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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?. H vs C Study Rationale.

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HvC Comparative Effectiveness Project Groups 5 and 6

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  1. HvC Comparative Effectiveness ProjectGroups 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?

  2. 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.

  3. 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

  4. 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

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

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

  7. 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.

  8. MRFIT: H and C Clinics

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

  10. Cumulative Mortality for Death From All Causes Before 4-1-80 by Study– Group and Clinic Group A. Predominantly H Clinics B. Initially C, Then H SI UC SI UC 0.03 0.03 Cumulative Proportion Dead Cumulative Proportion Dead 0.02 0.02 0.01 0.01 0 0 1 2 3 4 5 1 2 3 4 5 Time From Randomization in Years Time From Randomization in Years C. Predominantly C Clinics SI UC 0.03 Cumulative Proportion Dead 0.02 0.01 0 1 2 3 4 5 Time From Randomization in Years Bartsch G et al. Circulation. 1984;70(suppl II):II-1438.

  11. 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.

  12. Design Considerations • Conduct trial in large health care setting. • Utilize electronic medical record. • Point of care trial

  13. 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

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