Elsevier

The Lancet

Volume 356, Issue 9227, 29 July 2000, Pages 366-372
The Lancet

Articles
Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT)

https://doi.org/10.1016/S0140-6736(00)02527-7Get rights and content

Summary

Background

The efficacy of antihypertensive drugs newer than diuretics and β-blockers has not been established. We compared the effects of the calcium-channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high risk patients with hypertension.

Methods

We did a prospective, randomised, double-blind trial in Europe and Israel in 6321 patients aged 55–80 years with hypertension (blood pressure ≥150/95 mm Hg, or ≥160 mm Hg systolic). Patients had at least one additional cardiovascular risk factor. We randomly assigned patients nifedipine 30 mg in a long-acting gastrointestinal-transport-system (GITS) formulation (n=3157), or co-amilozide (hydrochlorothiazide 25 μg plus amiloride 2·5 mg; n=3164). Dose titration was by dose doubling, and addition of atenolol 25–50 mg or enalapril 5–10 mg. The primary outcome was cardiovascular death, myocardial infarction, heart failure, or stroke. Analysis was done by intention to treat.

Findings

Primary outcomes occurred in 200 (6·3%) patients in the nifedipine group and in 182 (5·8%) in the co-amilozide group (18·2 vs 16·5 events per 1000 patient-years; relative risk 1·10 [95% CI 0·91–1·34], p=0·35). Overall mean blood pressure fell from 173/99 mm Hg (SD 14/8) to 138/82 mm Hg (12/7). There was an 8% excess of withdrawals from the nifedipine group because of peripheral oedema (725 vs 518, p<0·0001), but serious adverse events were more frequent in the co-amilozide group (880 vs 796, p=0·02). Deaths were mainly non-vascular (nifedipine 176 vs co-amilozide 172; p=0·81). 80% of the primary events occurred in patients receiving randomised treatment (157 nifedipine, 147 co-amilozide, difference 0·33% [−0·7 to 1·4]).

Interpretation

Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular or cerebrovascular complications. The choice of drug can be decided by tolerability and blood-pressure response rather than long-term safety or efficacy.

Introduction

Results from trials of antihypertensive treatment in the 1970s and 1980s showed that reduction of blood pressure, mainly by use of diuretics and β-blockers, prevented stroke but did not yield the expected reduction in overall cardiovascular complications.1 The question arose of whether this finding was attributable to undesirable properties of the available drugs or reflected a weaker contribution of hypertension to myocardial infarction than to stroke. Studies in elderly patients, mainly with isolated systolic hypertension, raised less concern about the drugs used but did not provide full reassurance about efficacy in younger patients.2 However, placebo-controlled outcome studies of new drugs in patients in whom blood-pressure reduction had already been shown to prevent stroke were no longer ethical. The alternative, comparison of two active treatments, is expensive because of the large numbers of patients required. One solution has been to undertake open-label comparisons.3, 4

The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) is a double-blind randomised trial of morbidity and mortality, in which the comparison is between older and newer classes of antihypertensive drugs in patients at high absolute risk of cardiovascular events. These patients are the main target for treatment in modern guidelines.5, 6 Our primary objective was to compare the efficacy in preventing the major complications from hypertension of nifedipine, a calcium-channel blocker, administered in a long-acting gastrointestinal-transport-system (GITS) formulation and co-amilozide a common and effective combination of the diuretics hydrochlorothiazide and amiloride.7, 8

Section snippets

Study population

Between September, 1994, and June, 1996, inclusive, we enrolled mainly white hypertensive men and women, aged 55–80 years, from 703 centres in eight countries in western Europe and Israel. Hypertension was defined as systolic blood pressure 150 mm Hg or more and diastolic blood pressure 95 mm Hg or more, or systolic blood pressure 160 mm Hg or more. To increase the number of events expected, we required that, as well as hypertension, patients have at least one additional cardiovascular risk

Results

6575 patients were randomised. After exclusion of 254 patients from centres withdrawn for misconduct (132 nifedipine, 122 co-amilozide), there were 3157 and 3164 patients assigned these drugs, respectively (figure 1). Of these 6321 patients, there were 2929 men and 3392 women, mean age 65 years (SD 6·5), mean body-mass index 28·2 kg/m2 (4·6). At screening, when 87% of patients had been previously treated, overall mean blood pressure was 167/96 mm Hg (16/9). After the 2–4 week placebo phase

Discussion

Nifedipine once daily and co-amilozide had a similar efficacy in these patients with hypertension and additional cardiovascular risk factors. From one standpoint, our results will be seen as negative. If a planned meta-analysis of trials of antihypertensive drugs,13 however, confirms a lack of difference between the major classes of drugs, INSIGHT might be seen more positively, with reduction of blood pressure being accepted as a reasonable surrogate for long-term cardiovascular protection.

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