1. 1 Setting the Record Straight ALLHAT

2. 2 Major ALLHAT Findings CHD risk not improved for any of the 3 newer agents compared with chlorthalidone Total mortality was similar for the 4 groups Diuretic superior in preventing one or more major forms of CVD, including stroke and heart failure Subgroups consistent except stroke, combined CVD –Heterogeneity in L / C comparison by ethnicity – greater reductions in Blacks Diuretics drug of choice for initial therapy of HTN and should be included in multidrug regimens ALLHAT

3. 3 Setting the Record Straight – Study Design How could ALLHAT test first-step therapy, given the study’s inclusion criteria and lack of a washout period? ALLHAT

4. 4 Testing First-Step Therapy – The Ideal Trial Include all hypertensive patients –Low and high risk –Treated (with washout) and untreated BUT Require more patients More complex Unaffordable ALLHAT

5. 5 Practice-based trial mirrors community treatment of hypertension Obtained sufficient patients Captures diversity of patients High risk patients assure adequate numbers of outcome events No washout, except for β-blockers ALLHAT Testing First-Step Therapy – ALLHAT

6. 6 Setting the Record Straight – Study Design Why were diuretics and calcium- channel blockers avoided as second-step drugs? ALLHAT

7. 7 Second-Line Drugs Second- and third-line drugs available for BP control Discouraged step-up from same class as any of the first-step agents unless compelling indications Odd that β-blocker a step-up agent for ACEI? Reserpine, clonidine, hydralazine also provided as step-up therapy in addition to β-blocker – different mechanisms of action than first-step ALLHAT

8. 8 Second-Line Drugs & BP Control BP control with ALLHAT regimen more than twice that at entry Exceeded that observed in 3 rd NHANES ALLHAT

9. 9 Setting the Record Straight – Study Conduct Doesn’t the attrition rate necessarily bias the conclusions? ALLHAT

10. 10 Study Conduct – Attrition Mean length of follow-up 4.9 years 99% of expected person-years were observed 97.1% of participants had known vital status during closeout period Sensitivity analyses consistent with trial’s published conclusions ALLHAT

11. 11 Setting the Record Straight – Study Conduct Wasn’t the outcome ascertainment process flawed since end points were not systematically reviewed by a panel of experts? Aren’t the secondary outcomes “soft end points”? ALLHAT

12. 12 Study Conduct – Endpoint Ascertainment ALLHAT Not feasible to systematically verify all endpoints –11,000 CVD end points during follow-up AHT double-blind  no bias for or against any treatment when reporting and classifying endpoints LLT not double-blind  potential bias for all nonfatal outcomes  secondary endpoints for LLT “soft data”

13. 13 Study Conduct – Endpoint Ascertainment ALLHAT Investigators trained per definitions detailed in Manual of Operations Review of all end points at ALLHAT Clinical Trials Center by medical reviewers. –Verified investigator-assigned diagnoses using death certificates & discharge summaries

14. 14 Study Conduct – Endpoint Ascertainment ALLHAT Random 10% subset of CHD & stroke – more detailed information collected; reviewed by Endpoint Subcommittee –90% agreement for primary outcome (CHD) –84% agreement for stroke Smaller one-time sample of HF cases –85% agreement Rates of agreement similar across treatment groups.

15. 15 Setting the Record Straight – Conclusions and Interpretations Why do the authors emphasize the secondary outcome results? ALLHAT

16. 16 Conclusions & Interpretations – Primary vs Secondary Outcomes ALLHAT Identification of primary outcome assures statistical power to test question related to that end point –Primary outcome essentially identical in all treatment groups. Other important predefined clinical outcomes –Public health viewpoint, all major clinical outcomes are worth examining –E.g., Total mortality

17. 17 Setting the Record Straight – Conclusions and Interpretations Are the heart failure findings real? Can’t all or most of the heart failure findings be explained by the use of antihypertensive medications, such as diuretics and CCBs, before entry into ALLHAT? ALLHAT

18. 18 First validity sample - 85% agreement in 39 cases All HF hospitalizations and deaths – 3031 cases in 2091 patients –All relevant materials collected, 2 reviewers per case (blinded to treatment group) –ALLHAT and Framingham criteria, reviewer’s judgment –Confirmed 70-84% of cases in each treatment group, depending on criteria used –Analysis using only confirmed cases confirmed original ALLHAT findings regarding HF ALLHAT Conclusions & Interpretations – Heart Failure Validity

19. 19 Divergence continued after 1 year for doxazosin & amlodipine vs chlorthalidone For lisinopril vs chlorthalidone, curves converged between 6-7 years ALLHAT Conclusions & Interpretations – Early Divergence of HF Differences

20. 20 Precipitation of edema with amlodipine? Unmasking of edema upon withdrawal of diuretics at entry? Central review algorithm for HF disallowing peripheral edema –Did not alter HF confirmation rate –Did not alter treatment group differences ALLHAT Conclusions & Interpretations – Suggested Reasons for Divergence of HF Curves

21. 21 IMS data 1994-1998 (ALLHAT recruitment) –U.S. hypertensives taking diuretics decreased from 30% to just over 20% Central review of HF cases –No interaction of study treatment with pre- entry diuretic use ALLHAT Conclusions & Interpretations – HF Findings vs Meds at Entry

22. 22 Addition of 2 nd and 3 rd line drugs probably contributed to lessening of the divergence 6-12 months after randomization –Open-label diuretics, β-blockers, ACEI –Excess risk with doxazosin as monotherapy reduced but not eliminated after 1 year –Greatest differential in participants with controlled BP – difference not explained by BP differential ALLHAT Conclusions & Interpretations – HF vs 2 nd and 3 rd line drugs

23. 23 Δ HF  Δ total mortality? –9 excess cases of fatal HF for lisinopril <1% of all deaths –39 fatal HF for amlodipine, 3% of deaths –Differences unlikely to be detected ALLHAT Conclusions & Interpretations – HF vs Total Mortality

24. 24 Setting the Record Straight – Conclusions and Interpretations Can’t all or most of the outcome findings (especially the differential ethnicity subgroup findings for stoke) be explained by the observed blood pressure differences among the treatment groups? ALLHAT

25. 25 Goal – achieve equivalent BP control in all 4 groups –Mean decrease in BP not a declared outcome Chlorthalidone-based regimen the most effective in reducing clinical outcomes and, to a small degree, in lowering BP ALLHAT Conclusions & Interpretations – Blood Pressure Differences

26. 26 ALLHAT Conclusions & Interpretations – Blood Pressure Differences If a given agent is less effective in reducing clinical events unless it is combined with another agent like chlorthalidone to lower BP, not clear why treatment would be started with anything other than diuretic

27. 27 Δ achieved SBP  Δ in CV findings? Meta-regressions of BP differences on trial results –True to some extent, except for HF ALLHAT Conclusions & Interpretations – Blood Pressure Differences

28. 28 Δ BP for amlodipine vs chlorthalidone, and for lisinopril vs chlorthalidone in non- Black participants  1 mm Hg –Expect no / negligible effect on CV events –HF higher with amlodipine (38%) and with lisinopril (15%) than with chlorthalidone Larger differences in Black participants –4 mm Hg SBP in lisinopril vs chlorthalidone –Explains < ½ of observed higher risk for stroke (40%) and HF (32%) ALLHAT Conclusions & Interpretations – Blood Pressure Differences

29. 29 Setting the Record Straight – Conclusions and Interpretations Doesn’t the increased incidence of new diabetes in the chlorthalidone group portend greater long-term cardiovascular risk for patients taking this drug? ALLHAT

30. 30 Incident diabetes not a pre-specified outcome Thiazide diuretics  small increase in serum glucose (3-4 mg/dL) in short term –Consistent with other literatuve Results for major outcomes consistent by baseline diabetes status Conclusions & Interpretations – Incident Diabetes ALLHAT

31. 31 ↑ in serum glucose did not lead to ↑ CV events or ↑ total mortality during the trial Patients in doxazosin group had ↓ mean glucose compared to chlorthalidone –Did not translate in better CV reduction for doxazosin Conclusions & Interpretations – Incident Diabetes ALLHAT

32. 32 Thiazide-induced diabetes can probably be prevented or reversed: –Maintenance of potassium balance –Adequate weight control –Increased physical activity –Caution when using β-blockers in combination therapy Conclusions & Interpretations – Incident Diabetes ALLHAT

33. 33 Long follow-up for ALLHAT, avg. 4.9 years –Cannot predict outcomes beyond trial’s duration –Applies to any clinical trial –Lack of evidence that a result will hold up decades after trial ends does not prove that a different outcome will result Does thiazide-induced diabetes carry same prognosis as naturally-occurring diabetes? Conclusions & Interpretations – Incident Diabetes ALLHAT

34. 34 Setting the Record Straight – Conclusions and Interpretations Diuretics themselves may be cheaper, but does the cost of management with diuretics translate into less expensive therapy? ALLHAT

35. 35 Cost subordinate to safety & efficacy Still should be considered in selection of antihypertensive agents Could have major impact on health care expenditures in U.S. –Diuretic use declined from 56% of prescriptions in 1982 to 27% of prescriptions in 1992 –$3.1 billion in savings on drugs costs if diuretic use had remained at 1982 levels Conclusions & Interpretations – Cost of Antihypertensive Management ALLHAT

36. 36 Cost effectiveness analyses for ALLHAT are underway Preliminary analyses suggest costs driven by drug acquisition Cost for monitoring K+ and glucose not proven to be more than that required during treatment with ACEI or in routine care of patients with risk factors. Conclusions & Interpretations – Cost of Antihypertensive Management ALLHAT

37. 37 Setting the Record Straight – Conclusions and Interpretations Can the findings be extrapolated to drugs within class? ALLHAT

38. 38 For α-blockers, ACE inhibitors, & dihydropyridine CCBs, extrapolation seems reasonable Chlorthalidone  thiazide diuretics  HCTZ? MRFIT mortality trends less favorable at clinics where HCTZ favored over chlorthalidone –Based on post hoc subgroup analysis –Based on group identifier (clinic) rather than patients – results did not hold up at patient level Conclusions & Interpretations – Extrapolation to Drug Classes ALLHAT

39. 39 Data from other studies (except MRFIT) using various thiazide-type diuretics suggest similar benefit in CVD prevention –Chlorthalidone –HCTZ –Indapamide –Bendrofluazide Conclusions & Interpretations – Extrapolation to Drug Classes ALLHAT

40. 40 Setting the Record Straight – Conclusions and Interpretations Why do the findings from ALLHAT and the Second Australian National Blood Pressure Study seemingly conflict? ALLHAT

41. 41 Second Australian National Blood Pressure Study Practice-based open-label trial Diuretic-based vs ACEI-based treatment –Recommended – HCTZ, enalapril 6083 participants, 65-84 years of age Followed for a mean of 4.1 years Conclusions & Interpretations – ALLHAT vs ANBP2 ALLHAT

42. 42 Primary endpoint - composite of all CV events (initial & recurrent) plus all-cause mortality Results marginally favored ACEI –RR 0.89 (0.79 – 1.00, p=0.05) First CV event or death, p=0.06 First CV event, p=0.07 Conclusions & Interpretations – ALLHAT vs ANBP2 ALLHAT

43. 43 Frohlich NEJM. 2003;5:192-5 - samples studied, specific drugs used 2X CV events in ALLHAT as participants in ANBP2 ALLHAT double-blind vs ANBP2 PROBE design –increased potential for bias in ANBP2 Results consistent if upper confidence limit for relative risks in ANBP2 compared with estimates in ALLHAT Conclusions & Interpretations – ALLHAT vs ANBP2 ALLHAT

44. 44 New drugs have been or will soon be released –Angiotensin-receptor blockers, selective aldosterone antagonists Equivalent BP control not fully achieved Step-up agents  somewhat artificial regimen for ACE group  high BP in ACE group? –Mean BP well below 140/90 mm Hg in all groups Did not include low-risk individuals nor a wash-out period Information on previous AHT meds not collected Limitations & Expectations ALLHAT

45. 45 As 1 st -step agents, ACEI, CCB, and α-blockers add no value over and above diuretics in preventing CHD or other major forms of CVD –Less effective in preventing HF –More expensive than diuretics Conclusions ALLHAT

46. 46 Lowering high BP is of fundamental importance in reducing CVD risk How BP is lowered does matter Diuretics should remain the preferred 1 st step drugs for treatment of hypertension Diuretics should be a cornerstone in the arsenal for care of hypertensive patients. Conclusions ALLHAT

47. 47 Surprising ALLHAT findings –ACEI not the best in preventing CV events –CCB not the worst in terms of CHD and deaths Expectations derived from preclinical studies, extrapolation from surrogate outcomes, and case-control and other observational studies Results from randomized, double-blind, clinical endpoint trials needed whenever possible as basis for therapeutic decisions Other Remarks ALLHAT