First-line drugs for hypertension

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Abstract

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. 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. 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 We contacted authors of relevant papers regarding further published and unpublished work. 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. 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. 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. 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. 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.

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Most cited references 145

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The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.

Ryan Andersen, P Arner, … (2001)

Microalbuminuria and hypertension are risk factors for diabetic nephropathy. Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes, but similar data are lacking for hypertensive patients with type 2 diabetes. We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria. A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational, randomized, double-blind, placebo-controlled study of irbesartan, at a dose of either 150 mg daily or 300 mg daily, and were followed for two years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level. The base-line characteristics in the three groups were similar. Ten of the 194 patients in the 300-mg group (5.2 percent) and 19 of the 195 patients in the 150-mg group (9.7 percent) reached the primary end point, as compared with 30 of the 201 patients in the placebo group (14.9 percent) (hazard ratios, 0.30 [95 percent confidence interval, 0.14 to 0.61; P< 0.001] and 0.61 [95 percent confidence interval, 0.34 to 1.08; P=0.081 for the two irbesartan groups, respectively). The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group, 143/83 mm Hg in the 150-mg group, and 141/83 mm Hg in the 300-mg group (P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups). Serious adverse events were less frequent among the patients treated with irbesartan (P=0.02). Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria.

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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).

Michelle Fox, Michael Gnant (2003)

Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events. We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure. We recruited patients from October, 1997, to June, 2000. 13655 patients were registered with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test only (5%). After a run-in period of 4 weeks, in which all patients received perindopril, 12218 patients were randomly assigned perindopril 8 mg once daily (n=6110), or matching placebo (n=6108). The mean follow-up was 4.2 years, and the primary endpoint was cardiovascular death, myocardial infarction, or cardiac arrest. Analysis was by intention to treat. Mean age of patients was 60 years (SD 9), 85% were male, 92% were taking platelet inhibitors, 62% beta blockers, and 58% lipid-lowering therapy. 603 (10%) placebo and 488 (8%) perindopril patients experienced the primary endpoint, which yields a 20% relative risk reduction (95% CI 9-29, p=0.0003) with perindopril. These benefits were consistent in all predefined subgroups and secondary endpoints. Perindopril was well tolerated. Among patients with stable coronary heart disease without apparent heart failure, perindopril can significantly improve outcome. About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event. Treatment with perindopril, on top of other preventive medications, should be considered in all patients with coronary heart disease.

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Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial.

L Dyal, S Yusuf, K Teo … (2008)

Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage. After a 3-week run-in period, 5926 patients, many of whom were receiving concomitant proven therapies, were randomised to receive telmisartan 80 mg/day (n=2954) or placebo (n=2972) by use of a central automated randomisation system. Randomisation was stratified by hospital. The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00153101. The median duration of follow-up was 56 (IQR 51-64) months. All randomised patients were included in the efficacy analyses. Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study (weighted mean difference between groups 4.0/2.2 [SD 19.6/12.0] mm Hg). 465 (15.7%) patients experienced the primary outcome in the telmisartan group compared with 504 (17.0%) in the placebo group (hazard ratio 0.92, 95% CI 0.81-1.05, p=0.216). One of the secondary outcomes-a composite of cardiovascular death, myocardial infarction, or stroke-occurred in 384 (13.0%) patients on telmisartan compared with 440 (14.8%) on placebo (0.87, 0.76-1.00, p=0.048 unadjusted; p=0.068 after adjustment for multiplicity of comparisons and overlap with primary outcome). 894 (30.3%) patients receiving telmisartan were hospitalised for a cardiovascular reason, compared with 980 (33.0%) on placebo (relative risk 0.92, 95% CI 0.85-0.99; p=0.025). Fewer patients permanently discontinued study medication in the telmisartan group than in the placebo group (639 [21.6%] vs 705 [23.8%]; p=0.055); the most common reason for permanent discontinuation was hypotensive symptoms (29 [0.98%] in the telmisartan group vs 16 [0.54%] in the placebo group). Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors. Although the drug had no significant effect on the primary outcome of this study, which included hospitalisations for heart failure, it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke. Boehringer Ingelheim.

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Author and article information

Journal

Title: Cochrane Database of Systematic Reviews

Publisher: Wiley

ISSN (Electronic): 14651858

Publication date (Electronic): April 18 2018

Affiliations

[1 ]University of British Columbia; Department of Anesthesiology, Pharmacology and Therapeutics; 2176 Health Sciences Mall Vancouver BC Canada V6T 1Z3

[2 ]Manipal University; Department of Pharmacology; Manipal India