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Review of the Design and Initial Findings for Review of the Design and Initial Findings for Pre-specified Outcomes and SubgroupsPre-specified Outcomes and Subgroups

Paul K. Whelton, M.D., M.Sc.

Loyola University Medical Center

Maywood, Illinois, U.S.A.

ALLHAT RevisitedHow have the Initial Findings Held Up Five Years Later?

ALLHATALLHAT

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BP Trial Primary End Points:-Fatal CHD & Non-Fatal MIBP Trial Secondary End Points: -All-cause mortality-Stroke-Combined CHD –Fatal CHD, non-fatal MI, coronary revascularization, hospitalized angina-Combined CVD – combined CHD, stroke, lower extremity revascularization, treated angina, fatal / hospitalized / treated heart failure (HF), hospitalized or outpatient peripheral arterial disease (PAD)-Other – renal (reciprocal serum creatinine, ESRD, estimated GFR) and cancer

Predefined Subgroups -Age (<65 y; 65+y)-Gender-Race (Black; Non-Black)-Diabetes (Diabetic; Non-Diabetic)

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Eligible for BP trial:

>55 years Hypertension

At least 1 other CVD risk factor

Chlorthalidone Amlodipine Lisinopril

Eligible for Lipid Trial:Fasting LDL-C 120-189 mg/dlor 100-129 if history of CHD

Pravastatin Usual Care

Doxazosin

H/O MI or StrokeRevascularization procedure

Major ST depression/T wave inversionASCVDType II Diabetes MellitusHDL < 35 mg/dl X2LVHCurrent smoker

Discontinued due to higher relative risk of CVD events in doxazosin compared to chlorthalidone group

42,418 Eligable Participants Enrolled & Randomized to 5 years of Double-Blind Treatment

ALLHATALLHAT

3

33

CANADA

CANADA

Quebec

Ontario

Washington

Oregon

Quebec

California

MEXICO

MEXICO

Nevada

Idaho

Montana North Dakota

South Dakota

Wyoming

Utah

Colorado

Arizona

New Mexico

Texas

Oklahoma

Kansas

Nebraska

Minnesota

Iowa

Wisconsin

Michigan

Michigan

Illinois

Missouri

Indiana

Arkansas

LouisianaMississippi

AlabamaGeorgia

Tennessee

Kentucky

OhioWV

Virginia

N. Carolina

S. Carolina

Pennsylvania

DE

NJ

MD

New York

VT NH

CTMA

RI

Maine

New Brunswick

Nova Scotia

Prince EdwardIsland

Island ofNew Foundland

Puerto Rico(Area Enlarged)

St. Croix, Virgin Islands(Area Enlarged)

The Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial

FloridaCTC,UT

Program Office,NHLBI

-623 Clinical Centers-USA, Canada, Caribbean-Diverse practice settings

-Primary sponsor: NIH-NHLBI-Concurrent support from the VA-Assistance from pharmaceutical companies but no role in scientific conduct of trial

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Baseline Characteristics(33, 357 Participants)Chlorthalidone Amlodipine Lisinopril

Sample Size

Mean age, years

15,255

67

9,048

67

9,054

67

Mean SBP/DBP

Mean BMI, kg/m2

145 / 83

30

145 / 83

30

145 / 83

30

Women, %

Black, %

47

35

47

36

46

35

Current smoking, % 22 22 22

ASCVD, %

History of CHD, %

Type II diabetes, %

47

26

36

46

24

37

47

25

35

ALLHATALLHAT

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Treatment RegimenTreatment Regimen

Step 1 [Double Blinded] Dose 1

Dose 2 Dose 3

ChlorthalidoneChlorthalidone 12.5 mg12.5 mg 12.5 mg12.5 mg 25 mg25 mg

AmlodipineAmlodipine 2.5 mg2.5 mg 5 mg5 mg 10 mg10 mg

LisinoprilLisinopril 10 mg10 mg 20 mg20 mg 40 mg40 mg

Step 2

ReserpineReserpine 0.05 mg qd0.05 mg qd 0.1 mg qd0.1 mg qd 0.2 mg qd0.2 mg qd

ClonidineClonidine 0.1 mg bid0.1 mg bid 0.2 mg bid0.2 mg bid 0.3 mg bid0.3 mg bid

AtenololAtenolol 25 mg qd25 mg qd 50 mg qd50 mg qd 100 mg qd100 mg qd

Step 3

HydralazineHydralazine 25 mg bid25 mg bid 50 mg bid50 mg bid 100 mg bid100 mg bid

ALLHATALLHAT

Doses were escalated in an attempt to achieve a BP <140/80 mm Hg

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Percent Taking Blinded Study Drug or Drug from Same Class

87 878788909290838384858788

8383848486

0

20

40

60

80

100

6 12 24 36 48 60

Months of Follow-up

Per

cen

t

ALLHATALLHAT

ChlorthalidoneChlorthalidone AmlodipineAmlodipine LisinoprilLisinopril

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144.8

134.1134.0134.9136.0136.8138.6

145.0

136.0135.7136.7

138.5140.0

141.9

83.2

74.775.876.477.878.780.0 75.576.777.478.779.9

81.283.4

0 12 24 36 48 60

Mean Systolic and Diastolic BP,by Treatment Group

Months of Follow-up

mm

Hg

ALLHATALLHAT

70

75

80

85

90

135

140

145

150

~~

Systolic BPSystolic BP

Diastolic BPDiastolic BP

AmlodipineAmlodipine

LisinoprilLisinopril

ChlorthalidoneChlorthalidone

Lisinopril

ChlorthalidoneChlorthalidone

AmlodipineAmlodipine

8Biochemical Results

Sr. Cholesterol & Potassium

Chlorthalidone Amlodipine Lisinopril

Serum cholesterol- mg/dL

Baseline 216.1 (43.8) 216.5 (44.1) 215.6 (42.4)

4 Years 197.2 (42.1) 195.6 (41.0)* 195.0 (40.6)*

Serum potassium – mmol/L

Baseline 4.3 (0.7) 4.3 (0.7) 4.4 (0.7)*

4 Years 4.1 (0.7) 4.4 (0.7)* 4.5 (0.7)*

* p<.05 compared to chlorthalidone† Ann Intern Med. 1999;130:461-470

ALLHAT

JAMA 2002;288:2981-97

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Biochemical Results

Fasting GlucoseChlorthalidone Amlodipine Lisinopril

All Participants

Baseline 123.5 (58.3) 123.1 (57.0) 122.9 (56.1)

4 Years 126.3 (55.6) 123.7 (52.0) 121.5 (51.3)*

Participants with Baseline <126 mg/dL

Baseline 93.1 (11.7) 93.0 (11.4) 93.3 (11.8)

4 Years 104.4 (28.5) 103.1 (27.7) 100.5 (19.5)*

Diabetes Incidence (fasting glucose 126 mg/dL during follow-up)

4 Years 11.6% 9.8%* 8.1%*

*p<.05 compared to chlorthalidone

ALLHAT

JAMA 2002;288:2981-97

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Amlodipine / Chlorthalidone Lisinopril / Chlorthalidone

CHD 0.98 (0.91, 1.08) 0.99 (0.91, 1.08)

Death 0.96 (0.89, 1.02) 1.00 (0.94, 1.08)

CCHD 1.00 (0.94, 1.07) 1.05 (0.98, 1.11)

Stroke 0.93 (0.82, 1.06) 1.15 (1.02, 1.30)

CCVD 1.04 (0.99, 1.09) 1.10 (1.05, 1.16)

HF 1.38 (1.25, 1.52) 1.19 (1.07, 1.31)

Amlodipine Chlorthalidone Better Better

0.50 1 2Lisinopril Chlorthalidone Better Better

0.50 1 2

Summary of OutcomesRelative Risks (95% CI)ALLHAT

JAMA 2002;288:2981-97

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Stroke, by Treatment Group.RR (95% CI) in Predefined Subgroups

Amlodipine Chlorthalidone Better Better

0.50 1 2

Non-Diabetic 0.96 (0.81, 1.14)

Diabetic 0.90 (0.75, 1.08)

Non-Black 0.93 (0.79, 1.10)

Black 0.93 (0.76, 1.14)

Women 0.84 (0.69, 1.03)

Men 1.00 (0.85, 1.18)

Age >= 65 0.93 (0.81, 1.08)

Age < 65 0.93 (0.73, 1.19)

Total 0.93 (0.82, 1.06)

LisinoprilChlorthalidone Better Better

0.50 1 2

Non-Diabetic 1.23 (1.05, 1.44)

Diabetic 1.07 (0.90, 1.28)

Non-Black 1.00 (0.85, 1.17)

Black 1.40 (1.17, 1.68)

Women 1.22 (1.01, 1.46)

Men 1.10 (0.94, 1.29)

Age >= 65 1.13 (0.98, 1.30)

Age < 65 1.21 (0.97, 1.52)

Total 1.15 (1.02, 1.30)

ALLHAT

P = .01 for interaction

Amlodipine/Chlorthalidone Lisinopril/Chlorthalidone

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SummaryALLHAT BP Trial Design and Initial Findings

•5 y efficacy trial of antihypertensive drug regimens in 42,418 participants. Regimens designed to be similar except for double blinded treatment with

• chlorthalidone (C), amlodipine (A), lisinopril (L) or doxazosin

•Doxazosin comparison stopped prematurely due to difference in CVD events

•Baseline characteristics similar in 33,357 C, A and L participants•Strong representation of important subgroups

•Excellent adherence to assigned study drugs

•The three regimens differed slightly but significantly in BP control, Sr. Cholesterol, Sr. Potassium and fasting blood sugar•No difference in the primary outcome for C vs. A or C vs. L•C was better than A for HF•C was better than L for stroke, combined CVD events and HF. There was a significant C vs. L treatment X race interaction for the stroke outcome.

•The ALLHAT findings suggest thiazide-type diuretics are the preferred first-step antihypertensive drug therapy unless there is a contraindication to their use