The Framingham Heart Study showed that hypertension was associated with increased morbidity and mortality;24 intervention trials subsequently found that antihypertensive treatment with diuretics or calcium channel blockers reduced blood pressure and decreased morbidity and mortality.19,20 It became a common conclusion that any drug which reduced blood pressure would reduce the risk of cardiovascular disease.25 However, it has since been found that this is not always the case. Four independent studies with beta-blockers showed that, despite lowering blood pressure, beta-blockers did not reduce the risk of stroke and were less cerebroprotective than diuretics.26-29 In the recent Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS), risk of stroke in hypertensive and normotensive subjects was significantly reduced by the diuretic indapamide, but there was no apparent significant benefit from the addition of the ACE inhibitor perindopril.30
Several intervention trials have now investigated the use of AIIAs.
LIFE31
Losartan Intervention For Endpoint reduction in hypertension
This study compared losartan versus the beta-blocker atenolol in over 9,000 patients with previously untreated or treated hypertension with LVH. Mean blood pressure was substantially reduced in both groups, although the target BP of 140/90 mm Hg was achieved by <50% of patients in both groups. The primary composite endpoint of death, MI, or stroke occurred in 11% and 13% of patients in the losartan and atenolol groups, respectively, with the major difference being in the reduction in stroke … stroke rate was 5% with losartan and 7% with atenolol (RRR=25%).
SCOPE32
Study on Cognition and Prognosis in the Elderly (SCOPE)
This study investigated if candesartan would reduce cardiovascular events, cognitive decline, and dementia in 4,964 elderly patients with mild-to-moderate hypertension. Reductions in mean blood pressure were similar in patients treated with candesartan and those treated with other antihypertensives, but the relative risk of non-fatal stroke was reduced by 27.8% in the candesartan group (p=0.04). This indicates that blockade of the RAS provides beneficial effects over and above those of blood pressure reduction.
VALUE33
Valsartan Antihypertensive Long-term Use Evaluation
This study compared valsartan versus amlodipine in hypertensive patients over 50 years of age. There were unintended BP differences early in the trial in favour of amlodipine, but there were no significant differences between treatments in cardiac mortality, morbidity and stroke. Valsartan was significantly better in reducing the number of new cases of diabetes (p<0.001).
CHARM34
Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity
This study compared candesartan versus placebo in about 7,600 patients with varying degrees of heart failure. Compared with placebo, candesartan gave significant reductions in all-causes mortality (p=0.032), combined incidence of death and CHF hospital admission (p<0.0001), and in the number of patients developing new diabetes (p=0.02).
PRIME35
Program for Irbesartan Mortality and Morbidity Evaluations
This study compared irbesartan versus placebo in about 2,300 hypertensive patients with type-2 diabetes and kidney disease. Irbesartan reduced the risk of patients progressing to more advanced stages of kidney disease, and significantly reduced the number of hospitalisations due to congestive heart failure. Blockage of AII receptors ensures that the cardiovascular effects of AII are inhibited irrespective of their route of synthesis.