Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Primary Purpose
Cardiovascular Diseases, Coronary Disease, Diabetes Mellitus
Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Inhibitors, ACE
amlodipine
lisinopril
doxazosin
chlorthalidone
pravastatin
diet, fat-restricted
Sponsored by
About this trial
This is an interventional prevention trial for Cardiovascular Diseases
Eligibility Criteria
Men and women hypertensive patients, ages 55 and above. A total of 36 percent were diabetics.
Sites / Locations
Outcomes
Primary Outcome Measures
Secondary Outcome Measures
Full Information
NCT ID
NCT00000542
First Posted
October 27, 1999
Last Updated
July 28, 2016
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT00000542
Brief Title
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Study Type
Interventional
2. Study Status
Record Verification Date
February 2009
Overall Recruitment Status
Completed
Study Start Date
August 1993 (undefined)
Primary Completion Date
March 2002 (Actual)
Study Completion Date
March 2002 (Actual)
3. Sponsor/Collaborators
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
5. Study Description
Brief Summary
To determine if the combined incidence of nonfatal myocardial infarction and coronary heart disease death differs between diuretic-based and each of three alternative antihypertensive pharmacological treatments. Also, to determine, in a subset of this population, if lowering serum cholesterol with a HMG CoA reductase inhibitor in older adults reduces all-cause mortality compared to a control group receiving usual care. Conducted in conjunction with the Department of Veterans' Affairs.
Detailed Description
BACKGROUND:
An estimated 58 million people in the United States have elevated blood pressure (systolic blood pressure (SBP) of 140 mmHg or greater and/or diastolic blood pressure (DBP) of 90 mmHg or greater on initial examination) or are taking antihypertensive medication. Perhaps one-half to two-thirds of these have sustained hypertension.
Despite the known etiologic relationship of hypertension to coronary heart disease, large-scale randomized clinical trials in mild to moderate hypertension have failed to demonstrate conclusively that antihypertensive drug treatment, largely based on thiazide-like diuretics, reduces the occurrence of coronary heart disease death or non-fatal myocardial infarction. The pooled results of nine such trials, using primarily thiazide-like diuretics and involving over 43,000 subjects, suggest a 9 percent benefit, with 95 percent confidence limits consistent with a 19 percent benefit or 1 percent adverse outcome. This observed treatment effect compares with a maximum predicted effect on coronary heart disease of approximately 23 percent for an equivalent blood pressure difference, as derived from epidemiologic data. In contrast, the observed beneficial effect on stroke in these trials, 36 percent, is almost exactly that which would be predicted from epidemiologic data. A more recent overview of 14 trials in participants with all levels of hypertension estimated a somewhat larger benefit of 14 percent. While this may be an over-estimate of benefit, these overviews do not include the strongly positive results of the Systolic Hypertension in the Elderly Program (SHEP), in which diuretic-based treatment reduced stroke incidence by 36 percent and major coronary heart disease events by 27 percent.
In the early 1980s, two new classes of antihypertensive agents, the calcium antagonists and ACE inhibitors, were developed and licensed for use in chronic antihypertensive therapy. These agents cost more than older agents such as diuretics and beta-blockers, and evidence was limited that might justify their use despite the increased cost. The 1988 Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommended beta-blockers, calcium antagonists, ACE-inhibitors, and diuretics as equally acceptable first-line therapy. All four classes of drugs have been found to control diastolic blood pressure as single agents in 50 percent or more of patients with mild hypertension.
Of these drug classes, only beta-blockers have been compared directly to diuretics in large-scale, long-term clinical trials in hypertension. Three such trials completed in Europe in 1985-1986 showed approximate equivalence of effects on morbidity and mortality in diuretic- and beta-blocker-based regimens. Pooled analysis of these trials yields a 6 percent lower coronary heart disease mortality from beta-blockers. These data are in contrast to the recent Medical Research Council (MRC) Trial in the Elderly, in which patients treated with a thiazide diuretic had significantly lower rates of coronary heart disease compared to beta-blocker treatment or placebo, both by about 45 percent.
Circulating levels of cholesterol, specifically cholesterol associated with the low-density lipoprotein (LDL) fraction, have been established as a major etiologic factor in coronary heart disease in observational epidemiologic studies, in metabolic, pathologic, and genetic studies in humans and selected animal models, and in randomized clinical trials. The clinical trials that have demonstrated a reduction in coronary heart disease incidence from lowering LDL-cholesterol levels have been conducted primarily in middle-aged men with hypercholesterolemia or established coronary heart disease. Experimental evidence for the efficacy of cholesterol lowering in older men is confined to the analysis of small subgroups of clinical trials and is lacking for women of any age. The paucity of clinical trial data led the National Cholesterol Education Program's Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults in their 1987 Guidelines to allow for considerable physician judgement regarding the elderly.
DESIGN NARRATIVE:
Patients were recruited through office-based practices and hypertension clinics which were reimbursed by the Clinical Trials Center on a per-patient basis. Six hundred patients were entered into the vanguard or feasibility phase and a total of 42,448 were entered into the full-scale trial. The primary hypothesis of the antihypertensive trial was that the combined incidence of fatal coronary heart disease and nonfatal myocardial infarction would be lower in hypertensive patients randomized to amlodipine (a calcium antagonist), lisinopril (an angiotensin-converting enzyme (ACE) inhibitor), or doxazosin (an alpha adrenergic blocker) as compared to those randomized to chlorthalidone (a thiazide-like diuretic). Secondary endpoints were total cardiovascular mortality, major morbidity, all-cause mortality, and health-related quality of life.
The primary hypothesis of the cholesterol-lowering trial was that mortality from all causes would be lower in the subset of hypertensive patients with LDL cholesterol levels between 120 and 189 mg/dl (between 100 and 159 mg/dl for those with known coronary heart disease) who were randomized to receive pravastatin (a HMG CoA reductase inhibitor) plus the National Cholesterol Education Program Step I cholesterol-lowering diet than those randomized to receive usual care plus diet. Secondary endpoints were the combined incidence of nonfatal myocardial infarction and coronary heart disease death, major non-cardiovascular heart disease morbidity and mortality, and health-related quality of life.
Recruitment for the feasibility phase began in February 1994. The clinical phase of the feasibility study ended in September 1994. Recruitment for the full-scale trial began in October 1994 and ended in January, 1998. The mean follow-up was 4.9 years. There were over 600 clinics in 47 states, Puerto Rico, Virgin Islands and Canada.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiovascular Diseases, Coronary Disease, Diabetes Mellitus, Heart Diseases, Hypercholesterolemia, Hypertension, Myocardial Infarction, Myocardial Ischemia, Heart Failure
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Allocation
Randomized
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
Inhibitors, ACE
Intervention Type
Drug
Intervention Name(s)
amlodipine
Intervention Type
Drug
Intervention Name(s)
lisinopril
Intervention Type
Drug
Intervention Name(s)
doxazosin
Intervention Type
Drug
Intervention Name(s)
chlorthalidone
Intervention Type
Drug
Intervention Name(s)
pravastatin
Intervention Type
Behavioral
Intervention Name(s)
diet, fat-restricted
10. Eligibility
Sex
All
Minimum Age & Unit of Time
55 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Men and women hypertensive patients, ages 55 and above. A total of 36 percent were diabetics.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barry Davis
Organizational Affiliation
University of Texas
12. IPD Sharing Statement
Citations:
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Han BH, Sutin D, Williamson JD, Davis BR, Piller LB, Pervin H, Pressel SL, Blaum CS; ALLHAT Collaborative Research Group. Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older Adults: The ALLHAT-LLT Randomized Clinical Trial. JAMA Intern Med. 2017 Jul 1;177(7):955-965. doi: 10.1001/jamainternmed.2017.1442.
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PubMed Identifier
28430947
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Bang CN, Soliman EZ, Simpson LM, Davis BR, Devereux RB, Okin PM; ALLHAT Collaborative Research Group. Electrocardiographic Left Ventricular Hypertrophy Predicts Cardiovascular Morbidity and Mortality in Hypertensive Patients: The ALLHAT Study. Am J Hypertens. 2017 Sep 1;30(9):914-922. doi: 10.1093/ajh/hpx067.
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Lai D, Zhang Q, Yamal JM, Einhorn PT, Davis BR; ALLHAT Collaborative Research Group. Conditional moving linear regression: modeling the recruitment process for ALLHAT. Commun Stat Theory Methods. 2017;46(18):8943-8951. doi: 10.1080/03610926.2016.1197251. Epub 2017 May 19.
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Puttnam R, Davis BR, Pressel SL, Whelton PK, Cushman WC, Louis GT, Margolis KL, Oparil S, Williamson J, Ghosh A, Einhorn PT, Barzilay JI; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Collaborative Research Group. Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults: Secondary Analysis of a Randomized Clinical Trial. JAMA Intern Med. 2017 Jan 1;177(1):67-76. doi: 10.1001/jamainternmed.2016.6821.
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Whittle J, Yamal JM, Williamson JD, Ford CE, Probstfield JL, Beard BL, Marginean H, Hamilton BP, Suhan PS, Davis BR; ALLHAT Collaborative Research Group. Clinical and demographic correlates of medication and visit adherence in a large randomized controlled trial. BMC Health Serv Res. 2016 Jul 8;16:236. doi: 10.1186/s12913-016-1471-x.
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27367818
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Dewland TA, Soliman EZ, Davis BR, Magnani JW, Yamal JM, Piller LB, Haywood LJ, Alonso A, Albert CM, Marcus GM; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Collaborative Research Group. Effect of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) on Conduction System Disease. JAMA Intern Med. 2016 Aug 1;176(8):1085-92. doi: 10.1001/jamainternmed.2016.2502.
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27174798
Citation
Kaasenbrood L, Poulter NR, Sever PS, Colhoun HM, Livingstone SJ, Boekholdt SM, Pressel SL, Davis BR, van der Graaf Y, Visseren FL; CARDS, ALLHAT, and ASCOT Investigators. Development and Validation of a Model to Predict Absolute Vascular Risk Reduction by Moderate-Intensity Statin Therapy in Individual Patients With Type 2 Diabetes Mellitus: The Anglo Scandinavian Cardiac Outcomes Trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Collaborative Atorvastatin Diabetes Study. Circ Cardiovasc Qual Outcomes. 2016 May;9(3):213-21. doi: 10.1161/CIRCOUTCOMES.115.001980. Epub 2016 May 11.
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Alderman MH, Davis BR, Piller LB, Ford CE, Baraniuk MS, Pressel SL, Assadi MA, Einhorn PT, Haywood LJ, Ilamathi E, Oparil S, Retta TM; ALLHAT Collaborative Research Group. Should Antihypertensive Treatment Recommendations Differ in Patients With and Without Coronary Heart Disease? (from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]). Am J Cardiol. 2016 Jan 1;117(1):105-15. doi: 10.1016/j.amjcard.2015.10.012. Epub 2015 Oct 19.
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Yamal JM, Oparil S, Davis BR, Alderman MH, Calhoun DA, Cushman WC, Fendley HF, Franklin SS, Habib GB, Pressel SL, Probstfield JL, Sastrasinh S; ALLHAT Collaborative Research Group. Stroke outcomes among participants randomized to chlorthalidone, amlodipine or lisinopril in ALLHAT. J Am Soc Hypertens. 2014 Nov;8(11):808-19. doi: 10.1016/j.jash.2014.08.003. Epub 2014 Aug 19.
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Piller LB, Simpson LM, Baraniuk S, Habib GB, Rahman M, Basile JN, Dart RA, Ellsworth AJ, Fendley H, Probstfield JL, Whelton PK, Davis BR; ALLHAT Collaborative Research Group. Characteristics and long-term follow-up of participants with peripheral arterial disease during ALLHAT. J Gen Intern Med. 2014 Nov;29(11):1475-83. doi: 10.1007/s11606-014-2947-1.
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Reisin E, Graves JW, Yamal JM, Barzilay JI, Pressel SL, Einhorn PT, Dart RA, Retta TM, Saklayen MG, Davis BR; ALLHAT Collaborative Research Group. Blood pressure control and cardiovascular outcomes in normal-weight, overweight, and obese hypertensive patients treated with three different antihypertensives in ALLHAT. J Hypertens. 2014 Jul;32(7):1503-13; discussion 1513. doi: 10.1097/HJH.0000000000000204.
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Shah RV, Abbasi SA, Yamal JM, Davis BR, Barzilay J, Einhorn PT, Goldfine AB; ALLHAT Collaborative Research Group. Impaired fasting glucose and body mass index as determinants of mortality in ALLHAT: is the obesity paradox real? J Clin Hypertens (Greenwich). 2014 Jun;16(6):451-8. doi: 10.1111/jch.12325. Epub 2014 Apr 29. Erratum In: J Clin Hypertens (Greenwich). 2014 Oct;16(10):770-1. Goldfine, Allison [corrected to Goldfine, Alison B].
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Phillips W, Piller LB, Williamson JD, Whittle J, Jafri SZ, Ford CE, Einhorn PT, Oparil S, Furberg CD, Grimm RH Jr, Alderman MH, Davis BR, Probstfield JL; ALLHAT Collaborative Research Group. Risk of hospitalized gastrointestinal bleeding in persons randomized to diuretic, ACE-inhibitor, or calcium-channel blocker in ALLHAT. J Clin Hypertens (Greenwich). 2013 Nov;15(11):825-32. doi: 10.1111/jch.12180. Epub 2013 Aug 7.
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Oparil S, Davis BR, Cushman WC, Ford CE, Furberg CD, Habib GB, Haywood LJ, Margolis K, Probstfield JL, Whelton PK, Wright JT Jr; ALLHAT Collaborative Research Group. Mortality and morbidity during and after Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: results by sex. Hypertension. 2013 May;61(5):977-86. doi: 10.1161/HYPERTENSIONAHA.111.00213. Epub 2013 Mar 25.
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Drawz PE, Baraniuk S, Davis BR, Brown CD, Colon PJ Sr, Cujyet AB, Dart RA, Graumlich JF, Henriquez MA, Moloo J, Sakalayen MG, Simmons DL, Stanford C, Sweeney ME, Wong ND, Rahman M. Cardiovascular risk assessment: addition of CKD and race to the Framingham equation. Am Heart J. 2012 Dec;164(6):925-31.e2. doi: 10.1016/j.ahj.2012.09.003. Epub 2012 Oct 29.
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Rahman M, Ford CE, Cutler JA, Davis BR, Piller LB, Whelton PK, Wright JT Jr, Barzilay JI, Brown CD, Colon PJ Sr, Fine LJ, Grimm RH Jr, Gupta AK, Baimbridge C, Haywood LJ, Henriquez MA, Ilamaythi E, Oparil S, Preston R; ALLHAT Collaborative Research Group. Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. Clin J Am Soc Nephrol. 2012 Jun;7(6):989-1002. doi: 10.2215/CJN.07800811. Epub 2012 Apr 5.
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Zhang X, Lynch AI, Davis BR, Ford CE, Boerwinkle E, Eckfeldt JH, Leiendecker-Foster C, Arnett DK. Pharmacogenetic association of NOS3 variants with cardiovascular disease in patients with hypertension: the GenHAT study. PLoS One. 2012;7(3):e34217. doi: 10.1371/journal.pone.0034217. Epub 2012 Mar 28.
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Alderman MH, Piller LB, Ford CE, Probstfield JL, Oparil S, Cushman WC, Einhorn PT, Franklin SS, Papademetriou V, Ong ST, Eckfeldt JH, Furberg CD, Calhoun DA, Davis BR; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Clinical significance of incident hypokalemia and hyperkalemia in treated hypertensive patients in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension. 2012 May;59(5):926-33. doi: 10.1161/HYPERTENSIONAHA.111.180554. Epub 2012 Mar 19.
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Barzilay JI, Davis BR, Pressel SL, Cutler JA, Einhorn PT, Black HR, Cushman WC, Ford CE, Margolis KL, Moloo J, Oparil S, Piller LB, Simmons DL, Sweeney ME, Whelton PK, Wong ND, Wright JT Jr; ALLHAT Collaborative Research Group. Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension: the ALLHAT Diabetes Extension Study. Circ Cardiovasc Qual Outcomes. 2012 Mar 1;5(2):153-62. doi: 10.1161/CIRCOUTCOMES.111.962522. Epub 2012 Mar 6.
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Cushman WC, Davis BR, Pressel SL, Cutler JA, Einhorn PT, Ford CE, Oparil S, Probstfield JL, Whelton PK, Wright JT Jr, Alderman MH, Basile JN, Black HR, Grimm RH Jr, Hamilton BP, Haywood LJ, Ong ST, Piller LB, Simpson LM, Stanford C, Weiss RJ; ALLHAT Collaborative Research Group. Mortality and morbidity during and after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. J Clin Hypertens (Greenwich). 2012 Jan;14(1):20-31. doi: 10.1111/j.1751-7176.2011.00568.x. Epub 2011 Dec 9.
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Piller LB, Baraniuk S, Simpson LM, Cushman WC, Massie BM, Einhorn PT, Oparil S, Ford CE, Graumlich JF, Dart RA, Parish DC, Retta TM, Cuyjet AB, Jafri SZ, Furberg CD, Saklayen MG, Thadani U, Probstfield JL, Davis BR; ALLHAT Collaborative Research Group. Long-term follow-up of participants with heart failure in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Circulation. 2011 Oct 25;124(17):1811-8. doi: 10.1161/CIRCULATIONAHA.110.012575. Epub 2011 Oct 3.
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Haywood LJ, Ford CE, Crow RS, Davis BR, Massie BM, Einhorn PT, Williard A; ALLHAT Collaborative Research Group. Atrial fibrillation at baseline and during follow-up in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). J Am Coll Cardiol. 2009 Nov 24;54(22):2023-31. doi: 10.1016/j.jacc.2009.08.020.
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Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, Farber MA, Ford CE, Levy D, Massie BM, Nawaz S; ALLHAT Collaborative Research Group. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation. 2008 Nov 25;118(22):2259-67. doi: 10.1161/CIRCULATIONAHA.107.762229. Epub 2008 Nov 10.
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Rahman M, Baimbridge C, Davis BR, Barzilay J, Basile JN, Henriquez MA, Huml A, Kopyt N, Louis GT, Pressel SL, Rosendorff C, Sastrasinh S, Stanford C; ALLHAT Collaborative Research Group. Progression of kidney disease in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Kidney Dis. 2008 Sep;52(3):412-24. doi: 10.1053/j.ajkd.2008.05.027. Epub 2008 Aug 3.
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Wright JT Jr, Harris-Haywood S, Pressel S, Barzilay J, Baimbridge C, Bareis CJ, Basile JN, Black HR, Dart R, Gupta AK, Hamilton BP, Einhorn PT, Haywood LJ, Jafri SZ, Louis GT, Whelton PK, Scott CL, Simmons DL, Stanford C, Davis BR. Clinical outcomes by race in hypertensive patients with and without the metabolic syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2008 Jan 28;168(2):207-17. doi: 10.1001/archinternmed.2007.66.
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Black HR, Davis B, Barzilay J, Nwachuku C, Baimbridge C, Marginean H, Wright JT Jr, Basile J, Wong ND, Whelton P, Dart RA, Thadani U; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Metabolic and clinical outcomes in nondiabetic individuals with the metabolic syndrome assigned to chlorthalidone, amlodipine, or lisinopril as initial treatment for hypertension: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Diabetes Care. 2008 Feb;31(2):353-60. doi: 10.2337/dc07-1452. Epub 2007 Nov 13.
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Margolis KL, Piller LB, Ford CE, Henriquez MA, Cushman WC, Einhorn PT, Colon PJ Sr, Vidt DG, Christian R, Wong ND, Wright JT Jr, Goff DC Jr; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Blood pressure control in Hispanics in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension. 2007 Nov;50(5):854-61. doi: 10.1161/HYPERTENSIONAHA.107.092650. Epub 2007 Sep 10.
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Davis BR, Piller LB, Cutler JA, Furberg C, Dunn K, Franklin S, Goff D, Leenen F, Mohiuddin S, Papademetriou V, Proschan M, Ellsworth A, Golden J, Colon P, Crow R; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006 May 9;113(18):2201-10. doi: 10.1161/CIRCULATIONAHA.105.544031. Epub 2006 May 1.
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Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
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