SPECIAL FEATURE J Am Soc Nephrol 15: 1356–1357, 2004

Response to Dr. Brenner’s Comments

LEE A. HEBERT,* BRAD H. ROVIN,* and CHRISTOPHER J. HEBERT† *Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio; and †Case Western Reserve University, Louis Stokes VA Medical Center, Cleveland, Ohio.

We thank Dr. Brenner for his comments. He is correct in 2. The of the study drugs favored pointing out that we misquoted the Captopril Study results. It over captopril if doses of the study medication were missed. was the combined endpoints of death, end-stage renal disease Captopril has a short half-life (less than 2 h) compared with (ESRD), and doubling of the serum creatinine—not death that of valsartan (about 6 h). Thus, if doses of study med- alone—that was significantly reduced by captopril. Thus, in ication are missed, all other factors held constant, the cap- this respect, the outcome of the Captopril Trial was not differ- topril patient likely will be undertreated compared with the ent from that of the RENAAL Study. Nevertheless, our error valsartan patient. does not change our conclusion that ACE inhibitors (ACEI) 3. Missed doses of the study medication were common in the should be first-line therapy in proteinuric disease. Our VALIANT Study. At 1-yr follow-up, 44% of the valsartan conclusion, which is supported by others, is based on multiple patients and 44% of the captopril patients were not taking lines of strong evidence unrelated to the Captopril Study (1). the target dose of medication. Because of the differences in Also, our conclusion has been strengthened by two recent pharmacokinetics of the study drugs, the valsartan patients studies, published after our paper went to press. likely received more therapy than the captopril patients. In The first such study is a Cochrane-assisted meta-analysis by fact, there is clear evidence that generally the valsartan Strippoli et al. (2), which examined the outcomes of all studies group received more therapy than the captopril group. Spe- that compared ACEI or blockers (ARB) cifically, compared with the captopril group, the valsartan with placebo in diabetic patients with nephropathy. The meta- group was more likely to require study dose reduction analysis showed similar renal outcomes with ACEI or ARB because of hypotension (P Ͻ 0.05), “renal causes” (P Ͻ therapy, but survival benefit was shown only for the ACEI 0.05), or (44% greater incidence of hyperka- treatment (2). This work, however, has not yet been published lemia, although statistical significance was not reached). as a full manuscript. Thus, the final judgment must be held in Remarkably, despite the greater BP and renal effects of abeyance. valsartan compared with captopril, greater cardiovascular The other study that supports our contention of better car- benefit from valsartan was not seen. On this basis, we diovascular protection by ACEI than ARB is, paradoxically, hypothesize that the VALIANT Study was able to show the VALIANT Study (3). The VALIANT Study was a com- equivalent cardiovascular outcomes of ARB and ACEI ther- parison of ACEI and ARB therapy in nearly 20,000 patients apy because the ACEI group was undertreated. with acute and left ventricular dysfunc- tion, , or both (3). The patients were randomized in On the basis of the above, we suggest that the VALIANT approximately equal numbers to captopril, valsartan, or both. study should not change the paradigm for kidney protection: The primary outcome measure was death from any cause. ACEI should remain first-line therapy for progressive kidney Although the VALIANT Study concluded that captopril and disease. valsartan were equal in protection against death, there are We suggest further that studies such as OPTIMAAL, design flaws that likely biased the study results in favor of CHARM, and VALIANT, which studied ischemic heart dis- ARB therapy. The key points are as follows: ease to the point of heart failure, address only a part of the question of cardiovascular protection by ACEI compared with 1. The dosing regimen favored the ARB. Valsartan was dosed ARB. Most chronic renal insufficiency patients do not have at 160 mg twice daily, and captopril at 50 mg three times heart failure. Rather, they resemble more closely the patient daily. These regimens represent the top of the recommended populations of HOPE, LIFE, or EUROPA (4). In these studies, dosing scale for valsartan but about the midpoint for that of the main cardiovascular risk factors likely were chronic pro- captopril. cesses such as , atherosclerosis, inflammation, and vascular sclerosis. By contrast, the main cardiovascular risk factors in studies such as OPTIMAAL, CHARM, and VAL- Correspondence to Dr. Lee A. Hebert, The Ohio State University Medical IANT were likely acute processes such as arrhythmia and fluid Center, 1654 Upham Drive, Columbus, OH 43210-1250. Phone: 614-293- 4997; Fax: 614-293-3073; E-mail: [email protected] overload. It is plausible that the cardiovascular benefit of ACEI 1046-6673/1505-1356 versus ARB is different if severe heart failure is present. Journal of the American Society of Nephrology It is our belief that the nephrology community would em- Copyright © 2004 by the American Society of Nephrology brace a head-to-head study of ACEI versus ARB in a popula- J Am Soc Nephrol 15: 1356–1357, 2004 ACEI/ARB Controversy 1357 tion similar to HOPE. Should that happen, both the ACEI and 2. Strippoli GFM, Craig M, Schena FP, Craig JC: Improved sur- ARB should be long-acting drugs. Noncompliance with study vival with ACE inhibitors compared with angiotensin II receptor drugs is common, even in the best of studies. Study designs antagoniss in patients with [Abstract]. JAm should account for this inevitability. We suggest that the VAL- Soc Nephrol 14: 6A, 2003 3. Pfeffer MA, McMurray JJV, Velazquez EJ, et al, for the Valsar- IANT study did not. As a consequence, the published conclu- tan in Acute Myocardial Infarction Trial investigators: Valsartan, sion of the VALIANT study is not the only plausible interpre- captopril, or both in myocardial infarction complicated by heart tation of their data. failure, left ventricular dysfunction, or both. N Engl J Med 349: 1893–1906, 2003 4. Fox KM, et al, for the EUROPA Study: Efficacy of References in reduction of cardiovascular events among patients with stable 1. Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K, Hebert coronary artery disease: randomized, double-blind, placebo-con- LA: Management of glomerular : A commentary. trolled, multicentre trial (the EUROPA study). The Lancet 362: J Am Soc Nephrol 14: 3217–3232, 2003 782–788, 2003