CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Franz H. Messerli, MD*
* St. Lukes-Roosevelt Hospital Center, Cardiology, 1000 Tenth Avenue, Suite 3B-30, New York, New York 10019 (Email: fmesserli{at}chpnet.org).
In writing a viewpoint article on dual renin-angiotensin system (RAS) blockade (1), I seem to have inadvertently stepped into a hornet's nest. The ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) trial, like all studies, can be criticized, and in retrospect there is always "should've, would've, could've." This is particularly true when findings go against the grain of what is perceived as a major paradigm, namely, albuminuria/proteinuria being synonymous with renal outcome. Clearly, this paradigm was shattered by the ONTARGET study: in patients with relatively low urinary albumin excretion, dual RAS blockade compared with ramipril alone was associated with a decrement in glomerular filtration rate despite less progression in albuminuria. Thus, urinary albumin excretion can no longer be taken as a sign of renal outcome. Similarly, preventing microalbuminuria or the transition from microalbuminuria to macroalbuminuria can no longer be taken as a foolproof sign of renal protection.
Dr. Parving and colleagues are puzzled about the rise from baseline to final albumin/creatinine ratio in all 3 arms. They may have overlooked similar findings in the Micro-HOPE (Micro-Heart Outcomes Prevention Evaluation) study (2) and, of particular interest, in their own AVOID study (3) in the losartan arm. Since many participants were on a RAS blocker before entering the trial, an increase in urinary albumin excretion with time is not unexpected.
Most patients with renal disease die of cardiovascular events before they ever reach dialysis. The ONTARGET study has proven that dual RAS blockade as opposed to monotherapy with an angiotensin-converting enzyme (ACE) inhibitor has no cardiovascular advantage. All renal trials done so far (including by some of the authors of this letter to the editor) were underpowered to assess the effects of treatment on cardiovascular outcomes.
Dr. Parving and colleagues may also want to remember that in the ONTARGET study the maximal dose of an ACE inhibitor and an angiotensin-receptor blocker (ARB) were tested. With a combination of submaximal doses as was done in many other studies, not surprisingly, a greater effect will be achieved with a combination than with monotherapy.
The importance of the dose is acknowledged by McMurray (4) who stated in the accompanying editorial of the ONTARGET study, "The addition of an ARB to an ACE inhibitor has no benefit...in patients with arterial disease but seems to be beneficial in patients with heart failure, although the trials in heart failure did not test the addition of an ARB to a full dose of a proven ACE inhibitor." Could it be that indeed safety was the reason for not testing full doses in heart failure?
Dr. McMurray and colleagues may also want to consider that a mortality reduction of 11% (p = 0.086) in heart failure was only seen in the CHARM/added (Candesartan in Heart Failure–Added Trial) study and not in the ValHeft (Valsartan Heart Failure Trial) study or the CHARM/alternative (Candesartan in Heart Failure–Alternative Trial) study. Of note, the bulk of benefit in the ValHeft study occurred in a small group of patients who were ACE-inhibitor intolerant (and therefore only received valsartan and not dual RAS blockade). The dose issue notwithstanding, this would indicate that the benefits of dual RAS blockade in heart failure are not as ironclad as the authors would like us to think.
However, the CHARM study allows us to clearly identify a safety issue. Hyperkalemia was almost 5 times more common, and elevated creatinine occurred twice as much with dual RAS blockade than with monotherapy. Since close monitoring is mandatory in these patients, would it not it be more appropriate to add an aldosterone blocker as the next step in heart failure rather than an ARB? Mortality was reduced by 25% (p > 0.00001) with the addition of aldosterone blockade (5) as opposed to none of significance with dual RAS blockade (6). Thus, the data in aggregate (and cost) seem to favor aldosterone blockade over ARBs. Instead of fiddling around with dual and even triple RAS blockade, physicians and patients would be much better served by a prospective randomized controlled trial serving to identify this next step in heart failure patients on ACE inhibitors.
As to guidelines, we should remember that converting data into recommendations requires invariably subjective judgments. Inherent biases of the panel members may mold those judgments. Such molding becomes of particular concern when panel members are also principle authors of studies that provide the data to be converted into guideline recommendations.
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References
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1. Messerli FH. The sudden demise of dual renin-angiotensin system blockade or the soft science of the surrogate end point J Am Coll Cardiol 2009;53:468-470.[Abstract/Free Full Text]2. Heart Outcomes Prevention Evaluation Study Investigators Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy Lancet 2000;355:253-259.[CrossRef][Web of Science][Medline] 3. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, AVOID Study Investigators Aliskiren combined with losartan in type 2 diabetes and nephropathy N Engl J Med 2008;358:2433-2446.[Abstract/Free Full Text] 4. McMurray JJ. ACE inhibitors in cardiovascular disease—unbeatable? N Engl J Med 2008;358:1615-1616.[Free Full Text] 5. Ezekowitz JA, McAlister FA. Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials Eur Heart J 2009;30:469-477.[Abstract/Free Full Text] 6. Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction Ann Intern Med 2004;141:693-704.[Abstract/Free Full Text]
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