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Cardiovascular Outcomes in High-Risk Hypertensive Patients Stratified by Baseline Glomerular Filtration Rate

Mahboob Rahman, MD, MS; Sara Pressel, MS; Barry R. Davis, MD, PhD; Chuke Nwachuku, MA, MPH, DrPH; Jackson T. Wright Jr., MD, PhD; Paul K. Whelton, MD, MSc; Joshua Barzilay, MD; Vecihi Batuman, MD; John H. Eckfeldt, MD, PhD; Michael A. Farber, MD; Stanley Franklin, MD; Mario Henriquez, MD; Nelson Kopyt, DO; Gail T. Louis, RN; Mohammad Saklayen, MD; Carole Stanford, MD; Candace Walworth, MD; Harry Ward, MD; Thomas Wiegmann, MD, ALLHAT Collaborative Research Group*
[+] Article and Author Information

From Case Western Reserve University, Cleveland, Ohio; University of Texas School of Public Health, Houston, Texas; National Heart, Lung, and Blood Institute, Bethesda, Maryland; Tulane University Health Sciences Center, New Orleans, Louisiana; Kaiser Permanente of Georgia, Tucker, Georgia; University of Minnesota, Minneapolis, Minnesota; Pitman Internal Medicine Associates, Pitman, New Jersey; University of California, Irvine, Irvine, California; Bronx Nephrology Hypertension PC, Bronx, New York; Lehigh Valley Hospital, Allentown, Pennsylvania; Veterans Administration Medical Center, Dayton, Ohio; University of Missouri Kansas City and Veterans Administration Medical Center, Kansas City, Missouri; Androscoggin Clinical Associates, Lewiston, Maine; and King/Drew Medical Center and Veterans Administration Medical Center, Los Angeles, California.


ClinicalTrials.gov Identifier: NCT00000542.

Note: These data were presented in part at the National Kidney Foundation Annual Spring Clinical Meetings, Dallas, Texas, 5 April 2003.

Grant Support: This study was supported by contract NO1-HC-35130 with the National Heart, Lung, and Blood Institute (NHLBI). The ALLHAT investigators received contributions of study medications supplied by Pfizer (New York, New York) (amlodipine and doxazosin), AstraZeneca (Wilmington, Delaware) (atenolol and lisinopril), and Bristol-Myers Squibb (New York, New York) (pravastatin); the investigators also received financial support from Pfizer Inc.

Potential Financial Conflicts of Interest: Consultancies: M. Rahman (King Pharmaceuticals/Monarch), B.R. Davis (Bristol-Myers Squibb, Merck, Pfizer, SmithKline Beecham/Glaxo Wellcome, Takeda), J.T. Wright Jr. (Abbott Laboratories, AstraZeneca, Aventis, Bayer, Bioavail, Bristol-Myers Squibb, Forest Pharmaceuticals, Horizons Pharmaceuticals, King Pharmaceuticals/Monarch, Merck, NitroMed, Novartis, Pfizer, Pharmacia, Reliant Pharm, Sankyo, SmithKline Beecham/Glaxo Wellcome, Wyeth), P.K. Whelton (Pfizer), M. Henriquez (Abbott Laboratories, AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Sanofi-Synthelabo), N. Kopyt (Amgen, Merck, Novartis, Sankyo), H. Ward (Abbott Laboratories, Bristol-Myers Squibb, Covance, Keryx, Merck, Pfizer), T. Wiegmann (Boehringer Ingelheim); Honoraria: M. Rahman (Abbott Laboratories, Boehringer Ingelheim, King Pharmaceuticals/Monarch, Pfizer), B.R. Davis (Bristol-Myers Squibb, Merck, Pfizer, SmithKline Beecham/Glaxo Wellcome, Takeda), J.T. Wright Jr. (Abbott Laboratories, AstraZeneca, Aventis, Bayer, Bioavail, Bristol-Myers Squibb, Forest Pharmaceuticals, Horizons Pharmaceuticals, King Pharmaceuticals, Merck, NitroMed, Novartis, Pfizer, Pharmacia, Reliant Pharm, Sankyo, SmithKline Beecham/Glaxo Wellcome, Wyeth), P.K. Whelton (Pfizer), J. Barzilay (Takeda), M. Henriquez (Abbott Laboratories, AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Sanofi-Synthelabo), N. Kopyt (Amgen, Merck, Novartis, Sankyo), H. Ward (Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Pfizer), T. Wiegmann (Boehringer Ingelheim); Grants received: J.T. Wright Jr. (Bioavail, Forest Pharmaceuticals, Novartis, Pharmacia, Sankyo, SmithKline Beecham/Glaxo Wellcome), J. Barzilay (Boehringer Ingelheim), M. Henriquez (Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi-Synthelabo), M. Saklayen (Novartis, Otsuka Maryland), H. Ward (Abbott Laboratories), T. Wiegmann (Boehringer Ingelheim, Bristol-Myers Squibb, Keryx, Kureha/Japan); Stock ownership or options (other than mutual funds): J.H. Eckfeldt (Johnson & Johnson), M.A. Farber (Pfizer), C. Stanford (Merck, Pfizer).

Requests for Single Reprints: Barry R. Davis, MD, PhD, University of Texas Health Science Center, School of Public Health, Coordinating Center for Clinical Trials, 1200 Herman Pressler Street, Suite E801, Houston, TX 77030; e-mail, barry.r.davis@uth.tmc.edu.

Current Author Addresses: Dr. Rahman: Case Western Reserve University, University Hospitals of Cleveland, Louis Stokes Cleveland Veterans Administration Medical Center, Clinical Hypertension Program, WRN6053, 11100 Euclid Avenue, Cleveland, OH 44060-6053.

Ms. Pressel and Dr. Davis: University of Texas Health Science Center, School of Public Health, Coordinating Center for Clinical Trials, 1200 Herman Pressler Street, Suite E-801, Houston, TX 77030.

Dr. Nwachuku: National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Room 8135, Bethesda, MD 20892-7936.

Dr. Wright: University Hospitals of Cleveland, General Clinical Research Center, Horvitz Tower, Suite 7311, 11100 Euclid Avenue, Cleveland, OH 44106-5041.

Dr. Whelton: Tulane University Health Sciences Center, 1440 Canal Street, TW-5, Suite 2400, New Orleans, LA 70112.

Dr. Barzilay: Kaiser Permanente of Georgia, 200 Crescent Centre Parkway, Tucker, GA 30084.

Dr. Batuman: Tulane Medical School, Nephrology Section, Slot 45, 1430 Tulane, New Orleans, LA 70112.

Dr. Eckfeldt: Department of Laboratory Medicine and Pathology, University of Minnesota Hospital and Clinic, FUMC 609, Fairview-University Medical Center, Room B203 Mayo Building, 420 Delaware Street SE, Minneapolis, MN 55455.

Dr. Farber: Pitman Internal Medicine Associates, 410 North Broadway, Suite 1, Pitman, NJ 08071.

Dr. Franklin: 155 Barlock Avenue, Los Angeles, CA 90049.

Dr. Henriquez: Bronx Nephrology Hypertension PC, 2452 Bronx Park East, Bronx, NY 10467.

Dr. Kopyt: Nephrology–Hypertension Associates of Lehigh Valley, 401 North 17th Street, Suite 212, Allentown, PA 18104.

Ms. Louis: Tulane University Health Sciences Center, 1440 Canal Street, TW-5 Suite 2400, New Orleans, LA 70112.

Dr. Saklayen: Veterans Administration Medical Center, Wright State University, 4100 West 3rd Street, Dayton, OH 45428.

Dr. Stanford: University of Missouri Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64108-2792.

Dr. Walworth: Androscoggin Clinical Associates, 710 Main Street, Lewiston, ME 04240.

Dr. Ward: Department of Hypertension and Nephrology, King/Drew Medical Center, 12021 Wilmington Avenue, Los Angeles, CA 90059.

Dr. Wiegmann: Department of Veterans Affairs Medical Center (111A), Veterans Administration Medical Center Kansas City, 4801 East Linwood Boulevard, Kansas City, MO 64128-2295.

Author Contributions: Conception and design: B.R. Davis, J.T. Wright Jr., J.H. Eckfeldt, M. Saklayen, C. Stanford.

Analysis and interpretation of the data: M. Rahman, S. Pressel, B.R. Davis, C. Nwachuku, J.T. Wright Jr., P.K. Whelton, J. Barzilay, V. Batuman, J.H. Eckfeldt, M. Henriquez, N. Kopyt, G.T. Louis, M. Saklayen, C. Stanford, H. Ward, T. Wiegmann.

Drafting of the article: M. Rahman, S. Pressel, B.R. Davis, C. Nwachuku, J.T. Wright Jr., J. Barzilay, V. Batuman, M.A. Farber, S. Franklin, M. Henriquez, N. Kopyt, M. Saklayen, C. Stanford, C. Walworth, T. Wiegmann.

Critical revision of the article for important intellectual content: M. Rahman, B.R. Davis, J.T. Wright Jr., P.K. Whelton, J. Barzilay, J.H. Eckfeldt, S. Franklin, M. Henriquez, N. Kopyt, G.T. Louis, M. Saklayen, C. Stanford, C. Walworth.

Final approval of the article: M. Rahman, S. Pressel, B.R. Davis, J.T. Wright Jr., P.K. Whelton, J. Barzilay, M.A. Farber, S. Franklin, M. Henriquez, N. Kopyt, G.T. Louis, M. Saklayen, C. Stanford, H. Ward, T. Wiegmann.

Provision of study materials or patients: J. Barzilay, M.A. Farber, M. Henriquez, N. Kopyt, M. Saklayen, C. Stanford, C. Walworth, H. Ward, T. Wiegmann.

Statistical expertise: S. Pressel, B.R. Davis, P.K. Whelton.

Obtaining of funding: S. Pressel, B.R. Davis, C. Nwachuku, J.T. Wright Jr.

Administrative, technical, or logistic support: S. Pressel, B.R. Davis, C. Nwachuku, J.T. Wright Jr., P.K. Whelton, J.H. Eckfeldt, G.T. Louis.

Collection and assembly of data: M. Rahman, S. Pressel, B.R. Davis, J.T. Wright Jr., N. Kopyt, C. Stanford.


Ann Intern Med. 2006;144(3):172-180. doi:10.7326/0003-4819-144-3-200602070-00005
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The rationale and design of ALLHAT have been presented in detail elsewhere (13). The study received institutional review board approval, and participants provided written informed consent. Participants were men and women 55 years of age or older who had hypertension with at least 1 additional risk factor for coronary heart disease (CHD). The risk factors included previous (> 6 months) myocardial infarction (MI) or stroke, left ventricular hypertrophy demonstrated by electrocardiography or echocardiography, history of type 2 diabetes, current cigarette smoking, high-density lipoprotein cholesterol level of less than 0.91 mmol/L (<35 mg/dL), and documentation of other atherosclerotic CVD. Exclusion criteria included a history of symptomatic heart failure and/or a known left ventricular ejection fraction of less than 0.35 and a serum creatinine level greater than 176.8 µmol/L (>2 mg/dL) as reported by the investigator. Participants (n = 33 357) were recruited at 623 centers in the United States, Canada, Puerto Rico, and the U.S. Virgin Islands between February 1994 and January 1998 (Appendix Figure 1).

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Appendix Figure 1. CVD = cardiovascular disease; GFR = glomerular filtration rate. *As of 30 September 2002 database .
Randomization and follow-up of participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) by treatment group.(17)
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Appendix Figure 2. HR = hazard ratio. *  < 0.05 compared with highest decile, adjusted for age, race, sex, body mass index, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol level, low-density lipoprotein cholesterol level, fasting triglyceride level, history of diabetes, and cigarette smoking.
Coronary heart disease (CHD) and combined cardiovascular disease (CVD) by baseline glomerular filtration rate (GFR) in deciles.P
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Consequences of ALLHAT design flaws
Posted on March 5, 2006
Lee A. Hebert
The Ohio State University Medical Center
Conflict of Interest: None Declared

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

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Summary for Patients

Do the Effects of Blood Pressure Drugs Differ by Kidney Function?

The summary below is from the full report titled “Cardiovascular Outcomes in High-Risk Hypertensive Patients Stratified by Baseline Glomerular Filtration Rate.” It is in the 7 February 2006 issue of Annals of Internal Medicine (volume 144, pages 172-180). The authors are M. Rahman, S. Pressel, B.R. Davis, C. Nwachuku, J.T. Wright Jr., P.K. Whelton, J. Barzilay, V. Batuman, J.H. Eckfeldt, M.A. Farber, S. Franklin, M. Henriquez, N. Kopyt, G.T. Louis, M. Saklayen, C. Stanford, C. Walworth, H. Ward, and T. Wiegmann, for the ALLHAT Collaborative Research Group.

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