HvC Comparative Effectiveness Project

Groups 5 and 6

HvC Comparative Effectiveness Project

Groups 5 and 6

Is a chlorthalidone (C) – based regimen superior to a hydrochlorothiazide (H) – based regimen in preventing cardiovascular disease (CVD) morbidity and mortality among individuals with hypertension?

Is a chlorthalidone (C) – based regimen superior to a hydrochlorothiazide (H) – based regimen in preventing cardiovascular disease (CVD) morbidity and mortality among individuals with hypertension?

H vs C Study RationaleH vs C Study Rationale Nearly 50% of the 70 million people in the U.S. with

hypertension are not controlled.

A thiazide diuretic is an important component of antihypertensive regimens.

Current treatment recommendations do not differentiate among diuretics.

There is substantial evidence that low doses of C (25 mg daily) are effective reducing CVD morbidity and mortality.

There is less outcome data on low doses of H (12.5 or 25 mg daily).

H is used far more than C.

There are no large trials comparing H and C for CVD morbidity and mortality.

Drug treatments for elevated BP and lipids have been studied for many years and are safe.

There is considerable uncertainty about whether the benefits of risk factor - lowering extend to primary prevention among those without “high” levels.

Major Diuretic Trials Major Diuretic Trials

VA Coop (1967) HCTZ 50-100 mgPHS trial (1977) Chlorothiazide 500-1000

mgHDFP (1982) Chlorthalidone 25-100

mgMRFIT (1990) HCTZ 50-100 mg (BID)

or Chlorthalidone 50-100 mgEWPHE (1985) HCTZ 25-50 mgMRC (1992) HCTZ 25-50 mgSHEP (1991) Chlorthalidone 12.5-25

mgTOMHS (1993) Chlorthalidone 15-30 mgALLHAT (2002) Chlorthalidone 12.5-25 mgACCOMPLISH (2008) HCTZ 12.5-25 mg

Diuretics and CVD EventsDiuretics and CVD Events

5 trials have demonstrated the benefit of chlorthalidone-based regimen in reducing CVD events. No comparator has proven superior.

Some trials of HCTZ-based regimens have shown benefit; they used 25-50 mg/day

2 trials of low-dose (12.5-25 mg/day) HCTZ regimens (ACCOMPLISH, ANBP-2) were found not as effective in reducing CVD events as the comparator. BP differences between groups were similar in

ACCOMPLISH study

Data Source: IMS NPA - 72 months ending January 2007

Diuretics by Molecule

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

TRx

(000

s)

BENDROFLUMETHIAZIDE

CHLOROTHIAZIDE

CHLORTHALIDONE

HYDROCHLOROTHIAZIDE

HYDROFLUMETHIAZIDE

INDAPAMIDE

METHYCLOTHIAZIDE

METOLAZONE

POLYTHIAZIDE

QUINETHAZONE

TRICHLORMETHIAZIDE

IMS Health NDTI, 2001-06.

Chlorthalidone has been the preferred diuretic in NHLBI hypertension trials but is infrequently used.

ABPM: Mean 24-hour, Daytime, and Nighttime Systolic BP With Change From Baseline

ABPM: Mean 24-hour, Daytime, and Nighttime Systolic BP With Change From Baseline

Ernst ME et al. Hypertension. 2006;47:352-358.

MRFITMRFIT

• Men ages 35-57 years, upper 10%-15% of CHD risk, randomization to Special Intervention (SI) or Usual Care (UC), stratified by clinical center

• Choice of diuretic allowed to initiate treatment in SI group; some clinics predominantly used HCTZ (50 or 100 mg) while others used predominantly chlorthalidone (50 or 100 mg)

Multiple Risk Factor Intervention Trial Research Group. Circulation. 1990;82:1616-1628.

MRFIT: H and C ClinicsMRFIT: H and C Clinics

H Clinics C Clinics

No. Clinics 9 6

No. Participants 5,466 3,193

% Hypertensive at entry 62.2 % 66.1%

No. SI 1725 1046

No. UC 1674 1066

Baseline BP

SBP (mm Hg) 141.5 142.0

DBP (mm Hg) 95.5 95.8

MRFITMRFIT

• Four years into the study (4/1/80) the DSMB requested all SI participants on HCTZ be converted to chlorthalidone.

Cumulative Mortality for Death From All Causes Before 4-1-80 by Study – Group and Clinic GroupCumulative Mortality for Death From All Causes

Before 4-1-80 by Study – Group and Clinic Group

Time From Randomization in Years

Cum

ula

tive

Pro

por

tion

Dea

d

A. Predominantly H Clinics

SIUC

0.03

0.02

0.010

1 2 3 4 5

Cum

ula

tive

Pro

por

tion

Dea

d

B. Initially C, Then H

Time From Randomization in Years

SIUC

0.03

0.02

0.010

1 2 3 4 5

Time From Randomization in Years

Cum

ula

tive

Pro

por

tion

Dea

d

C. Predominantly C Clinics

SIUC

0.03

0.02

0.010

1 2 3 4 5

Bartsch G et al. Circulation. 1984;70(suppl II):II-1438.

MRFITMRFIT Leading up to protocol change

H clinics: 44% more CHD, 16% more death (vs UC patients)

C clinics: 58% less CHD, 41% less death (vs UC patients; majority of diuretic use in UC remained HCTZ)

After switch to C H clinics: 28% less CHD, 26% less death

vs UC (P = 0.04, 0.06)

Multiple Risk Factor Intervention Trial Research Group. Circulation. 1990;82:1616-1628.Bartsch G et al. Circulation. 1984;70(suppl II):II-1438.

Design Considerations Design Considerations

Conduct trial in large health care setting.

Utilize electronic medical record.

Point of care trial

Questions To Consider Questions To Consider

Target population – patients already on treatment (e.g., add diuretic to existing treatment if not controlled, discontinue diuretic) as well as those not treated. Also, presence of other CVD risk factor (s)?

Doses of chlorthalidone (12.5 or 25 mg) and hydrochlorothiazide (12.5 or 25 mg) and additional agent to add to control BP

Definition of CVD outcome

Management of participants whose BP cannot be controlled