Reviews for Primary Care - Fall 2007 - (Page 36) The Renin-Angiotensin System and Cardiovascular Diseases continued Proportion reaching endpoint (%) 30 25 20 15 10 5 P 0 0 6 12 18 24 Months after randomization 84 83 86 79 75 83 65 72 76 30 36 .02 Combination Losartan Trandolapril Number at risk Losartan 89 Trandolapril 86 Combination 88 88 85 87 59 63 73 47 58 67 Figure 3. Renoprotective benefits of angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) combination therapy in the combination treatment of angiotensin-II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease (COOPERATE) trial. Figure indicates the percentage of patients in the COOPERATE trial reaching the primary study endpoint (time to doubling of serum creatinine concentration or end stage renal disease). Patients received treatment with either the ACE inhibitor trandolapril, the ARB losartan, or a combination of both drugs. Reprinted with permission from Elsevier.37 www.medreviews.com RAS Suppression by Inhibiting Renin Given that overall RAS activity is regulated by the activity of renin, and that the effects of ACE inhibitors and ARBs are potentially attenuated by the increased release of renin, inhibiting the action of renin stands out as a logical approach to improving the completeness of RAS suppression. Indeed, inhibition of renin was identified as the optimum means of inhibiting the RAS as long ago as 1957.31 Efforts to develop a clinically effective renin inhibitor have been ongoing for longer than 30 years, but until recently they have been thwarted by problems with poor pharmacokinetics, low efficacy, and complexity of synthesis.39 Renin inhibition prevents the formation of angiotensin I and angiotensin II (whether generated by ACE-dependent or ACE-independent pathways), as well as all the angiotensin peptides that are subsequently derived from angiotensin I and angiotensin II.39 The addition of a renin inhibitor to ACE inhibitor or ARB therapy would neutralize the compensatory rise in plasma renin activity that these agents induce (Figure 2), potentially enhancing suppression of the RAS. Moreover, because the renin enzyme is so specific— angiotensinogen is its only known natural substrate—renin inhibition would be expected to provide these additional benefits without additional side effects.40 As yet, however, the clinical effects of this type of dual RAS blockade have not been tested, although the results of a study measuring the combined effects of an ACE inhibitor (ramipril) and a renin inhibitor (aliskiren) on components of the RAS are expected to be reported soon. Because attempts to develop an effective oral renin inhibitor have long met with failure, many experts doubted that an agent such as a cardiovascular drug could be created. However, interest in renin as a target for antihypertensive therapy has recently been resurrected by the development of aliskiren, the first in a new class of orally effective renin inhibitors.41 Studies in healthy volunteers showed that treatment with aliskiren caused dose-dependent reductions in plasma renin activity and angiotensin II levels.42 Early clinical trials in patients with hypertension showed that this drug provided antihypertensive efficacy comparable to that of the ARBs losartan and irbesartan,43,44 with placebo-like tolerability.44,45 Moreover, a pilot study in healthy volunteers showed that aliskiren in combination with valsartan neutralized the compensatory rise in plasma renin activity and angiotensin II that is normally stimulated by the ARB,46 suggesting that a renin inhibitor might be able to expand the reach of existing RAS inhibitors. The results of further studies investigating the organ-protective and outcome benefits of aliskiren are awaited. The Importance of Target Organ Damage: The Hypertension Writing Group New Definition of Hypertension The discovery that RAS activation is a contributor to the development of target organ damage in some patients with hypertension, independent of the effects of BP, has led to a growing realization that BP values alone represent an incomplete indicator of the presence of target organ damage and overall cardiovascular risk. Indeed, trials such as HOPE and EUROPA showed that RAS inhibitor treatment can provide outcome benefits even in patients who have BP levels below the threshold for diagnosis of hypertension.7,8 The Hypertension Writing Group has responded to this realization by proposing a new definition of hypertension in which BP values are 36 VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE http://www.medreviews.com
For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.