Angiotensin receptor blockers : baseline therapy in hypertension ?

The provocative editorial by Verma and Strauss in the BMJ 5 years ago stating that angiotensin receptor blockers (ARBs) ‘may increase myocardial infarction—and patients may need to be told’ caused a tempest in the teapot and led to extensive scrutiny of outcome data with this drug class. In 2007 the blood pressurelowering treatment trialists collaboration found that there were similar blood pressure-dependent effects of angiotensin-converting enzyme (ACE) inhibitors and ARBs for the risk of stroke, coronary heart disease, and heart failure. The authors cautioned, however, that only for ACE inhibitors but not for ARBs, was there evidence of a blood pressure-independent effect on the risk of major coronary disease events. Also, ONTARGET, a thorough, double-blind prospective randomized trial, documented equal outcome efficacy of an ARB and an ACE inhibitor in a high-risk population, although there was a trend for better stroke prevention in the ARB (telmisartan) arm and better coronary artery disease prevention in the ACE inhibitor (ramipril) arm. When analysing these studies and including the most recent ARB trials such as TRANSCEND, PRoFESS, CASE-J trial, HIJ-CREATE, JIKEI, and KYOTO, we found, in a database of 100 000 patients from 26 randomized non-heart failure trials of ARBs, a 13% reduction in the risk of stroke (P 1⁄4 0.022) (Figure 1) but a trend towards increased risk of myocardial infarction, especially when compared with active treatment (P 1⁄4 0.06) (Figure 2). Much ink has been wasted on the outcome of TRANSCEND and PRoFESS, in both of which telmisartan, despite a fall in blood pressure, did not reduce cardiovascular events better than placebo. We perhaps also should consider that a majority of patients in both of these trials were pre-treated with a blocker of the renin–angiotensin system (RAS). Thus, both trials were evaluating the effects of discontinuation of RAS blockade rather than the effects of starting RAS blockade. Conceivably we are observing, in both of these studies, a ‘legacy effect’ of pre-randomization RAS blockade. Also, we should not forget that several ACE inhibitor trials such as QUIET, PEACE, PROGRESS, and CAMELOT did not beat placebo despite a significant fall in blood pressure. For once, in the present KYOTO study, there was no significant difference in blood pressure between the two treatment arms. At study end, 50% more patients were treated with a calcium antagonist in the non-ARB arm. Thus, KYOTO is somewhat reminiscent of VALUE in which patients were, in a double-blind prospective study design, randomized to either valsartan or amlodipine. However, the results of KYOTO are diametrically different from those of VALUE in that KYOTO, for a given blood pressure reduction, showed a 45% reduction of the primary endpoint compared with the non-ARB arm. This benefit was driven mainly by stroke and, somewhat surprisingly, angina, while there was no significant difference in myocardial infarction, heart failure, and allcause mortality. In contrast, in VALUE, stroke, if anything, was reduced less well in the valsartan arm than in the amlodipine arm. While the disparity in blood pressure control in favour of amlodipine may have confounded the interpretation of the results of the (double-blind) VALUE trial, in (open label) KYOTO, despite the difference in treatment options, surprisingly exactly the same blood pressure reduction was achieved in the ARB and non-ARB arm throughout the study. Similar to VALUE, the risk of new-onset diabetes was significantly less in the valsartan than in the non-ARB arm. Could the different results of VALUE and KYOTO be explained by the study populations? Asians may be particularly receptive to the protective effects of ARBs, as was shown in RENAAL where most of the benefits occurred in the Asian subpopulation. Cerebrovascular disease is more prevalent and coronary artery disease less prevalent in Asians than in western societies. Not surprisingly, therefore, a reduction of strokes is easier to document than a reduction of coronary artery disease, as was shown in both the JIKEI-Heart Study and KYOTO. With regard to angina, we should remember that this is a rather soft endpoint and that because of the open label design, investigators were fully aware