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Articles: Mahboob Rahman, Sara Pressel, Barry R. Davis, Chuke Nwachuku, Jackson T. Wright, Jr., Paul K. Whelton, Joshua Barzilay, Vecihi Batuman, John H. Eckfeldt, Michael A. Farber, Stanley Franklin, Mario Henriquez, Nelson Kopyt, Gail T. Louis, Mohammad Saklayen, Carole Stanford, Candace Walworth, Harry Ward, Thomas Wiegmann for the ALLHAT Collaborative Research Group* Cardiovascular Outcomes in High-Risk Hypertensive Patients Stratified by Baseline Glomerular Filtration Rate Ann Intern Med 2006; 144: 172-180 [Abstract] [Full text] [PDF]

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Consequences of ALLHAT design flaws

Lee A. Hebert, Brad H. Rovin, Christopher J. Hebert   (8 March 2006)

Consequences of ALLHAT design flaws 8 March 2006
Lee A. Hebert, M.D. The Ohio State University Medical Center, Brad H. Rovin, Christopher J. Hebert Send rapid response to journal: Re: Consequences of ALLHAT design flaws lee.hebert{at}osumc.edu Lee A. Hebert, et al.	We suggest ALLHAT’s results (1,2) should not change chronic kidney disease (CKD) management (3) because ALLHAT has design flaws that likely exaggerated diuretic’s cardiovascular (CV) and renal benefits. The design flaws and their consequences are: 1) ALLHAT deliberately recruited hypertensives with CV disease, and made diuretic one of the blinded monotherapies. This is a design flaw because CV patients are particularly vulnerable to intravascular fluid overload which can worsen hypertension, pulmonary congestion, and myocardial ischemia—and abrogate ACE inhibitor’s (ACEI’s) antiproteinuria effects (4). This design flaw advantaged the diuretic cohort, and disadvantaged the ACEI and calcium channel blocker (CCB) cohorts because neither ACEI nor CCB are appropriate to manage fluid overload. Recall that ACEI’s remarkable CV and renal benefits were demonstrated when ACEI was combined with diuretic, if needed (4). Thus, ALLHAT’s design flaw caused ACEI to underperform. By using diuretic as blinded monotherapy, ALLHAT deviated from all previous modern hypertension trials that deliberately recruited patients with CV disease. Those trials used diuretic as needed, acknowledging diuretic’s unique role in hypertension and volume control. 2) The other design flaw is ALLHAT required advancing the blinded monotherapy to achieve the blood pressure (BP) goal. This would not be a design flaw if the study subjects were uncomplicated hypertensives. In ALLHAT, however, this design biased the outcome in favor of diuretic. Consider the following, which likely was a common ALLHAT scenario. Hypertension worsens. Incipient fluid overload is suspected. The blinded monotherapy is advanced hoping it is diuretic. Unfortunately, it is ACEI or CCB. Over the ensuing weeks the fluid overload and hypertension worsen. The patient returns now manifesting an ALLHAT CV endpoint (stroke, heart failure, or MI). The corresponding renal scenario is an ALLHAT CKD patient assigned to ACEI. However, proteinuria is not reduced because of fluid overload (4). Thus, kidney function continues to decline. ALLHAT gave diuretic a monopoly on BP and volume control and still diuretic could not outperform ACEI in reducing cardiovascular death or MI (ALLHAT’s primary endpoints) or CKD progression (1,2). Viewed in this light, diuretic performed poorly. We suggest diuretic’s multiple metabolic dysfunctions, which increase CV and renal risk (5), negated the advantage given to the diuretic cohort by its monopoly on BP and volume control. ACEI should continue to be initial CKD therapy, with diuretic as needed. The rationale is diuretic enhances ACEI’s antihypertensive and antiproteinuria effects (3), ACEI mitigates diuretic’s metabolic dysfunctions (3). Lee A. Hebert, MD1 Brad H. Rovin, MD1 Christopher J. Hebert, MD2 1The Ohio State University Medical Center, Columbus, OH 2 Cleveland Clinic Foundation, Cleveland, OH 1. Wright Jr JT, Dunn JK, Cutler JA, et al: Outcomes in hypertensive black and non-black patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA 2005;293(13):1595-1608. 2. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT, Whelton PK, et al: Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Int Med 2006;144:172-180. 3. Levey AS, Uhlig K: Which antihypertensive agents in chronic kidney disease? Ann Int Med 2006;144:213-215. 4. Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K, Hebert LA: Management of glomerular proteinuria: A commentary. J Am Soc Nephrol 2003;14:3217-3232. 5. Houston MC. ALLHAT debate: diuretics are not preferred, first- line initial therapy for hypertension. Arch Intern Med 2004;164(5):570- 571 (author reply). Conflict of Interest: None declared