First‐line drugs for hypertension New search for studies and content updated (no change to conclusions)
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 We contacted authors of relevant papers regarding further published and unpublished work.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.
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.
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.
James M Wright, Vijaya M Musini, Rupam Gill
Plain language summary
Thiazides best first choice for hypertension
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.
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.
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.
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.
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.
James M Wright, Vijaya M Musini, Rupam Gill
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.
- 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.Get full text at The Cochrane Library
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