Inhibitors of the RAS: Evidence-Based Medicine

Abstract

This chapter provides an overview of clinical evidence for angiotensin converting enzyme inhibitors (ACEi) and angiotensin 11 receptor blockers (ARBs or A2As). Only those data are presented which are relevant and fulfill the criteria of evidence-based medicine. The chapter is a snapshot of the current evidence as many trials are still ongoing . Given that the RAS is a ubiquitous system, it is conceivable that both drug classes are interacting with many organs . Evidence for treatment and prevention of cardiovascular (myocardial infarction, congestive heart failure) and cerebrovascular diseases (stroke), diabetes mellitus, and glomerular renal disease is extensively described. The position of both drug classes in relation to each other as well as in relation to other drug classes has been clarified for many indications. The clinical development of both substance classes was interesting: ARBs had a worse starting position because they entered the market later than ACE inhibitors. Unequivocal proof of efficacy could be shown with ACE inhibitors in placebo-controlled trials for the major indications. Thereafter, those indications were occupied by ACE inhibitors; repetition of placebo-controlled studies with ARBs was ethically unconscionable. These major indications were almost lost for ARBs. Strenuous head-to-head comparisons with the aim to demonstrate at least non-inferiority were done; add-on trials were performed, or studies in patients intolerant to ACE inhibitors. As major indications were difficult to develop with ARBs, a fruitful evolution has focused on the more minor indications such as nephropathy. ACE inhibitors and ARBs are both suitable for first-line therapy of hypertension. In unconditional CHF, ACE inhibitors are the first-line therapy; ARBs are good in patients intolerant to ACE inhibitors, or may serve as add-on therapy to ACE inhibitors. In acute MI, ACE inhibitors are effective from the first day onwards, while no data exist for ARBs on day 30. In unselected patients after MI, ACE inhibitors are effective, while no data exist for ARBs. In patients after MI with poor LV function, ACE inhibitors are effective and ARBs are at best equally effective. In primary and secondary prevention of stroke, ACE inhibitors are effective and ARBs are likely equally effective. In type 1 diabetic and nondiabetic nephropathy, ACE inhibitors have demonstrated efficacy; in type 2 diabetic nephropathy, ARBs were shown to be effective. Are ACE inhibitors and ARBs alike or not alike? Do the effects of ACE inhibitors on the bradykinin system play a significant clinical role? One puzzling observation was seen in several trials: myocardial infarctions and cardiovascular mortality were apparently not as much reduced with ARBs as with ACE inhibitors. This last mystery is addressed in a prospective clinical trial—the ongoing ONTARGET trial—with about 30,000 patients randomized