Setting the Record Straight

1. ALLHAT Setting the Record Straight

2. ALLHAT 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

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

4. ALLHAT 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

5. ALLHAT Testing First-Step Therapy –ALLHAT • 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

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

7. ALLHAT 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

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

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

10. ALLHAT 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

11. 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 Setting the Record Straight –Study Conduct

12. ALLHAT Study Conduct –Endpoint Ascertainment • 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. ALLHAT Study Conduct –Endpoint Ascertainment • 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. ALLHAT Study Conduct –Endpoint Ascertainment • 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. Why do the authors emphasize the secondary outcome results? ALLHAT Setting the Record Straight –Conclusions and Interpretations

16. ALLHAT Conclusions & Interpretations –Primary vs Secondary Outcomes • 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. 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 Setting the Record Straight –Conclusions and Interpretations

18. ALLHAT Conclusions & Interpretations –Heart Failure Validity • 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

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

20. ALLHAT Conclusions & Interpretations –Suggested Reasons for Divergenceof HF Curves • 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

21. ALLHAT Conclusions & Interpretations –HF Findings vs Meds at Entry • 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

22. ALLHAT Conclusions & Interpretations –HF vs 2nd and 3rd line drugs • Addition of 2nd and 3rd 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

23. ALLHAT Conclusions & Interpretations –HF vs Total Mortality • 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

24. 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 Setting the Record Straight –Conclusions and Interpretations

25. ALLHAT Conclusions & Interpretations –Blood Pressure Differences • 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

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

28. ALLHAT Conclusions & Interpretations –Blood Pressure Differences • 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%)

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

30. ALLHAT Conclusions & Interpretations –Incident Diabetes • 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

31. ALLHAT Conclusions & Interpretations –Incident Diabetes • ↑ 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

32. ALLHAT Conclusions & Interpretations –Incident Diabetes • 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

33. ALLHAT Conclusions & Interpretations –Incident Diabetes • 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?

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

35. ALLHAT Conclusions & Interpretations –Cost of Antihypertensive Management • 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

36. ALLHAT Conclusions & Interpretations –Cost of Antihypertensive Management • 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.

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

38. ALLHAT Conclusions & Interpretations –Extrapolation to Drug Classes • 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

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

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

41. ALLHAT Conclusions & Interpretations –ALLHAT vs ANBP2 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

42. ALLHAT Conclusions & Interpretations –ALLHAT vs ANBP2 • 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

43. ALLHAT Conclusions & Interpretations –ALLHAT vs ANBP2 • 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

44. ALLHAT Limitations & Expectations • 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

45. ALLHAT Conclusions • As 1st-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

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

47. ALLHAT Other Remarks • 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