Even with successful reduction of blood pressure, hypertensive patients have significantly increased rates of cardiovascular disease. Left ventricular hypertrophy (LVH) is believed to be the crucial factor in this continued risk of morbidity and mortality and, in theory, blockage of angiotensin II could reverse LVH. Angiotensin II blocking drugs such as losartan could therefore have direct cardioprotective effects in addition to the effect of lowering blood pressure. Dahlöf and colleagues compared rates of cardiovascular morbidity and death in patients treated with losartan and patients treated with conventional antihypertensive therapy consisting of atenolol and diuretics.
They enrolled more than 9,000 Scandinavian patients 55 to 80 years of age who had hypertension and evidence of LVH on electrocardiography (ECG). Exclusions included patients with secondary hypertension, recent myocardial infarction or stroke, angina, heart failure, or contraindications to the study medications. Untreated blood pressures at the beginning of the study were in the range of 160 to 200 mm Hg systolic and 95 to 115 mm Hg diastolic. Patients were randomly assigned to treatment based on losartan or atenolol, and the study was double-masked. Treatment was adjusted to attain blood pressures of less than 140/90 mm Hg, and patients were followed clinically, including ECG monitoring, for at least four years.
The 4,605 patients assigned to losartan were closely matched to the 4,588 assigned to atenolol therapy. Eighty-four percent of patients assigned to losartan remained on that drug throughout the study compared with 80 percent of those assigned to atenolol. Both regimens successfully reduced blood pressure, with systolic blood pressure falling by 29.1 and 30.2 mm Hg in the losartan and atenolol groups, respectively. Diastolic pressure was reduced by 16.8 mm Hg with losartan and by 16.6 mm Hg with atenolol. The mean blood pressures at the last visit were 144/81 mm Hg for losartan and 145/80 for atenolol. In the losartan group, 49 percent of patients achieved target systolic blood pressure compared with 46 percent of those assigned to atenolol. For diastolic pressures the figure was 89 percent of both groups. Heart rates decreased significantly more in patients assigned to atenolol.
Deaths from cardiovascular disease occurred in 204 losartan and 234 atenolol patients, but myocardial infarction occurred in 198 and 188 in each group, respectively. Although these differences were not statistically significant, the difference in all-stroke rate (232 compared with 309) was highly significant. Overall, primary cardiovascular events (death, myocardial infarction, or stroke) occurred in 23.8 per 1,000 patient-years for losartan and 27.9 per 1,000 patient-years for atenolol. The trend toward lower total mortality was in favor of losartan, and patients treated with losartan also had a 25 percent lower incidence of new-onset diabetes. Adverse events associated with therapy were significantly less common with losartan.
The authors conclude that losartan was significantly better than atenolol in reducing cardiovascular death, stroke, and myocardial infarction and has other advantages, including a reduced incidence of diabetes. Since both medications effectively reduced blood pressure, they suggest that angiotensin II blockade has direct protective actions on the cardiovascular system.
editor's note: In a second study, the results from participants with diabetes are reported independently and show a significant 24 percent reduction in risk for the combined end point. An editorial hails the two reports as proving what proponents have advocated for years—that angiotensin II inhibitors are a significant advance in hypertension therapy. The editorial points out that the impressive results reported were achieved with relatively low dosages and that even greater benefit can be expected with higher dosages. Finally, they point to evidence that the effects of angiotensin II inhibitors may be particularly effective in patients with diabetes, nephropathy, and other conditions that further increase risk to the cardiovascular system. Can we anticipate these becoming first-line drugs for hypertension?—a.d.w.