ArticlesRandomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study
Introduction
The scientific background and rationale of the Nordic Diltiazem (NORDIL) study have been published previously.1 In brief, calcium antagonists have been used extensively to treat hypertension for more than 15 years and are among the compounds listed as first-line treatment in the 1989 WHO/International Society of Hypertension guidelines for the management of mild hypertension.2 A large trial that compared several classes of antihypertensive compounds in 1993, reported that diltiazem was more effective in lowering blood pressure than the other drugs.3 In addition, many observations on intermediary endpoints, especially reversal of left-ventricular hypertrophy, a powerful risk indicator in hypertension,4, 5 showed that a calcium-antagonist-based antihypertensive regimen was more effective than regimens based on diuretics, β-blockers, or both.6, 7 Later meta-analyses showed calcium antagonists to be as effective as angiotensin-converting-enzyme (ACE) inhibitors.8, 9 Such findings suggested that calcium antagonists ought to be at least as effective as diuretics or β-blockers in lowering cardiovascular risks.
No data from prospective randomised intervention trials have, however, shown that antihypertensive treatment with calcium antagonists decreased cardiovascular morbidity and mortality, as had been shown for diuretics and β-blockers in 13 previous trials of this kind.10 The first such trial data were reported in the Shanghai trial of nifedipine in the elderly (STONE),11 and the Systolic Hypertension in Europe (Syst-Eur) trial12 and the Systolic Hypertension in China (Syst-China) trial.13 The latter two trials showed that a nitrendipine-based regimen significantly lowered the frequency of stroke compared with placebo. Moreover, the Swedish Trial in Old Patients with Hypertension-2 (STOP-2)14 reported that elderly hypertensive patients were equally well protected by a regimen that included the dihydropyridine calcium antagonists felodipine and isradipine as by a conventional regimen based on diuretics, β-blockers, or both, or an ACE-inhibitor-based strategy. We started the NORDIL trial in 1992 before these data were published. All of the currently available trial data with calcium antagonists are in elderly hypertensive patients,11, 14 and mainly in patients with isolated systolic hypertension.12, 13 Moreover, all those studies were of dihydropyridine-derived calcium antagonists11, 12, 13, 14 and three of the four trials showed efficacy compared only with placebo.11, 12, 13 We did the NORDIL study, a prospective, randomised, open trial with blinded-endpoint evaluation (PROBE), which reflects routine clinical practice,15, 16 to compare the effects of diltiazem, a non-dihydropyridine calcium antagonist, with diuretics, β-blockers, or both in middle-aged patients with hypertension.
Section snippets
Patients
We recruited patients from Oct 9, 1992, to Oct 31, 1999 from 1032 health centres in Norway and Sweden. The baseline data for patients and the effect of treatment on blood pressure have been published previously.17 Eligible patients had diastolic blood pressure of 100 mm Hg or more on two occasions, were aged 50–69 years (extended to 74 years during the trial), and were previously untreated. Previously treated patients could be included if they had blood pressure of 100 mm Hg or more on two
Results
10 916 patients were randomised (figure 1). After randomisation, one centre (with 35 patients) was excluded because of uncertainty about data quality. 5290 men and 5591 women with a mean age of 60 years, therefore, remained in the study (figure 1). Of the 10 881 patients, 7108 were recruited in Sweden and 3773 in Norway. Patients were studied at primary-health-care centres by their normal physicians, but several doctors at local hospitals, who had an interest in hypertension, nephrology, or
Discussion
Although we used the PROBE design for the study, which aims to create conditions similar to clinical practice,15 inclusion in an intervention trial of this kind, with the special attention that follows, may positively affect results. In analysis of prevention of the combined primary endpoint of all stroke, myocardial infarction, and cardiovascular death, the two treatment approaches were almost indistinguishable, with a relative risk of 1·00·803 patients had such events, which gave the study an
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