ALLHAT Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial JAMA 2002;288: Assoc. Prof. Konstantinos Kyriazis ATU, 2014

ALLHAT study overview Double-blind, randomized trial to determine whether the occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (amlodipine, lisinopril, or doxazosin) compared with a diuretic (chlorthalidone) Cohort 42,418 patients (55 years old) from 623 sites in North America –Stage 1 or 2 hypertension –1 additional risk factor for CHD Comparisons between chlorthalidone and amlodipine and chlorthalidone and lisinopril have been reported together, excluding the doxazosin arm (n=9,062), which was terminated early ALLHAT Research Group. JAMA. 2002;288: CHD=coronary heart disease; MI=myocardial infarction

42,418 patients with hypertension SBP >140mmHg and/or DBP >90 mmHg or Took medication for hypertension and had at least one additional risk factor for CHD Age >55 years NHLBI funded trial 42,418 patients with hypertension SBP >140mmHg and/or DBP >90 mmHg or Took medication for hypertension and had at least one additional risk factor for CHD Age >55 years NHLBI funded trial Diuretic Chlorthalidone mg/day (n=15,255) Diuretic Chlorthalidone mg/day (n=15,255) Endpoints: Primary – Fatal coronary heart disease and nonfatal MI Secondary – All-cause mortality, stroke, and major cardiovascular disease events (CHF, coronary revascularization, angina, and peripheral artery disease) Mean follow-up 4.9 years Endpoints: Primary – Fatal coronary heart disease and nonfatal MI Secondary – All-cause mortality, stroke, and major cardiovascular disease events (CHF, coronary revascularization, angina, and peripheral artery disease) Mean follow-up 4.9 yearsALLHAT JAMA 2002;288: Calcium Blocker Amlodipine mg/day (n=9,048) Calcium Blocker Amlodipine mg/day (n=9,048) ACE Inhibitor Lisinopril mg/day (n=9,054) ACE Inhibitor Lisinopril mg/day (n=9,054) Alpha Blocker Doxazosin* 2-8 mg/day (n=9,061) Alpha Blocker Doxazosin* 2-8 mg/day (n=9,061) * Discontinued prior to study completion

ALLHAT Study Design n=13,854 2,235 (16.1%) stopped drug Chlorthalidone n=15,255 Amlodipinen=9,048 Randomized n=42,418 n=15, (2.2%) lost to follow-up 80 (0.5%) refused follow-upn=9, (2.2%) lost to follow-up 58 (0.6%) refused follow-up n=6,210 n=6,210 1,873 (30.2%) stopped drug n=9, (2.4%) lost to follow-up 58 (0.6%) refused follow-up n=8,215 1,357 (16.5%) stopped drug n=3,769 n=3,769 1,052 (27.9%) stopped drug YEAR 1 n=8,158 1,842 (22.6%) stopped drug n=3,605 1,399 (38.8%) stopped drug Lisinopriln=9,054 YEAR 5 ALLHAT Research Group. JAMA. 2002;288: Intent-to- Treat Analysis Doxazosin n=9,062 Discontinued early at 3.3 yrs

ALLHAT Endpoints Primary endpoint Composite of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) Other predefined endpoints –all-cause mortality –stroke –combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina –combined cardiovascular disease – combined CHD, stroke, lower extremity revascularization, treated angina, fatal/ hospitalized/treated congestive heart failure, hospitalized or outpatient peripheral arterial disease –other – renal ALLHAT Research Group. JAMA. 2002;288:

Chlorthalidone n=15,255 Amlodipine n=9,048 Lisinopril n=9,054 systolicdiastolicsystolicdiastolicsystolicdiastolic Mean BP (mmHg) Treated (90%) Untreated (10%) Mean age (yrs)67 Black (%)3536 Women (%)47 46 Current smoking (%)22 History of CHD (%) Type 2 diabetes (%) ALLHAT Baseline Characteristics ALLHAT Research Group. JAMA. 2002;288: BP=blood pressure CHD=coronary heart disease

ALLHAT Mean Systolic and Diastolic Blood Pressure During Follow-up Systolic BP (mmHg) Follow-up, yrs Diastolic BP (mmHg) Chlorthalidone Amlodipine Lisinopril Chlorthalidone Amlodipine Lisinopril ALLHAT Research Group. JAMA. 2002;288: Copyright ©2002, American Medical Association. SBP=systolic blood pressure DBP=diastolic blood pressure Compared to chlorthalidone: DBP significantly lower in amlodipine group (~1 mmHg). Compared to chlorthalidone: SBP significantly higher in amlodipine (~1 mmHg) and lisinopril (~2 mmHg) groups.

ALLHAT BP Controlled to

ALLHAT Treatment and Blood Pressure Control 6 mos1 yr3 yr5 yr 1 Drug2 Drugs 3 Drugs Patients (%) Cushman WC, et al. J Clin Hypertens. 2002;4: Average # of drugs Blood pressure controlled

ALLHAT Primary Outcome by Treatment Group Cumulative Fatal CHD and Nonfatal MI event rate (%) Time to event, yrs No. at Risk Chlorthalidone Amlodipine Lisinopril Chlorthalidone Amlodipine Lisinopril ALLHAT Research Group. JAMA. 2002;288: Copyright ©2002, American Medical Association.

Relative Risk (95% CI) Relative Risk (95% CI) TOTAL 0.98 ( ) 0.99 ( ) Age

Relative Risk (95% CI) Relative Risk (95% CI) TOTAL 0.96 ( ) 1.00 ( ) Age

Relative Risk (95% CI) Relative Risk (95% CI) TOTAL 1.04 ( ) 1.10 ( ) Age

ALLHAT Stroke by Treatment Group No. at Risk Chlorthalidone Amlodipine Lisinopril Cumulative event rate (%) Chlorthalidone Amlodipine Lisinopril Time to event, yrs ALLHAT Research Group. JAMA. 2002;288: Copyright ©2002, American Medical Association.

Relative Risk (95% CI) Relative Risk (95% CI) TOTAL 0.93 ( ) 1.15 ( ) Age

ALLHAT Heart Failure by Treatment Group No. at Risk Chlorthalidone Amlodipine Lisinopril Cumulative event rate (%) Chlorthalidone Amlodipine Lisinopril Time to event, yrs P

Relative Risk (95% CI) Relative Risk (95% CI) TOTAL 1.38 ( ) 1.20 ( ) Age

Chlorthalidone vs Amlodipine Primary Endpoint RR = 0.98 p = 0.65 ALLHAT: Primary Endpoint* Chlorthalidone JAMA 2002;288: Amlodipine * Primary Endpoint = Fatal CHD or nonfatal MI Chlorthalidone vs Lisinopril Primary Endpoint RR = 0.99 p = 0.81 Chlorthalidone Lisinopril

All Cause Mortality RR = 0.96 p = 0.20 ALLHAT: Secondary Endpoints Chlorthalidone JAMA 2002;288: Amlodipine Heart Failure RR = 1.38 p < Chlorthalidone Amlodipine Chlorthalidone vs Amlodipine

All Cause Mortality RR = 1.00 p = 0.90 ALLHAT: Secondary Endpoints Chlorthalidone JAMA 2002;288: Lisinopril Heart Failure RR = 1.19 p < Chlorthalidone vs Lisinopril Chlorthalidone Lisinopril Chlorthalidone Lisinopril Stroke RR = 1.15 p = 0.02

ALLHAT Conclusions Better control of syst. BP with chlorthalidone than with amlodipine or lisinopril No differences in risk for CHD death/nonfatal MI between chlorthalidone and amlodipine or lisinopril In secondary endpoints, chlorthalidone better: 38% heart failure with Amlodipine 15% stroke, 19% heart failure, 11% angina pectoris with Lisinopril MI=myocardial infarction CHD=coronary heart disease HF=heart failure ALLHAT Research Group. JAMA. 2002;288:

ALLHAT Implications Diuretics should be the initial drug of choice in antihypertensive regimens Only 30 percent of patients achieve both systolic BP

Lipid Lowering Substudy Trial of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial JAMA 2002;288: ALLHAT- LLT

www. Clinical trial results.org 10,355 patients with moderate hypercholesterolemia All patients enrolled in the ALLHAT antihypertensive trial Fasting LDL-C level of mg/dL with no known CHD or mg/dL with known CHD Fasting triglyceride levels

www. Clinical trial results.org All Cause Mortality RR = 0.99 p = 0.88 All Cause Mortality RR = 0.99 p = 0.88 ALLHAT- LLT: Clinical Endpoints Pravastatin Usual Care Fatal Heart Disease or Nonfatal MI RR = 0.91 p = 0.16 Fatal Heart Disease or Nonfatal MI RR = 0.91 p = 0.16 Stroke RR = 0.91 p = 0.31 Stroke RR = 0.91 p = 0.31 JAMA 2002;288: Pravastatin Usual Care Pravastatin Usual Care

www. Clinical trial results.org Pravastatin 17.2% Pravastatin 17.2% ALLHAT- LLT: Total Cholesterol Baseline 4 Year Follow-up Usual Care 7.6% Usual Care 7.6% mg/dL Baseline 4 Year Follow-up JAMA 2002;288: mg/dL

www. Clinical trial results.org Pravastatin 27.7% Pravastatin 27.7% ALLHAT- LLT: LDL Cholesterol Baseline 4 Year Follow-up Usual Care 11.0% Usual Care 11.0% mg/dL Baseline 4 Year Follow-up JAMA 2002;288: mg/dL

www. Clinical trial results.org ALLHAT- LLT: Summary Despite moderate reduction in cholesterol with pravastatin, there was no difference in mortality, CHD or stroke compared with usual care for moderate hypercholesterolemia –High crossover rate from usual care to statin treatment (8% at year 2 and 17% at year 4) may explain the only moderate difference in cholesterol reduction and the lack of clinical benefit between the two arms –A greater benefit was observed in blacks than in nonblacks with pravastatin for fatal heart disease or nonfatal MI endpoint (RR 0.73 vs 1.02, p=0.03) –Lack of clinical benefit with statin therapy contrasts with other large statin trials (4S, CARE, LIPID, and PROSPER) –Meta-analysis of 9 large statin trials including ALLHAT-LLT shows CHD events 27% and mortality 14% with statin therapy Despite moderate reduction in cholesterol with pravastatin, there was no difference in mortality, CHD or stroke compared with usual care for moderate hypercholesterolemia –High crossover rate from usual care to statin treatment (8% at year 2 and 17% at year 4) may explain the only moderate difference in cholesterol reduction and the lack of clinical benefit between the two arms –A greater benefit was observed in blacks than in nonblacks with pravastatin for fatal heart disease or nonfatal MI endpoint (RR 0.73 vs 1.02, p=0.03) –Lack of clinical benefit with statin therapy contrasts with other large statin trials (4S, CARE, LIPID, and PROSPER) –Meta-analysis of 9 large statin trials including ALLHAT-LLT shows CHD events 27% and mortality 14% with statin therapy