antihypertensive and lipid-lowering treatment to prevent heart attack trial jama 2002;288:2981-2997...

Antihypertensive and Lipid-Lowering Treatment to Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack TrialPrevent Heart Attack Trial

Antihypertensive and Lipid-Lowering Treatment to Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack TrialPrevent Heart Attack Trial

JAMA 2002;288:2981-2997JAMA 2002;288:2981-2997

ALLHATALLHAT

www. Clinical trial results.org

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

DiureticChlorthalidone 12-25 mg/day

(n=15,255)

DiureticChlorthalidone 12-25 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 years

ALLHATALLHATALLHATALLHAT

JAMA 2002;288:2981-2997JAMA 2002;288:2981-2997

Calcium Channel Blocker

Amlodipine 2.5-10 mg/day

(n=9,048)

Calcium Channel Blocker

Amlodipine 2.5-10 mg/day

(n=9,048)

ACE Inhibitor Lisinopril

10-40 mg/day(n=9,054)

ACE Inhibitor Lisinopril

10-40 mg/day(n=9,054)

Alpha BlockerDoxazosin*2-8 mg/day(n=9,061)

Alpha BlockerDoxazosin*2-8 mg/day(n=9,061)

* Discontinued prior to study completion


11.5% 11.3%

0%

5%

10%

15%

11.5% 11.3%

0%

5%

10%

15%

Chlorthalidone vs AmlodipinePrimary Endpoint

RR = 0.98p = 0.65

Chlorthalidone vs AmlodipinePrimary Endpoint

RR = 0.98p = 0.65

ALLHAT: Primary Endpoint*ALLHAT: Primary Endpoint*ALLHAT: Primary Endpoint*ALLHAT: Primary Endpoint*

ChlorthalidoneChlorthalidone

JAMA 2002;288:2981-2997JAMA 2002;288:2981-2997

AmlodipineAmlodipine

11.5% 11.4%

0%

5%

10%

15%

11.5% 11.4%

0%

5%

10%

15%

* Primary Endpoint = Fatal CHD or nonfatal MI

Chlorthalidone vs LisinoprilPrimary Endpoint

RR = 0.99p = 0.81

Chlorthalidone vs LisinoprilPrimary Endpoint

RR = 0.99p = 0.81

ChlorthalidoneChlorthalidone LisinoprilLisinopril


17.3% 16.8%

0%

5%

10%

15%

20%17.3% 16.8%

0%

5%

10%

15%

20%

All Cause MortalityRR = 0.96p = 0.20


ALLHAT: Secondary EndpointsALLHAT: Secondary EndpointsALLHAT: Secondary EndpointsALLHAT: Secondary Endpoints


JAMA 2002;288:2981-2997JAMA 2002;288:2981-2997

AmlodipineAmlodipine

7.7%

10.2%

0%

5%

10%

15%

7.7%

10.2%

0%

5%

10%

15%

Heart FailureRR = 1.38p < 0.001


ChlorthalidoneChlorthalidone AmlodipineAmlodipine

Chlorthalidone vs AmlodipineChlorthalidone vs Amlodipine


5.6%6.3%

0%

2%

4%

6%

8%

10%

5.6%6.3%

0%

2%

4%

6%

8%

10%

17.3% 17.2%

0%

5%

10%

15%

20%

17.3% 17.2%

0%

5%

10%

15%

20%



ALLHAT: Secondary EndpointsALLHAT: Secondary EndpointsALLHAT: Secondary EndpointsALLHAT: Secondary Endpoints


JAMA 2002;288:2981-2997JAMA 2002;288:2981-2997

LisinoprilLisinopril

7.7%8.7%

0%

5%

10%

15%

7.7%8.7%

0%

5%

10%

15%



Chlorthalidone vs LisinoprilChlorthalidone vs Lisinopril

ChlorthalidoneChlorthalidone LisinoprilLisinopril ChlorthalidoneChlorthalidone LisinoprilLisinopril

StrokeRR = 1.15p = 0.02

StrokeRR = 1.15p = 0.02


ALLHAT: SummaryALLHAT: SummaryALLHAT: SummaryALLHAT: Summary

Prespecified primary endpoint of fatal CHD or nonfatal MI did not differ between initial use of the diuretic chlorthalidone vs initial use of the ACE inhibitor lisinopril or the calcium antagonist amlodipine for the treatment of hypertension

– Secondary outcome of heart failure was lower among patients treated with chlorthalidone vs lisinopril or amlodipine

– Each of the 3 drugs reduced blood pressure from baseline, although chlorthalidone use was associated with larger SBP reductions vs lisinopril or amlodipine

– Increased risk of heart failure in lisinopril arm unexpected and in contrast to the benefits of ACE inhibitors observed in other trials for the treatment of heart failure such as SOLVD

Prespecified primary endpoint of fatal CHD or nonfatal MI did not differ between initial use of the diuretic chlorthalidone vs initial use of the ACE inhibitor lisinopril or the calcium antagonist amlodipine for the treatment of hypertension

– Secondary outcome of heart failure was lower among patients treated with chlorthalidone vs lisinopril or amlodipine

– Each of the 3 drugs reduced blood pressure from baseline, although chlorthalidone use was associated with larger SBP reductions vs lisinopril or amlodipine

– Increased risk of heart failure in lisinopril arm unexpected and in contrast to the benefits of ACE inhibitors observed in other trials for the treatment of heart failure such as SOLVD


ALLHAT: LimitationsALLHAT: LimitationsALLHAT: LimitationsALLHAT: Limitations

Diabetic risk– Important side effect in the chlorthalidone arm was higher fasting glucose levels vs lisinopril or

amlodipine arms in all patients and in non-diabetics – Impact of chlorthalidone on diabetes and cardiovascular disease may not be fully manifested in the

relatively short follow-up period of 4 years – ACE inhibitors have previously been associated with a reduction in the development of diabetes and

the progression of diabetic nephropathy

Add-on therapy– ACE inhibitor arm 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 calcium channel blocker, both of which are more commonly used in clinical practice

Large crossover rate by 4 year follow-up

Diabetic risk– Important side effect in the chlorthalidone arm was higher fasting glucose levels vs lisinopril or

amlodipine arms in all patients and in non-diabetics – Impact of chlorthalidone on diabetes and cardiovascular disease may not be fully manifested in the

relatively short follow-up period of 4 years – ACE inhibitors have previously been associated with a reduction in the development of diabetes and

the progression of diabetic nephropathy

Add-on therapy– ACE inhibitor arm 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 calcium channel blocker, both of which are more commonly used in clinical practice

Large crossover rate by 4 year follow-up

antihypertensive and lipid-lowering treatment to prevent heart attack trial jama 2002;288:2981-2997...

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