Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials

Abstract

Objective To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination. Design Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose. Subjects 40 000 treated patients and 16 000 patients given placebo. Main outcome measures Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs. Results All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose. Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.

Nifedipine GITS/Candesartan Combination Therapy Lowers Blood Pressure Across Different Baseline Systolic and Diastolic Blood Pressure Categories: DISTINCT Study Subanalyses

“…The results are also consistent with previous studies of combination therapy consisting of a CCB and an ARB 28, 29, 30, 31. Importantly, a greater and earlier effect on BP control via combination therapy has the potential to provide greater CV benefit, as suggested by meta‐analysis2 and by review of major clinical trials with CCB/RAS blocker therapies 32…”

“…In up to 50% of patients in these trials, SBP remained above 140 mm Hg even when patients received multiple antihypertensive therapies from different drug classes, emphasizing that SBP control is difficult to achieve even if DBP has been normalized. However, the current analysis and previous studies2 suggest that better control rates may be achieved even with low‐dose combination therapy than with higher doses of monotherapy.…”

“…A large number of studies have shown that the magnitude of blood pressure (BP) response to antihypertensive treatment is related to baseline BP values; ie, the higher the initial BP, the higher is the BP‐lowering effect of any treatment regimen;1, 2, 3 however, this does not translate into a greater rate of BP control. For example, an analysis of the Framingham participants that classified patients according to baseline systolic BP (SBP) reported that higher baseline SBP was associated with lower likelihood of reaching goal BP (defined as SBP <140 mm Hg and diastolic BP [DBP] <90 mm Hg) 4.…”

“…Individual clinical trials and meta‐analyses have also documented that combinations of antihypertensive drugs lower BP more effectively than escalating‐dose monotherapy2, 6 and thus have the potential for greater reduction in cardiovascular (CV) risk 7. Management guidelines8, 9, 10 support this view, with the latest guidelines from the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) recommending initial 2‐drug combination therapy for patients at high CV risk or with markedly high BP 8.…”

Accumulation of 30 min of moderately intense physical activity is a clinically meaningful treatment to reduce systolic blood pressure in prehypertension

“…19 Fourth, the overall reductions in systolic blood pressure of 3-5 mm Hg achieved by regular physical exercise as well as by exercise accumulation are relatively small compared with the 9 mm Hg reduction reached with antihypertensive drug therapy. 20 However, medication is currently not considered a treatment option for the prehypertensive patient. 1 In addition, recent research found that each 5 mm Hg decrease in systolic blood pressure reduced mortality from stroke by 14% and from coronary heart disease by 9%, 6 suggesting that the 4 mm Hg decrease in response to three 10 min walking sessions considerably benefits prehypertensive individuals in terms of reducing their cardiovascular risk.…”