Morbidity and mortality on combination versus monotherapy: a posthoc analysis of the Systolic Hypertension in Europe trial

Background The current literature supports the immediate use of combinations of antihypertensive drugs in terms of ease of use and adherence, but the key issue whether combination therapy is more effective than monotherapy in the prevention of cardiovascular complications remains unproven. Methods We analysed the double-blind (median follow-up 2.0 years) and open follow-up (6.0 years) phases of the Systolic Hypertension in Europe trial. Patients were 60 years or more with an entry systolic/diastolic blood pressure (BP) of 160-219/less than 95 mmHg. Antihypertensive treatment started immediately after randomization in the active-treatment group, but only after completion of the double-blind trial in control patients. Treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day). We adjusted our analyses for sex, age, history of cardiovascular complications, baseline systolic BP and previous antihypertensive treatment. Results During the double-blind trial, adding enalapril to nitrendipine (n=515), compared with the equivalent combination of placebos (n=559), decreased systolic BP by a further 9.5 mmHg and reduced all cardiovascular events by 51% (P=0.0035) and heart failure by 66% (P=0.032), with similar trends for stroke (-51%; P=0.066) and cardiac events (-44%; P=0.075). Over the whole duration of follow-up, combination therapy (n=871), compared with nitrendipine monotherapy (n=1552), decreased systolic BP by 3.1 mmHg and reduced total mortality (-32%; P=0.023), with similar trends for all cardiovascular events (-23%; P=0.081) and stroke (-42%; P=0.054). Conclusion Despite the limitations of a posthoc analysis, but congruent with the stronger BP reduction, our results suggest that combination therapy with nitrendipine plus enalapril might improve outcome over and beyond the benefits seen with nitrendipine monotherapy. J Hypertens 28:865-874