1. Did Type of Prior Antihypertensive Therapy Influence the Heart Failure Results in ALLHAT? Richard Grimm, Barry Davis, Linda Piller, Karen Margolis, Joshua Barzilay, Richard Dart, James Graumlich, Robert Murden, Otelio Randall, Katrina Sawyer, for the ALLHAT Collaborative Research Group ALLHAT

2. 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

3. Secondary Outcomes All-cause mortality Stroke Combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina Combined CVD – combined CHD, stroke, lower extremity revascularization, treated angina, fatal / hospitalized / treated CHF All components of CVD – prespecified ALLHAT

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

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

6. Background: Treated, Hospitalized, and Fatal Heart Failure RRP value95% CI A vs. C*1.38< 0.0011.25-1.52 L vs. C*1.19< 0.0011.07-1.31 D vs. C † 1.80< 0.0011.61-2.02 ALLHAT *JAMA 2002;288:2981-2997 † Hypertension 2003;42:239-246

7. Background: Hospitalized and Fatal Heart Failure HRP value95% CI A vs. C*1.35< 0.0011.21-1.50 L vs. C*1.100.110.98-1.23 D vs. C † 1.66< 0.0011.46-1.89 ALLHAT *JAMA 2002;288:2981-2997 † Hypertension 2003;42:239-246

8. Cumulative Event Rates for Hospitalized/Fatal Heart Failure by Treatment Group Cumulative Event Rate Years 01234567 0.02.04.06.08.1 RR95% CI A-C1.351.21-1.50 L-C1.100.98-1.23 Chlorthalidone Amlodipine Lisinopril ALLHAT

9. Cumulative Event Rates for Hospitalized/ Fatal Heart Failure by Treatment Group RR (95% CI)p value D/C1.66 (1.46-1.89)<0.001 ALLHAT Cumulative Fatal+Hosp HF Event Rate Years to Fatal or Hosp HF 012345 0.03.06.09.12 Chlorthalidone Doxazosin

10. ALLHAT Question to be Addressed by these Analyses Kaplan-Meier curves for the HF outcome show an early divergence of the curves for chlorthalidone vs. amlodipine, lisinopril, or doxazosin. Question: Can the heart failure findings in part be explained by discontinuing antihypertensive medications such as diuretics and ACE-inhibitors upon entry into ALLHAT?

11. HF Validation Study – BP Meds at Entry 2091 pts w/ 3032 hosp/fatal HF cases centrally reviewed Criteria – ALLHAT, Framingham, reviewer judgment 70-84% confirmed on central review (similar across Rx groups; Rx group effects larger in confirmed cases) Requested information about pts’ BP drug use at trial entry just before end of study Received information for 1418 pts (~ 2/3 total)  population for this study ALLHAT

13. ID Label ALLHAT BLOOD PRESSURE MEDICATION AT STUDY ENTRY Received ALLHAT

15. Baseline Characteristics HF Ppts with BP Med Data Total HF Ppts Number14182091 Age, mean, yr70.370.1 Female, %43.943.3 Ethnicity White, %62.461.1 Black, %33.234.8 RX at baseline, %93.693.5 BP, mean, mg Hg148.5 / 82.0148.5 / 81.9 ALLHAT

16. Baseline Characteristics ALLHAT HF Ppts with BP Med Data Total HF Ppts Hx of CHD, %38.437.2 Hx of coro. revasc., %23.121.5 Hx of diabetes, %47.549.4 Cigarette smoker,%15.319.1 LVH on ECG, %18.018.8 T-chol, mean, mg/dL217.8216.9 Fast. trig., mean, mg/dL181.4182.2

17. Source of Entry Drug Information Source of informationDistribution ALLHAT RZ records66.2% Other medical chart53.7% Asked patient1.6% Other4.1% ALLHAT Note: More than one source was used for some patients.

18. Heart Failure During ALLHAT: Percent of Patients on Prior BP Meds Prior BP MedCALDTotal Diuretics3641374239 CCB4647454947 ACE-I3839353437 Beta Blockers1714221617 Total # of ppts* † 4603692853041418 *Participants may have been on one, multiple, or no prior BP meds. † Refers to participants with HF during ALLHAT and for whom prior medication data is available. ALLHAT

19. Heart Failure Within the First Year Following Randomization: Percent of Patients on Prior BP Meds ALLHAT Prior BP MedCALDTotal Diuretics4547524948 CCB3544514645 ACE-I43423640 Beta Blockers1011241014 Total # of ppts* † 49797599302 *Participants may have been on one, multiple, or no prior BP meds. † Refers to participants with HF during first year following randomization and for whom prior medication data is available.

20. Cumulative Event Rates for Heart Failure by Prior Meds Status ALLHAT RR (95% CI)p value Y/N1.48 (1.25-1.75)<.001 Cumulative HF Rate Years to HF 01234567 0.03.06.09 No Prior Meds Prior Meds

21. Case-Only Analyses Cannot do analyses on entire population since pre-ALLHAT BP meds data was only collected for HF cases. A technique know as case-only analyses will allow us to examine if there was interaction. Do “full” analyses and case-only analyses provide comparable results? ALLHAT

22. Interactions of Step 1 Treatment and Use of ANY Prior BP Meds for Occurrence of HF* Full logisticCase-only Year 1ORP P A vs C1.81 + 0.291.830.28 L vs C3.520.073.490.07 D vs C1.700.301.690.30 ALLHAT * All hospitalized/fatal heart failure cases + OR (A vs. C) = 2.32 (1.75, 3.08) for those on meds; 1.28 (.44, 3.71) for those not on meds

23. Interaction of Treatment (L vs. C) and Specific Prior BP Meds for Occurrence of HF UnivariateMultivariate* Prior BP MedsOR95% CIOR95% CI Diuretic 1.330.65-2.741.570.73-3.38 ACE-I 0.750.36-1.571.030.47-2.29 CCB 1.930.92-4.062.511.13-5.60 Beta blocker 2.780.96-8.073.301.08-10.07 ALLHAT * Controlled for use of other classes of BP drugs

24. Interaction of Treatment (A vs. C) and Specific Prior BP Meds for Occurrence of HF ALLHAT UnivariateMultivariate* Prior BP MedsOR95% CIOR95% CI Diuretic 1.080.53-2.211.170.55-2.47 ACE-I 0.960.47-1.971.060.49-2.28 CCB 1.500.72-3.131.680.77-3.68 Beta blocker 1.130.36-3.601.420.43-4.72 * Controlled for use of other classes of BP drugs

25. Interaction of Treatment (D vs. C) and Specific Prior BP Meds for Occurrence of HF ALLHAT UnivariateMultivariate* Prior BP MedsOR95% CIOR95% CI Diuretic 1.160.58-2.301.260.61-2.59 ACE-I 0.900.45-1.811.020.49-2.13 CCB 1.630.80-3.321.810.85-3.85 Beta blocker 0.990.32-3.071.140.35-3.65 * Controlled for use of other classes of BP drugs

26. Potential Confounders Confounders by indication: why was the patient placed on a specific class of drug prior to participation in the study? Use of additional meds during the study: what conditions developed that caused the patient to be placed on additional meds? Possibility of misclassification of drugs used prior to study entry Missing data: approximately one third of heart failure cases lacked information on specific drugs used prior to entry into ALLHAT ALLHAT

27. Conclusions Among the HF cases, CCB’s were the most used BP drug prior to entry into ALLHAT, followed by diuretics and ACE inhibitors. Pts on any prior BP med (vs. none) were at higher risk of developing HF. These findings are noteworthy for those on CCB’s and BB’s at entry (confounding by indication?). These findings suggest that the type of BP drug at entry is not a major determinant of the HF results. ALLHAT