ArticlesMorbidity 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)
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
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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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