Principal results from the international nifedipine GITS study: Intervention as a goal in hypertension treatment (INSIGHT)*1

Background We compared the effects of a long-acting calcium-channel blocker with a thiazide-amiloride combination on cardiovascular mortality and morbidity in patients with additional cardiovascular risk factors. The primary objective was to demonstrate 25% superiority of nifedipine GITS. A secondary objective was to establish non-inferiority compared with co-amilozide. Methods A prospective, randomized, double-masked trial was carried out in Europe and Israel, involving 6321 patients of 55-80 years of age with hypertension (blood pressure greater than or equal to 150/95 mmHg or systolic greater than or equal to 160 mmHg). Patients were also required to have at least one out of ten additional cardiovascular risk factors, such as diabetes or hypercholesterolaemia. Patients were assigned randomly to initial treatment with either nifedipine GITS (N), 30 mg, or co-amilozide (C) (hydrochlorothiazide, 25 mg, and amiloride, 2.5 mg), so that similar numbers of patients with each risk factor could be compared between the two drugs. Dose titration was principally by dose doubling, and addition of atenolol, 25-50 mg, or enalapril, 5-10 mg. Patients were followed for a mean period of 3 years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, heart failure or stroke. Secondary outcome variables included death from any cause. Superiority analysis was of time to first event, by intention-to-treat. Non-inferiority analysis required the difference (Delta) in event-rate, and the 95% CI around Delta, to be <2% in patients remaining on randomized treatment. Findings Mean blood pressure was decreased similarly in both treatment groups, from 173/99 (14/8) mmHg to 138/82 (12/7) mmHg; 72% of patients were controlled on monotherapy. There were more withdrawals from the N group than from the C group, because of peripheral oedema in 8% and because of more serious adverse events (880 vs 776, P=0.02) in the C group. A primary end-point occurred in 200 (6.3%) of 3157 patients in the N group (182 events per 1000 patient-years) and in 182 (5.8%) of 3164 patients in the C group (16.5 events per 1000 patient-years; relative risk 1.1 [95% CI 0.90-1.3], P=0.35). Adding secondary variables, there were end-points in 383 (12.1%) of the N group (35.1 per 1000 patient-years), and 397 (12.7%) of the C group (36.5 per 1000 patient-years; relative risk 0.97 [95% CI 0.84-1.11], P=0.32). Deaths were predominantly non-vascular (N, 176 vs C, 172; P=0.81). Interpretation The INSIGHT treatment regimens achieve optimal blood pressure control in most high-risk patients. This appears to be more important than choice of individual drugs in determining outcome in hypertension. Against a previous 'gold standard', nifedipine GITS was found to be effective in preventing cardiovascular or cerebrovascular complications, and may be regarded as appropriate first-line therapy in hypertension.