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? I will review with you the current status of adjuvant therapy in colon cancer, describe ongoing trials, and then speak about studies that are in development. I will briefly, at the end, talk about rectal cancer, with regard to the current status of adjuvant therapy and then describe a couple of trials that are in development.

H 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 VA Coop (1967) HCTZ 50-100 mg PHS trial (1977) Chlorothiazide 500-1000 mg HDFP (1982) Chlorthalidone 25-100 mg MRFIT (1990) HCTZ 50-100 mg (BID) or Chlorthalidone 50-100 mg EWPHE (1985) HCTZ 25-50 mg MRC (1992) HCTZ 25-50 mg SHEP (1991) Chlorthalidone 12.5-25 mg TOMHS (1993) Chlorthalidone 15-30 mg ALLHAT (2002) Chlorthalidone 12.5-25 mg ACCOMPLISH (2008) HCTZ 12.5-25 mg 3

Diuretics 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

Chlorthalidone has been the preferred diuretic in NHLBI hypertension trials but is infrequently used. IMS Health NDTI, 2001-06.

ABPM: Mean 24-hour, Daytime, and Nighttime Systolic BP With Change From Baseline Ernst ME et al. Hypertension. 2006;47:352-358.

MRFIT 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. 7

MRFIT: 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

MRFIT 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 Group Time From Randomization in Years Proportion Dead Cumulative A. Predominantly H Clinics SI UC 0.03 0.02 0.01 1 2 3 4 5 Proportion Dead Cumulative B. Initially C, Then H Time From Randomization in Years SI UC 0.03 0.02 0.01 1 2 3 4 5 Time From Randomization in Years Proportion Dead Cumulative C. Predominantly C Clinics SI UC 0.03 0.02 0.01 1 2 3 4 5 Bartsch G et al. Circulation. 1984;70(suppl II):II-1438. 10

MRFIT 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 Conduct trial in large health care setting. Utilize electronic medical record. Point of care trial

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