Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial - ALLHAT
Contribution To Literature:
The ALLHAT trial showed that fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) did not differ between initial use of the chlorthalidone versus lisinopril or amlodipine.
ALLHAT was a randomized, double-blind, active-controlled clinical trial comparing the effects of amlodipine, lisinopril, or doxazosin versus chlorthalidone in patients with hypertension.
Patients Enrolled: 33,357
Mean Follow-Up: 4.9 years
Mean Patient Age: 55+ (average 67 years)
Men and women age ≥55 years with systolic blood pressure (BP) ≥140 mm Hg and/or diastolic BP ≥90 mm Hg or took medication for hypertension and had at least one additional risk factor for CHD (prior MI or stroke, left ventricular hypertrophy by ECG or echocardiogram, type 2 diabetes, current smoking, or low high-density lipoprotein cholesterol)
History of hospitalized or treated symptomatic heart failure and/or known left ventricular ejection fraction <35%
Fatal CHD and nonfatal MI
All-cause mortality, stroke, and major cardiovascular disease (CVD) events (congestive heart failure [CHF], coronary revascularization, angina, and peripheral artery disease)
Patients were randomized to chlorthalidone (12.5-25 mg/day; n = 15,255), doxazosin (2-8 mg/day, n = 9,067), amlodipine (2.5-10 mg/day, n = 9,048), or lisinopril (10-40 mg/day, n = 9,054) in a ratio of 1.7:1:1:1. The therapeutic goal was systolic BP <140 mm Hg and diastolic BP <90 mm Hg. If the BP goal was not met on maximal dosage, an open-label Step 2 or 3 agent could be added (atenolol, reserpine, or clonidine). Patients were seen every 3 months during the first year and every 4 months thereafter.
In the chlorthalidone arm, 13.2% of patients were taking a diuretic with a calcium channel blocker (CCB) or an angiotensin-converting enzyme (ACE) inhibitor and 9.0% were taking a CCB or an ACE inhibitor without a diuretic at 5 years.
In the amlodipine arm, 16.6% of patients were taking a diuretic with a CCB and 6.9% were taking a CCB without a diuretic at 5 years.
In the lisinopril arm, 15.7% of patients were taking a diuretic with an ACE inhibitor and 8.5% were taking an ACE inhibitor without a diuretic at 5 years.
No significant difference was observed between the amlodipine and chlorthalidone arms for the primary outcome of fatal CHD or nonfatal MI (11.3% vs. 11.5%, relative risk [RR] 0.98, p = 0.65) or for the secondary outcomes of all-cause mortality (16.8% vs. 17.3%, RR 0.96, p = 0.20), combined CHD (19.9% vs. 19.9%, RR 1.00, p = 0.97), stroke (RR 0.93, p = 0.28), combined CVD, angina, coronary revascularization, peripheral arterial disease, cancer, or end-stage renal disease (ESRD).
For the individual components of the secondary composite endpoints, the amlodipine arm was associated with a higher risk of CHF (10.2% vs. 7.7%, RR 1.38, p < 0.001) and a higher risk of hospitalized/fatal CHF (RR 1.35, p < 0.001). Similar treatment effects were observed for all outcomes across the predefined subgroups and CHD status at baseline.
No significant difference was observed between the lisinopril and chlorthalidone arms for the primary outcome of fatal CHD or nonfatal MI (11.4% vs. 11.5%, RR 0.99, p = 0.81) or for the secondary outcomes of all-cause mortality (17.2% vs. 17.3%, RR 1.00, p = 0.90), combined CHD (20.8% vs. 19.9%, RR 1.05, p = 0.18), peripheral arterial disease, cancer, or ESRD.
The lisinopril arm was associated with a higher risk of stroke (RR 1.15, p = 0.02) and combined CVD (RR 1.10, p < 0.001), including a higher risk of CHF (RR 1.19, p < 0.001), hospitalized or treated angina (RR 1.11, p = 0.01), and coronary revascularization (RR 1.10, p = 0.05). The lisinopril arm was associated with a 19% reduction in conduction system abnormalities. Similar treatment effects were observed for all outcomes across the predefined subgroups of gender, diabetics, and CHD status at baseline.
Systolic BP at 5 years was statistically significantly higher with both amlodipine (0.8 mm Hg, p = 0.03) and lisinopril (2 mm Hg, p < 0.001) versus chlorthalidone, but diastolic BP at 5 years was statistically lower with amlodipine (0.8 mm Hg lower vs. chlorthalidone, p < 0.001).
In January 2000, an interim analysis led to discontinuation of the doxazosin treatment arm based on comparisons with chlorthalidone. The incidence of the primary composite of fatal CHD or nonfatal MI was similar in the two groups (RR 1.03, p = 0.71). The all-cause mortality rates were also similar (4-year rates 9.62% [doxazosin] and 9.08%, RR 1.03, p = 0.56).
The doxazosin group did have a significantly higher incidence of stroke (RR 1.19, p = 0.04) and combined CVD events consisting of CHF, coronary revascularization, angina, and peripheral artery disease (4-year rates 25.5% vs. 21.8%, RR 1.25, p < 0.001). The risk of CHF was twice as high in the doxazosin group (4-year rates 8.13% vs. 4.45%, RR 2.04, p < 0.001). At 10 years, there was no difference in all-cause mortality: amlodipine vs. chlorthalidone (p = 0.43) or lisinopril vs. chlorthalidone (p = 0.19), or in CV mortality: amlodipine vs. chlorthalidone (p = 0.89) or lisinopril vs. chlorthalidone (p = 0.33).
Hip or pelvic fracture: Chlorthalidone vs. lisinopril: hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.58-0.98; p = 0.04. Chlorthalidone vs. amlodipine: HR 0.82, 95% CI 0.63-1.08; p = 0.17.
The risk of the prespecified primary endpoint of fatal CHD or nonfatal MI did not differ between initial use of the diuretic chlorthalidone versus initial use of the ACE inhibitor lisinopril or the calcium antagonist amlodipine for the treatment of hypertension. However, for certain secondary outcomes, such as CHF, rates were lower among patients treated with chlorthalidone versus lisinopril or amlodipine. For amlodipine, this CHF difference persisted into long-term follow-up. Each of the three drugs reduced BP from baseline, although chlorthalidone use was associated with larger systolic BP reductions versus lisinopril or amlodipine. Chlorthalidone seemed to be associated with a lower risk of hip/pelvic fractures.
It has been speculated that potential metabolic effects of diuretics such as hypokalemia, dyslipidemia, and insulin resistance might offset the beneficial effects of BP reduction. As a result, therapies without such potential side effects, such as ACE inhibitors and CCBs, have frequently been used for the treatment of hypertension, with the belief that CHD outcomes would be improved with these therapies over diuretics. While some side effects were more common in the chlorthalidone arm, such results did not translate to an increase in CV events.
A potentially important side effect in the chlorthalidone arm was the higher fasting glucose levels versus the lisinopril or amlodipine arms in an analysis of all patients and in nondiabetics. In contrast, ACE inhibitors have been associated with a reduction in the development of diabetes and the progression of diabetic nephropathy. The impact of chlorthalidone on diabetes and CVD may not be fully manifested in the relatively short follow-up period of 4 years, the last timepoint reported in the manuscript.
One criticism of the trial is that the ACE inhibitor arm was potentially at a disadvantage since the first add-on therapy specified by the trial treatment algorithm for this arm was a beta-blocker, rather than a diuretic or CCB, both of which are more commonly used in clinical practice. The increased risk of heart failure in the lisinopril arm was unexpected and is in contrast to the benefits of ACE inhibitors observed in other trials for the treatment of heart failure, such as SOLVD.
The present analysis was an intent-to-treat analysis. Because of the large rate of crossover in both arms (13% of patients in the chlorthalidone arm were taking a diuretic with a CCB or an ACE inhibitor and 9% were taking a CCB or an ACE inhibitor without diuretic), it will be important to see the results of an "as treated" analysis.
Because BP reduction with the ACE inhibitor lisinopril was lower than with the diuretic chlorthalidone, it is unclear if the improvement in the secondary clinical outcomes with chlorthalidone over lisinopril was due to greater improvements in BP or other effects of the diuretic. In the case of amlodipine, the situation is more complicated. The reduced risk of CHF in the chlorthalidone arm versus the amlodipine arm may represent a drug-specific effect since the BP differences between amlodipine and chlorthalidone were small (<1 mm Hg) and there was lower systolic BP in chlorthalidone, but lower diastolic BP for amlodipine.
Further substudies addressing the economic impact of these medications in ALLHAT for treatment of hypertension are forthcoming. Given the fact that more than 40 million adults have hypertension and 21.9 million are treated with medication, the ALLHAT study may have a potentially large economic impact on health care delivery.
In the lay press, it has been emphasized that patients not discontinue or change current hypertensive medications without consulting their physician. Physicians can anticipate being contacted by patients about the issues raised in the ALLHAT trial.
Puttnam R, Davis BR, Pressel SL, et al., on behalf of the 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 2016;Nov 21:[Epub ahead of print].
Dewland TA, Soliman EZ, Davis BR, et al., on behalf of the 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;176:1085-92.
Long-term follow-up presented by Dr. William Cushman at the American Heart Association Scientific Sessions, Orlando, FL, November 18, 2009.
1) ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97.
2) Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA 2000;283:1967-75.
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