PMC free article] [PubMed] [Google Scholar]

NORDIL 2000 {published data only}

• Hansson L. Hedner T. Lund‐Johnson P. Kjeldsen SE, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta‐blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Dilitazem (NORDIL) study. Lancet 2000;356(9227):359‐65. [MEDLINE: ] [PubMed] [Google Scholar]

PEACE 2004 {published data only}

• Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL, PEACE Trial Investigators. Angiotensin converting‐ enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058‐68. [PMC free article] [PubMed] [Google Scholar]

Pool 2007 {published data only}

• Pool JL, Glazer R, Weinberger M, et al. Comparison of valsartan/hydrochlorothiazide combination therapy at doses up to 320/25mg versus monotherapy: a double‐blind, placebo‐controlled study followed by long‐term combination therapy in hypertensive adults. Clin Ther 2007;29(1):61‐73. [PubMed] [Google Scholar]

PRoFESS 2008 {published data only}

• Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, etal. PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359:1225‐37. [PMC free article] [PubMed] [Google Scholar]

PROGRESS 2001 {published data only}

• PROGRESS Collaborative Group. Randomised trial of a perindopril‐based blood‐pressure‐lowering regimen among 6105 individuals with previous stroke or transient ischemic attack.. Lancet 2001;358:1033‐41. [PubMed] [Google Scholar]

QUIET 2001 {published data only}

• Pitt B, O'Neill B, Feldman R, Ferrari R, Schwartz L, Judra H, Bass T, et al. The QUinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol 2001;87:1058‐1063. [PubMed] [Google Scholar]

REIN 1997 {published data only}

• GISEN Group. Randomised placebo‐controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non‐diabetic nephropathy [Gruppo Italiano di Studi Epidemiologici in Nefrologia]. Lancet 1997;349:1857‐63. [PubMed] [Google Scholar]

RENAAL 2001 {published data only}

• Brenner BM, Cooper ME, Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861‐9. [PubMed] [Google Scholar]

ROAD 2007 {published data only}

• Hou FF, Xie D, Zhang X, Chen PY, Zhang WR, Liang M, Guo ZJ, Jiang JP. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol 2007;18:1889‐98. [PubMed] [Google Scholar]

ROADMAP 2011 {published data only}

• Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, et al. ROADMAP Trial Investigators. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907‐17. [PubMed] [Google Scholar]

SCAST 2015 {published data only}

• Jusufovic M, Sandset EC, Bath PM, Karlson BW, Berge E. Scandinavian Candesartan Acute Stroke Trial Study Group. Effects of blood pressure lowering in patients with acute ischemic stroke and carotid artery stenosis. International Journal of Stroke 2015;10:354‐9. [PubMed] [Google Scholar]

SCAT 2000 {published data only}

• Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W, Dzavik V, Taylor D, Yokoyama S, Montague TJ. Long‐term effects of cholesterol lowering and angiotensin converting enzyme inhibition on coronary atherosclerosis.. Circulation 2000;102:1748‐54. [PubMed] [Google Scholar]

Schmieder 2012 {published data only}

• Schmieder RE, Philipp T, Guerediaga J, Gorostidi M, et al. Long‐term antihypertensive efficacy and safety of the oral direct renin Inhibitor aliskiren. A 12‐month randomized, double‐blind comparator trial with hydrochlorothiazide. Circulation 2009;119:417‐25. [PubMed] [Google Scholar]

SCOPE 2003 {published data only}

• Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double‐blind intervention trial. J Hypertension 2003;21:875‐886. [PubMed] [Google Scholar]

SHELL 1995 {published data only}

• Zanchetti A. Evaluating the benefits of an antihypertensive agent using trials based on event and organ damage: the systolic Hypertension in the Elderly Long‐term Lacidipine (SHELL) trial and European Lacidipine Study on Atherosclerosis (ELSA). J of Hypertension‐ supplement 1995;13(4):S35‐9. [MEDLINE: ] [PubMed] [Google Scholar]

Sprackling 1981 {published data only}

• Sprackling ME, Mitchell JRA, Short AH, Watt G. Blood pressure reduction in the elderly: a randomised controlled trial of methyldopa. BMJ 1981;283:1151‐3. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]

STONE 1996 {published data only}

• Gong L. Zwang W. Zhu Y, et al. Shanghai Trial of Nifedipine in the Elderly (STONE) Study. J Hypertens 1996;14:1237‐46. [MEDLINE: ] [PubMed] [Google Scholar]

STOP 1991 {published data only}

• Dahlof B, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOPHypertension). Lancet 1991;338:1281‐1285. [MEDLINE: ] [PubMed] [Google Scholar]

STOP‐2 1993 {published data only}

• Dahlof B. Hansson L. Lindholm LH, et al. STOP ‐ Hypertension 2: A prospective intervention trial of "newer" vs "older" treatment alternatives in old patients with hypertension. Blood Pressure 1993;2:136‐141. [MEDLINE: ] [PubMed] [Google Scholar]

Strandberg 1991 {published data only}

• Strandberg E, et al. Long‐term mortality after 5‐year multifactorial primary prevention of cardiovascular diseases in middle‐aged men. JAMA 1991;266:1255‐1259. [MEDLINE: ] [PubMed] [Google Scholar]

SYST‐CHINA 1993 {published data only}

• Anonymous. [Systolic hypertension in the elderly: Chinese trial (Syst‐China)‐‐second interim report]. [Chinese] Chung‐Hua Hsin Hsueh Kuan Ping Tsa Chih [Chinese Journal of Cardiology] 1993;21(3):135‐7,185. [Accession number 1993350344] [PubMed] [Google Scholar]

TOMHS 1993 {published data only}

• Neaton JD. Brimm RH. Prineas RJ, et al. Treatment of mild hypertension study. Final results. JAMA 1993;270:713‐724. [MEDLINE: ] [PubMed] [Google Scholar]

TRANSCEND 2008 {published data only}

• Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P. Effects of the angiotensin‐receptor blocker telmisartan on cardiovascular events in high‐risk patients intolerant to angiotensin converting enzyme inhibitors: a randomised controlled trial. Lancet 2008;372:1174‐83. [PubMed] [Google Scholar]

VACS 1982 {published data only}

• Veterans Administrative Cooperative Study Group on Antihypertensive Agents. Comparison of propanolol and hydrochlorothiazide for the initial treatment of hypertension. II Results of long term therapy. JAMA 1982;248:2004‐2011. [MEDLINE: ] [PubMed] [Google Scholar]

VHAS 1997 {published data only}

• Agabiti RE, Dal Palu D, Leonetti G, Magnani G, Pessina A, Zanchetti A. Clinical results of the verapamil in hypertension and atherosclerosis study.. J Hypertens 1997;15:1337‐1344. [PubMed] [Google Scholar]

White 1995 {published data only}

• White WB, Stimpel M. Long‐term safety and efficacy of moexipril alone and in combination with hydrochlorothiazide in elderly patients with hypertension. J Hum Hypertension 1995;9(11):879‐84. [MEDLINE: ] [PubMed] [Google Scholar]

Additional references

BBLTTC 2005

• Turnbull F, Neal B, Albert C, Chalmers J, Chapman N, Cutler J, Woodward M, MacMahon S: Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood pressure‐lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials.. Arch Intern Med 2005;165(12):1410‐1419. [MEDLINE: ] [PubMed] [Google Scholar]

Boissel 2005

• Boissel JP, Gueyffier F, Boutitie F, Pocock S, Fagard R. Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments.. Fund Clin Pharmacol 2005;19:579‐584. [PubMed] [Google Scholar]

BPLTTC 2000

• Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure‐lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000;355:1955‐64. [PubMed] [Google Scholar]

Chen 2010

• Chen N, Zhou M, Yang M, Guo J, Zhu C, Yang J, Wang Y, Yang X, He L. Calcium channel blocker versus other classes of drugs for hypertension. Cochrane Database of Systematic Reviews 2010, Issue 8. [DOI: 10.1002/14651858.CD003654.pub4] [PubMed] [CrossRef] [Google Scholar]

Collins 1990

• Collins, R, Peto, R, Macmahon, S, Hebert, P, Fiebach, N.H, Eberlein, k.A, Godwin, J, Qizilbash, N, Taylor, J.O, Hennekens, C.H. Blood pressure, stroke, and coronary heart disease‐ Part 2. Short‐term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827‐38. [MEDLINE: ] [PubMed] [Google Scholar]

Diao 2012

• Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database of Systematic Reviews 2012, Issue 8. [DOI: 10.1002/14651858.CD006742.pub2] [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Duarte 2010

• Duarte JD, Cooper‐DeHoff RM. Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide‐like diuretics. Expert Rev Cardiovasc Ther. 2010;8(6):793‐802. [PMC free article] [PubMed] [Google Scholar]

Frishman 2005

• Frishman W.H, Cheng‐Lai A, Nawarskas J. Current Cardiovascular Drugs. Fourth. Current Science Group, 2005:153. [Google Scholar]

Goeres 2014

• Goeres LM, Eckstrom E, Lee DS. Pharmacotherapy for Hypertension in Older Adults: A Systematic Review. Drugs Aging 2014;31:897‐910. [PubMed] [Google Scholar]

GRADEpro GDT [Computer program]

• McMaster University (developed by Evidence Prime). GRADEpro GDT. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015.

Gueyffier 1996

• Gueyffier F. Froment A, Gouton M. New meta‐analysis of treatment trials of hypertension: improving the estimate of therapeutic benefit. J Human Hyperten 1996;10:1‐8. [MEDLINE: ] [PubMed] [Google Scholar]

Gueyffier 1999

• Gueyffier F, Bulpitt C, Boissel JP, Schron E, Ekbom T, et al. for the INDANA Group. Antihypertensive drugs in very old people: a subgroup meta‐analysis of randomised controlled trials. Lancet 1999;353:793‐96. [PubMed] [Google Scholar]

Higgins 2011a

• Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration. Available from handbook.cochrane.org, 2011. [Google Scholar]

Higgins 2011b

• Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JP, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration. Available from handbook.cochrane.org, 2011. [Google Scholar]

Hughes 2004

• Hughes AD. "How do thiazide and thiazide‐like diuretics lower blood pressure?". J Renin Angiotensin Aldosterone Syst 2004;5(4):155‐60. [PubMed] [Google Scholar]

Insua 1994

• Insua JT. Sacks HS. Lau TS. Lau J, et al. Drug treatment of hypertension in the elderly: A meta‐analysis. Ann Intern Med 1994;121:355‐62. [MEDLINE: ] [PubMed] [Google Scholar]

Kang 2004

• Kang S, Wu FY, An N, Ren M. A Systematic Review and Meta‐Analysis of the Efficacy and Safety of a Fixed,Low‐Dose Perindopril‐Indapamide Combination as First‐Line Treatment of Hypertension. Clinical Therapeutics 2004;26(2):257‐70. [PubMed] [Google Scholar]

Kızılırmak 2017

• Kızılırmak P, Uresin Y, Ozdemir O, Kilickiran B, et al. Renin‐angiotensin‐aldosterone system blockers and cardiovascular outcomes: a meta‐analysis of randomized clinical trials [Renin‐anjiyotensin‐aldosteron sistemi blokerleri ve kardiyovasküler sonuçları: Randomize klinik çalışmaların meta‐analizi]. Turk Kardiyol Dern Ars 2017;45(1):49‐66. [DOI: 10.5543/tkda.2016.78006] [PubMed] [CrossRef] [Google Scholar]

Law 2009

• Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta‐analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665. [PMC free article] [PubMed] [Google Scholar]

MacMahon 1993

• MacMahon S, Rogers A. The effects of blood pressure reduction in older patients: an overview of five randomized controlled trials in elderly hypertensives. Clin Exper Hypertension 1993;15(6):967‐78. [Accession number 1993344587] [PubMed] [Google Scholar]

Mulrow 1994

• Mulrow CD, Cornell JA, Herrera CR, Kadri A, et al. Hypertension in the elderly: Implications and generalizability of randomized trials. JAMA 1994;272:1932‐8. [MEDLINE: ] [PubMed] [Google Scholar]

Mulrow 1998

• Mulrow C, Lau J, Cornell J, Brand M. Pharmacotherapy for hypertension in the elderly. Cochrane Database of Systematic Reviews 1998, Issue 2. [DOI: 10.1002/14651858.CD000028] [PubMed] [CrossRef] [Google Scholar]

Musini 2009

• Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy of hypertension in the elderly. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD000028.pub2] [PubMed] [CrossRef] [Google Scholar]

Musini 2017

• Musini VM, Gueyffier F, Puil L, Salzwedel DM, Wright JM. Pharmacotherapy for hypertension in adults aged 18 to 59 years. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD008276.pub2] [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Nikolaus 2000

• Nikolaus T, Sommer N, Becker C. Treatment of arterial hypertension with diuretics, beta‐ and calcium channel blockers in old patients. Z Gerontol Geriat 2000;33:427‐32. [PubMed] [Google Scholar]

Parsons 2016

• Parsons C, Murad MH, Andersen S, Mookadam F, Labonte H. The effect of antihypertensive treatment on teh incidence of stroke and cognitive decline in the elderly: a meta‐analysis. Future Cardiology 2016;12(2):237‐48. [PubMed] [Google Scholar]

Pearce 1995

• Pearce KA, Furberg CD, Rushing J. Does Antihypertensive Treatment of the Elderly Prevent Cardiovascular Events or Prolong Life? A Meta‐analysis ofHypertension Treatment Trials. Archives of Family Medicine 1995;4:943‐50. [PubMed] [Google Scholar]

Psaty 1997

• Psaty BM, Smith NL, Siscovick DS, Koepsell TD, et al. Health outcomes associated with antihypertensive therapies used as first‐line agents. A systematic review and meta‐analysis.. JAMA 1997;277:739‐745. [MEDLINE: ] [PubMed] [Google Scholar]

Psaty 2003

• Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, Weiss NS. Health outcomes associated with various antihypertensive therapies used as first‐line agents: A network meta‐analysis. JAMA 2003;289:2534‐2544. [PubMed] [Google Scholar]

Puttnam 2017

• Puttnam J, Davis BR, Pressel SL, Whelton PK, Cushman WC, Louis GT, Margolis KL, Oparil S, Williamson J, Ghosh A, Einhorn PT and, Barzilay JI. Association of 3 different antihypertensive medications with hip and pelvic fracture risk in older adults. Secondary analysis of a randomized clinical trial. JAMA Internal Medicine 2017;177(1):67‐76. [PubMed] [Google Scholar]

Quan 1999

• Quan A, Kerlikowske K, Gueyffier F, Boissel JP and INDANA investigators. Efficacy of Treating Hypertension in Women. J General Internal Medicine 1999;14:718‐29. [PMC free article] [PubMed] [Google Scholar]

Reinhart 2011

• Reinhart M, Musini VM, Salzwedel DM, Dormuth C, Wright JM. First‐line diuretics versus other classes of antihypertensive drugs for hypertension. Cochrane Database of Systematic Reviews 2011, Issue 6. [DOI: 10.1002/14651858.CD008161.pub2] [CrossRef] [Google Scholar]

RevMan 2014 [Computer program]

• Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager. Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Sundstro¨m 2015

• Sundstro¨m J, Arima H, Jackson R, Turnbull F, et al. Effects of Blood Pressure Reduction in Mild Hypertension. A Systematic Review and Meta‐analysis. Annals of Internal Medicine 2015;162:184‐191. [PubMed] [Google Scholar]

Tan 2016

• Tan Xue‐ Ying, Hu Jing‐Bo. ACEIs/ARBs for the prevention of type 2 diabetes in patients with cardiovascular diseases: a systematic review and meta‐analysis. Int J Clin Exp Med 2016;9(5):7624‐37. [Google Scholar]

Taverny 2016

• Taverny G, Mimouni Y, LeDigarcher A, Chevalier P, Thijs L, Wright JM, Gueyffier F. Antihypertensive pharmacotherapy for prevention of sudden cardiac death in hypertensive individuals. Cochrane Database of Systematic Reviews 2016, Issue 3. [DOI: 10.1002/14651858.CD011745.pub2] [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Thijs 1992

• Thijs L. Fagard R. Lijnen P. Staessen J, et al. A meta‐analysis of outcome trials in elderly hypertensives. Journal of Hypertension 1992;10:1103‐9. [MEDLINE: ] [PubMed] [Google Scholar]

Thomopoulos 2014

• Thomopoulos C, Parati G, Zanchetti. A. Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta‐analyses, and meta‐regression analyses of randomized trials. Journal of Hypertension 2014;32(12):2285‐95. [PubMed] [Google Scholar]

Thomopoulos 2016

• Thomopoulos, C, Parati, G, Zanchetti, A. Effects of blood pressure‐lowering treatment. 6. Prevention of heart failure and new‐onset heart failure ‐ Meta‐analyses of randomized trials. Journal of Hypertension March 2016;34(3):373‐84. [PubMed] [Google Scholar]

Turnbull 2003

• Turnbull F. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood‐pressure‐lowering regimens on major cardiovascular events: results of prospectively‐designed overviews of randomised trials. Lancet 2003;362:1527‐35. [PubMed] [Google Scholar]

Wiysonge 2017

• Wiysonge, Charles S. Bradley, Hazel A. Volmink, Jimmy. Mayosi, Bongani M. Opie, Lionel H. Beta‐blockers for hypertension. Cochrane Database of Systematic Reviews 2017, Issue 1. [DOI: 10.1002/14651858.CD002003.pub2] [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Xue 2015

• Xue H, Lu Z, Tang WL, Pang LW, Wang GM, Wong GWK, Wright JM. First‐line drugs inhibiting the renin angiotensin system versus other first‐line antihypertensive drug classes for hypertension. Cochrane Database of Systematic Reviews 2015, Issue 1. [DOI: 10.1002/14651858.CD008170.pub2] [PubMed] [CrossRef] [Google Scholar]

Zanchetti 2015

• Zanchetti, A, Thomopoulos, C, Parati, G. Randomized Controlled Trials of Blood Pressure Lowering in Hypertension: A Critical Reappraisal. Circulation Research 2015;116(6):1058‐73. [PubMed] [Google Scholar]

Zhu 2005

• Zhu Z, Zhu S, Liu D, Cao T, Wang L, Tepel M. Thiazide‐like diuretics attenuate agonist‐induced vasoconstriction by calcium desensitisation linked to Rho kinase". Hypertension 2005;45(2):233‐9. [PubMed] [Google Scholar]

References to other published versions of this review

Wright 1999

• Wright JM. Cheng‐Han Lee, Chambers KC. Systematic review of antihypertensive therapies: does the evidence assist in choosing a first‐line drug?. CMAJ 1999;161(1):25‐32. [MEDLINE: ] [PMC free article] [PubMed] [Google Scholar]

Articles from The Cochrane Database of Systematic Reviews are provided here courtesy of Wiley