1. 1 Role of Diuretics in the Prevention of Heart Failure - The Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial ALLHAT Davis BR, Piller LB, Cutler JA, et al. Circulation 2006.113:2201-2210.

2. 2 Introduction and Background Heart failure is a major public health problem, especially in persons 65 years of age and older (= number one reason for hospitalizations in this age group). Age-adjusted incidence per 100,000 person- years during 1990-1999 was 564 for men and 327 for women, age 65-74 years (NEJM, 2002, Framingham) Five-year age-adjusted survival rate was only 59% among men and 45% for women. In 91% of HF cases, hypertension is an antecedent (Framingham, JAMA, 1996) ALLHAT

3. 3 Hypertension Control and Heart Failure In a meta-analysis of 12 trials of patients with hypertension it was found that, compared to placebo, drug therapy for hypertension prevents over 50% of HF events (Moser, JACC, 1996). In another meta-analysis, diuretics and beta- blockers (BB) were equally effective in preventing HF events (Psaty, JAMA, 1997). ALLHAT

4. 4 Hypertension Control and Heart Failure A meta–analysis of active comparator trials found no significant difference between ACE- inhibitors and diuretics for preventing HF; ACE- inhibitors were more efficacious than CCBs (BPLTT Collaboration, Lancet, 2002). The INSIGHT trial found that a long-acting nifedipine regimen was associated with a > 2x higher incidence of HF events compared to a diuretic combination (HCTZ/amiolride) (Brown, Lancet, 2000). ALLHAT

5. 5 Objectives Characterize HF in ALLHAT by its antecedent risk factors and underlying conditions. Examine occurrence of HF by treatment group overall, in subgroups, and over time. Explore relation of initial occurrence of HF to pre-randomization type of BP medication used. Explore follow-up BP and use of additional drugs as mediating/modifying factors. Examine post-HF mortality overall and by treatment group. ALLHAT

6. 6 42,418 high-risk hypertensive patients 90% previously treated 10% untreated STEP 1 AGENTS Chlorthalidone 12.5-25 mg Amlodipine 2.5-10 mg Lisinopril 10-40 mg Doxazosin 1-8 mg N=15,255 N=9,048 N=9,054 N=9,061 STEP 2 AND 3 AGENTS (5 years) Atenolol 28.0% Clonidine 10.6% Reserpine 4.3% Hydralazine 10.9% Randomized Design of ALLHAT Hypertension Trial ALLHAT Other AHT Drugs

7. 7 Decision to Stop Doxazosin Arm NHLBI Director accepted recommendation of independent review group to terminate doxazosin arm (early in year 2000), due to: –Futility of finding a significant difference for primary outcome –Statistically significant 25 percent higher rate of major secondary endpoint, combined CVD outcomes, along with twofold higher rate of HF Detailed HF analyses published (Davis et al. Ann Intern Med 2002). ALLHAT

8. 8 Heart Failure Data Collection Hospitalized nonfatal – discharge summary Hospitalized fatal – death certificate, discharge summary Nonhospitalized fatal – death certificate Nonhospitalized nonfatal (treated) – clinician report 100% review of discharge summaries and death certificates by CTC Medical Reviewers –Queries to clinics if diagnosis questionable ALLHAT

9. 9 ALLHAT Criteria for HF Evaluation* Must have one from each category: Category “A”Category “B” Paroxysmal nocturnal dyspneaRales Dyspnea at rest2+ ankle edema NYHA Classification IIITachycardia OrthopneaCardiomegaly by CXR CXR characteristic of CHF S 3 gallop Jugular venous distention *ALLHAT Manual of Operations, 5.3.4; adopted from the SHEP trial ALLHAT

10. 10 Validity of HF Outcome Verified Traditional risk factors in agreement with previous studies, e.g., Framingham HF Validation Study confirmed original observed treatment differences –Independent central review using both ALLHAT and Framingham criteria ALLHAT

11. 11 Heart Failure Validation Study Criteria% Agreement ALLHAT71% Framingham Heart Study80% Reviewers’ judgement84% ALLHAT

12. 12 Inclusion/Exclusion Criteria for Antihypertensive Trial Men and women > 55 years old If untreated:  140/90,  180/110 mm Hg (2 visits) If treated: ≤ 160/100 mm Hg (visit 1), ≤ 180/110 mm Hg (visit 2) – No washout required At least one additional cardiovascular risk factor Exclude if symptomatic HF or EF < 35%, creatinine  2 mg/dL, require diuretics, CCB, ACEI, or AB’s for non-BP indication ALLHAT

13. 13 Step 1 Treatment Protocol Step 1 AgentInitial Dose* Dose 1*Dose 2* Dose 3* Chlorthalidone12.5 25 Amlodipine2.5 510 Lisinopril10 2040 Doxazosin1248 * mg/day ALLHAT Step 2/3 drugs –– atenolol, reserpine, clonidine, hydralazine “Non-study” drugs –– all other antihypertensive medications

14. 14 Baseline Characteristics ALLHAT Hospitalized/Fatal HF During Trial YesNoDifferencep N1,77331,584 Age (mean)70.366.7+3.6<0.001 Men, %55.2%53.0%+2.2%0.008 Pre-RZ Treatment, %93.1%90.0%+3.1%0.004 SBP (mean mm Hg)148.2146.2+2.0<0.001 DBP (mean mm Hg)81.884.1-2.3<0.001 Pulse (mean bpm)74.673.5+1.1<0.001 Cigarette smoking, %18.3%22.1%-3.8<0.001 Diabetes, %49.435.4+14.0%<0.001 LVH by ECG, %18.4%16.3%+2.1%<0.001 History of CHD, %37.6%24.7%+12.9<0.001 BMI (mean)30.329.7+0.6<0.001

15. 15 Hospitalized/ Fatal Heart Failure by ALLHAT Treatment Group Cumulative Event Rate Years 01234567 0.02.04.06.08.1 RR95% CI A-C1.351.21-1.50 L-C1.110.99-1.24 A-L1.231.09 – 1.38 Chlorthalidone Amlodipine Lisinopril ALLHAT

16. 16 Heart Failure Before and After 1 Year Observed HF differences were larger earlier in the follow-up. The lisinopril group had a lower HF rate than the amlodipine group, but event curves did not separate until later. A test of the proportional hazards assumption for Cox regression revealed that RRs were not constant over time. Therefore, a Cox regression that used a time-dependent indicator variable ( 1 year) was utilized. ALLHAT

17. 17 1234567.02.04.06.08.1 0 Cumulative Hosp/Fatal HF Rate 0.51 0.01.02 Years to Hosp/Fatal HF Chlorthalidone Amlodipine Lisinopril Years to Hosp/Fatal HF 0 Baseline to Year 1 RR95% CI A-C2.221.69 – 2.91 L-C2.081.58 – 2.74 A-L1.070.82 – 1.38 > Year 1 RR95% CI A-C1.221.08 – 1.38 L-C0.960.85 – 1.10 A-L1.271.10 – 1.46 Hospitalized/ Fatal Heart Failure by ALLHAT Treatment Group Within 1 Year and >1 Year ALLHAT

18. 18 1.83 (1.25 - 2.67)Non-Diabetic 2.71 (1.83 - 4.02)Diabetic 2.17 (1.46 - 3.21)Women 2.27 (1.56 - 3.30)Men 2.37 (1.55 - 3.63)Black 2.12 (1.49 - 3.01)Non-Black 2.06 (1.51 - 2.80)Age ≥ 65 2.89 (1.62 - 5.17)Age < 65 2.22 (1.69 - 2.91)Total 0.50123456 Favors Amlodipine Favors Chlorthalidone Relative Risk (95% CI) Hospitalized/fatal HF in Subgroups - Amlodipine / Chlorthalidone Relative Risks from Baseline to 1 Year of Follow-up ALLHAT

19. 19 Hospitalized/fatal HF in Subgroups - Amlodipine / Chlorthalidone Relative Risks After 1 Year of Follow-up 0.50123456 Favors Amlodipine Favors Chlorthalidone Relative Risk (95% CI) 1.21 (1.02 - 1.43)Non-Diabetic 1.23 (1.04 - 1.46)Diabetic 1.16 (0.97 - 1.39)Women 1.28 (1.09 - 1.50)Men 1.28 (1.03 - 1.58)Black 1.20 (1.04 - 1.39)Non-Black 1.17 (1.02 - 1.35)Age ≥ 65 1.38 (1.10 - 1.73)Age < 65 1.22 (1.08 - 1.38)Total ALLHAT

20. 20 Hospitalized/fatal HF in Subgroups - Lisinopril / Chlorthalidone Relative Risks from Baseline to 1 Year of Follow-up 2.16 (1.50 - 3.10) 1.99 (1.31 - 3.05) 2.40 (1.63 - 3.54) 1.80 (1.22 - 2.67) 2.15 (1.39 - 3.33) 2.04 (1.43 - 2.90) 1.98 (1.45 - 2.70) 2.53 (1.39 - 4.59) 2.08 (1.58 - 2.74) 0.5012345 Relative Risk (95% CI) Favors Lisinopril Favors Chlorthalidone Non-Diabetic Diabetic Women Men Black Non-Black Age ≥ 65 Age < 65 Total ALLHAT

21. 21 Non-Diabetic Diabetic Women Men Black Non-Black Age ≥ 65 Age < 65 Total 0.93 (0.77 - 1.12) 1.01 (0.84 - 1.22) 0.89 (0.73 - 1.09) 1.02 (0.86 - 1.21) 1.10 (0.88 - 1.37) 0.90 (0.77 - 1.06) 0.97 (0.84 - 1.13) 0.95 (0.74 - 1.23) 0.96 (0.85 - 1.10) 0.5012 Relative Risk (95% CI) Favors Lisinopril Favors Chlorthalidone Hospitalized/fatal HF in Subgroups - Lisinopril / Chlorthalidone Relative Risks After 1 Year of Follow-up ALLHAT

22. 22 HF Development and Relation to Other Outcomes HF development associated with: –6.6-fold increase in death rate –11.7-fold increase in CV death rate Previous MI → 5.7-fold increased HF risk Of participants with hospitalized HF: –72% hospitalized once –23.3% hospitalized 2-3 times –4.7% hospitalized 4+ times ALLHAT

23. 23 Why are hazard ratios not constant throughout? Hypotheses? Withdrawal from BP meds used prior to enrollment Time course for effect of first-step (primary) drug –Diuretic – immediate? –ACEI – delayed? Addition of step-up meds (esp. anti-HF meds) Differences in BP ALLHAT

24. 24 Prior Use of Antihypertensive Agents Prior medication use associated with  HF risk, especially during first year –RR 1.42 (1.18 – 1.71) Relative benefits of chlorthalidone consistent with or without prior antihypertensive medication use ALLHAT

25. 25 Specific Prior Antihypertensive Agents Data not collected within ALLHAT –Available for 1115 / 1773 HF cases Case-only analysis –No evidence for any statistically significant interaction between prior drug type (e.g., diuretic) and treatment effect for HF, overall or during the first year ALLHAT CCB’s47% ACEI37% Diuretics39%

26. 26 Immediate vs Delayed Effects Do diuretics have a more immediate effect on HF prevention than ACEI or ARB? –Effect of diuretics begins at trial onset –Several ACEI vs placebo studies suggest that ACEI effect is not immediate –VALUE trial – valsartan vs amlodipine – HF similar in first 2 years, strong trend afterward favoring valsartan ALLHAT

27. 27 Use of Step-up BP Meds Addition of Step 2 and Step 3 meds could have contributed to lessening or cessation of divergence of HF curves after 1 year. ALLHAT

28. 28 Open-Label ACEI and Atenolol Use ALLHAT

29. 29 Open-Label Diuretic and CCB Use ALLHAT

30. 30 Diuretic, ACEI, or Atenol Use ALLHAT

31. 31 BP Results by Treatment Group Compared to chlorthalidone: SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg). Compared to chlorthalidone: DBP significantly lower in the amlodipine group (~1 mm Hg). ALLHAT

32. 32 BP Differences Adjustment for follow-up SBP as time- dependent covariates in a Cox regression model only slightly modified the relative risks Amlodipine/chlorthalidone 2.22  2.16 first year, 1.22  1.18 after 1 year Lisinopril/chlorthalidone 2.08  2.01 first year, 0.96  0.93 after 1 year ALLHAT

33. 33 Cumulative Event Rate Years from Hospitalized HF to Death 01234567 0.1.2.3.4.5.6 Chlorthalidone Amlodipine Lisinopril All-Cause Mortality ALLHAT

34. 34 Post-HF Mortality Mortality rates after hospitalized HF high relative to those seen in ALLHAT overall –25% vs 5% at 2.5 years, respectively No significant treatment group differences for post-HF mortality The reason that the treatment difference for hospitalized HF did not translate into an effect on total mortality is that only 5.6% of all deaths were attributed to HF. ALLHAT

35. 35 Heart Failure and Total Mortality Lisinopril-chlorthalidone absolute difference in hospitalized HF over 6 years was 0.4%. –The excess of cases in the lisinopril group = 36 patients. –Case-fatality rate over average follow-up of 2.5 years = 25%. –Thus, 9 excess cases of fatal HF would be expected in the lisinopril group. This is fewer than 1% of all deaths in the lisinopril group (n=1314). Similar calculations for the amlodipine group: –154 excess cases of hospitalized HF –Estimated number of fatal HF cases was 39, 3% of the amlodipine deaths (n=1256). ALLHAT

36. 36 Effect on Total Mortality HF differences in the trial would not have affected differences in total mortality –Also noted in the BPLTTC analyses –Absolute HF risk low –Increase in RR outweighed by even small reduction in higher absolute risks for stroke and CHD –Differences in # of HF events during trial result in only very small differences in # of deaths –ALLHAT post-trial mortality surveillance to examine this further ALLHAT

37. 37 Conclusions 1 Chlorthalidone superior to amlodipine in both time periods Chlorthalidone superior to lisinopril during the first year True for subgroups – age, race, sex, diabetes history Other factors could not individually account for all of the observed treatment differences –Prior antihypertensive meds –Other open-label BP meds –Follow-up BP differences ALLHAT

38. 38 Conclusions 2 Developing HF is associated with a high mortality rate (~50% at 5 years) It may take time for HF differences to translate into detectable mortality differences between treatments Diuretics are clearly preferred over CCBs overall and over ACE inhibitors, at least in the short term, in preventing HF. ALLHAT

39. 39 Extra Slides

40. 40 Placebo-Controlled Trials Most placebo-controlled trial have used diuretics and/or β-blockers as active regimens Diuretics & ACEI shown to prevent HF in patients with hypertension –SHEP, HOPE CCB vs placebo trials less conclusive –Syst-Eur Meta-analyses – active therapy of hypertension can prevent >40% of HF events –Psaty, Smith, Siscovick, et al. ALLHAT

41. 41 Active-Controlled Trials VALUE STOP Hypertension-2 ANBP2 INVEST CONVINCE – CCB or diuretic/β-blocker –BP reduced similarly, HF 30% more with CCB ALLHAT

42. 42 BPLTTC Meta-Analyses CCB-based therapies –NS 20% increase in HF incidence compared with placebo –33% higher risk of HF compared with diuretic/β-blocker ACEI-based therapies –18% fewer HF events than with CCB or placebo –7% NS higher risk than with diuretic/ β-blocker CCBs less effective in preventing HF than other regimens ACEI no more effective in preventing HF than diuretic/ β-blocker ALLHAT

43. 43 Randomized Design of ALLHAT High-risk hypertensive patients ≥ 55 years Consent / Randomize (42,418) Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipid- lowering Not eligible for lipid-lowering Consent / Randomize (10,355) Pravastatin Usual care Follow for CHD and other outcomes until death or end of study (up to 8 yr). ALLHAT

44. 44 Event Reduction in SHEP, Syst-Eur, and HOPE SHEP: Systolic Hypertension in the Elderly, n=4,736; chlorthalidone Syst-Eur: Systolic Hypertension in Europe, n=4,695; nitrendipine HOPE: Heart Outcomes Prevention Evaluation Study, n=9,297; ramipril