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)

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 mmHg, or ≥ 160 mmHg 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 mmHg (SD 14/8) to 138/82 mmHg (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.