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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
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional prevention trial for Cardiovascular Diseases

Eligibility Criteria

55 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

    First Posted
    October 27, 1999
    Last Updated
    July 28, 2016
    Sponsor
    National Heart, Lung, and Blood Institute (NHLBI)
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    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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    Dewland TA, Soliman EZ, Yamal JM, Davis BR, Alonso A, Albert CM, Simpson LM, Haywood LJ, Marcus GM. Pharmacologic Prevention of Incident Atrial Fibrillation: Long-Term Results From the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). Circ Arrhythm Electrophysiol. 2017 Dec;10(12):e005463. doi: 10.1161/CIRCEP.117.005463.
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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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    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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    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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    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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    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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    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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    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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