1. Heart Failure With Preserved And Impaired Systolic Left Ventricular Function In ALLHAT JB Kostis, B Davis, L Simpson, H Black, W Cushman, P Einhorn, M Farber, C Ford, D Levy, B Massie, S Nawaz For The ALLHAT Collaborative Research Group ALLHAT

2. Antihypertensive Trial Design Randomized, double-blind, multi-center clinical trial Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic 42,418 high-risk hypertensive patients ≥ 55 years ALLHAT

3. Randomized Design of ALLHAT BP Trial 42,418 High-risk hypertensive patients Consent / Randomize AmlodipineChlorthalidoneDoxazosinLisinopril Follow until death or end of study (4-8 years, mean 4.9 years) ALLHAT

4. Rationale for the Heart Failure Validation Study: Background Early termination of the doxazosin arm February 2000, due to: Early termination of the doxazosin arm February 2000, due to: 25% higher risk of CVD events in doxazosin compared to chlorthalidone, mostly driven by two-fold increase in HF 25% higher risk of CVD events in doxazosin compared to chlorthalidone, mostly driven by two-fold increase in HF a very low probability of finding a significant difference for the primary outcome by the scheduled trial end a very low probability of finding a significant difference for the primary outcome by the scheduled trial end Higher risk of HF in amlodipine and lisinopril arms compared with chlorthalidone Higher risk of HF in amlodipine and lisinopril arms compared with chlorthalidone ALLHAT DSMB recommended that this study be done ALLHAT DSMB recommended that this study be done Early termination of the doxazosin arm February 2000, due to: Early termination of the doxazosin arm February 2000, due to: 25% higher risk of CVD events in doxazosin compared to chlorthalidone, mostly driven by two-fold increase in HF 25% higher risk of CVD events in doxazosin compared to chlorthalidone, mostly driven by two-fold increase in HF a very low probability of finding a significant difference for the primary outcome by the scheduled trial end a very low probability of finding a significant difference for the primary outcome by the scheduled trial end Higher risk of HF in amlodipine and lisinopril arms compared with chlorthalidone Higher risk of HF in amlodipine and lisinopril arms compared with chlorthalidone ALLHAT DSMB recommended that this study be done ALLHAT DSMB recommended that this study be done ALLHAT

5. Heart Failure Validation Study: Design and Methods Protocol developed in collaboration with heart failure experts. Protocol developed in collaboration with heart failure experts. Additional documentation collected for all hospitalized heart failure events. Additional documentation collected for all hospitalized heart failure events. Documentation reviewed by cardiology fellows (blinded to treatment assignment), for signs, symptoms, past history, concomitant conditions, procedures, treatments. Documentation reviewed by cardiology fellows (blinded to treatment assignment), for signs, symptoms, past history, concomitant conditions, procedures, treatments. Analyses performed using computer algorithm to determine whether each case met ALLHAT or Framingham criteria. Analyses performed using computer algorithm to determine whether each case met ALLHAT or Framingham criteria. Protocol developed in collaboration with heart failure experts. Protocol developed in collaboration with heart failure experts. Additional documentation collected for all hospitalized heart failure events. Additional documentation collected for all hospitalized heart failure events. Documentation reviewed by cardiology fellows (blinded to treatment assignment), for signs, symptoms, past history, concomitant conditions, procedures, treatments. Documentation reviewed by cardiology fellows (blinded to treatment assignment), for signs, symptoms, past history, concomitant conditions, procedures, treatments. Analyses performed using computer algorithm to determine whether each case met ALLHAT or Framingham criteria. Analyses performed using computer algorithm to determine whether each case met ALLHAT or Framingham criteria. ALLHAT

6. Heart failure developing in patients with hypertension is associated either with preserved or with impaired left ventricular systolic function. Heart failure developing in patients with hypertension is associated either with preserved or with impaired left ventricular systolic function. ALLHAT provides the to examine occurrence and differences in symptoms, signs and case fatality of heart failure with preserved or impaired left ventricular systolic function. ALLHAT provides the to examine occurrence and differences in symptoms, signs and case fatality of heart failure with preserved or impaired left ventricular systolic function. Heart failure developing in patients with hypertension is associated either with preserved or with impaired left ventricular systolic function. Heart failure developing in patients with hypertension is associated either with preserved or with impaired left ventricular systolic function. ALLHAT provides the to examine occurrence and differences in symptoms, signs and case fatality of heart failure with preserved or impaired left ventricular systolic function. ALLHAT provides the to examine occurrence and differences in symptoms, signs and case fatality of heart failure with preserved or impaired left ventricular systolic function. Introduction HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT

7. HF With Preserved And Impaired Systolic Left Ventricular Function To verify the heart failure outcomes of ALLHAT, all available hospitalized heart failure events reported by ALLHAT Investigators were systematically reviewed. To verify the heart failure outcomes of ALLHAT, all available hospitalized heart failure events reported by ALLHAT Investigators were systematically reviewed. Estimate of left ventricular ejection fraction by contrast ventriculography, echocardiography or radionuclide study was available in 928 (66%) of 1,300 first hospitalized heart failure events meeting ALLHAT criteria. Estimate of left ventricular ejection fraction by contrast ventriculography, echocardiography or radionuclide study was available in 928 (66%) of 1,300 first hospitalized heart failure events meeting ALLHAT criteria. To verify the heart failure outcomes of ALLHAT, all available hospitalized heart failure events reported by ALLHAT Investigators were systematically reviewed. To verify the heart failure outcomes of ALLHAT, all available hospitalized heart failure events reported by ALLHAT Investigators were systematically reviewed. Estimate of left ventricular ejection fraction by contrast ventriculography, echocardiography or radionuclide study was available in 928 (66%) of 1,300 first hospitalized heart failure events meeting ALLHAT criteria. Estimate of left ventricular ejection fraction by contrast ventriculography, echocardiography or radionuclide study was available in 928 (66%) of 1,300 first hospitalized heart failure events meeting ALLHAT criteria. Methods ALLHAT

8. HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT HF by EF level 50% N=928 EF>50% EF<50% 45%

9. HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT HF by EF level N=1399 EF N/A EF<40% EF>50% EF 40-49%

10. HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT HF by EF level (% of those with available EF) N=928 EF<40% EF 40-49% EF>50%

11. HF With Preserved And Impaired Systolic Left Ventricular Function Baseline Characteristics Normal Impaired P value Normal vs Impaired Total ALLHAT Age69.769.60.9166.9 Ethnicity White non-Hispanic Black non-Hispanic Other 60.9% 31.5% 7.6% 58.5% 34.2% 7.3% 0.7547.1% 32.3% 4.9% Women51.2%37.5%<0.00146.8% Current Smoker18.7%19.2%0.8621.9% Treated95.0%92.5%0.1290.2% Atherosclerotic CVD61.4%64.4%0.3451.6% ST dep. or T Wave Invers.11.1%12.2%0.3910.3% Type II Diabetes50.2% 0.9936.0% LVH by ECG18.7%20.6%0.4816.4% LVH by ECHO6.6%4.9%0.274.5% ALLHAT

12. HF With Preserved And Impaired Systolic Left Ventricular Function Baseline Characteristics NormalImpaired P value Normal vs. Impaired Total ALLHAT History of CHD32.5%38.2%0.0725.6% Blood Pressure SBP mean DBP mean 149.6 80.7 147.9 81.6 0.10 0.18 146.3 84.0 Fasting Glucose mean >126 mg/dL 140.8 40.5% 144.0 46.7% 0.65 0.10 123.0 29.1% LDL mean133.4137.50.14135.8 HDL mean <35 mg/dL 45.2 22.1% 42.5 29.3% 0.003 0.02 46.8 19.2% Triglyceride mean182.7189.80.44175.7 ALLHAT

13. Symptoms of Heart Failure NormalImpaired P value Normal vs. Impaired % Missing PND29.4%35.8%0.0456.5% Orthopnea41.7%45.5%0.2545.8% Dyspnea at rest50.7%49.6%0.7345.6% DOE69.0%67.4%0.6130.9% NYHA Class III64.0%57.1%0.0339.2% Night Cough11.6%8.1%0.0782.0% HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT

14. SYMPTOMS HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT

15. Signs of Heart FailureNormalImpaired P value Normal vs. Impaired % Missing Ankle Edema 2+37.9%26.5%0.000215.3% Bilateral Ankle Edema67.1%54.2%0.000110.9% Tachycardia 120+11.8%13.4%0.4728.7% Jugular Venous Distention36.3%37.2%0.7828.2% Increased Venous Pressure >8 AND <16 CM H2O10.9%9.5%0.4861.6% Hepatojugular Reflux2.6%4.3%0.1590.9% Rales73.7%76.5%0.3311.5% S3 Gallop10.0%19.6%<0.000139.9% Hepatomegaly2.4%5.7%0.0150.4% Cardiomegaly60.0%62.8%0.3727.7% HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT

16. Signs of Heart FailureNormalImpaired P value Normal vs. Impaired % Missing Acute Pulmonary Edema No 28.4% 13.7% 30.6% 14.2% 0.4756.4% Pleural Effusion No 35.1% 16.4% 40.7% 13.2% 0.0847.2% Pulmonary Vascular Engorgement Redistribution 39.6% 16.4% 37.2% 22.1% 0.45 0.03 54.1% 73.9% X-Ray Characteristic of HF Reviewer Opinion Report 48.3% 50.7% 52.6% 55.5% 0.20 0.14 39.9% 36.6% HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT

17. SIGNS HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT

18. EF Range by Drug HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT *lisinopril vs. chlorthalidone p=0.04

19. EF Range by Drug; % of Those With Available EF HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT * lis vs. chlor, p=0.02

20. Vital Status (% Dead) 28.1 37.1 P=0.004 P=0.02 P=0.06 HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT Total

21. Vital Status by Drug and EF Group HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT

22. Cumulative HF Rate Among All HF Cases Using ALLHAT Criteria; With EF by EF Class 0.00 0.20 0.40 0.60 0.80 1.00 Conditional Cumulative ALLHAT#1 HF Rate 01234567 Time to event, y >50% 40 - 49% <40% ALLHAT

23. Cumulative HF Rate Among All HF Cases Using ALLHAT Criteria; With EF by EF Class 0.00 0.20 0.40 0.60 0.80 1.00 Conditional Cumulative ALLHAT#1 HF Rate 01234567 Time to event, y Normal (EF>50) Impaired (EF<50) ALLHAT

24. Cumulative HF Rate Using ALLHAT Criteria; With EF<50 0.00 0.01 0.02 0.03 Cumulative ALLHAT#1 HF Rate 01234567 Time to event, y Chlorthalidone Amlodipine Lisinopril RR (95%CI)P value A/C1.28 (1.02-1.61)0.03 L/C0.90 (0.70-1.16)0.43 ALLHAT

25. Cumulative HF Rate Using ALLHAT Criteria; With EF>50 0.00 0.01 0.02 0.03 Cumulative ALLHAT#1 HF Rate 01234567 Time to event, y Chlorthalidone Amlodipine Lisinopril ALLHAT RR (95%CI)P value A/C1.56 (1.21-2.01)0.0005 L/C1.38 (1.06-1.80)0.02

26. Cumulative HF Rate Using ALLHAT Criteria; With EF<50 0.00 0.01 0.02 Cumulative ALLHAT#1 HF Rate 01234 Time to event, y Chlorthalidone Doxazosin ALLHAT RR (95% CI)P value D/C1.64 (1.27-2.12)0.0001

27. Cumulative HF Rate Using ALLHAT Criteria; With EF>50 0.00 0.01 0.02 Cumulative ALLHAT#1 HF Rate 01234 Time to event, y Chlorthalidone Doxazosin RR (95% CI)P value D/C1.84 (1.35-2.52)0.0001 ALLHAT

28. Post-HF Mortality With Preserved Systolic Function (EF >50) 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 Cumulative Post-HF Mortality Rate 0123456 Time to event, y Chlorthalidone Amlodipine Lisinopril RR (95%CI)P value A/C0.70 (0.46-1.07)0.10 L/C1.07 (0.74-1.54)0.73 ALLHAT

29. Post-HF Mortality With Impaired Systolic Function (EF<50) 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 Cumulative Post-HF Mortality Rate 0123456 Time to event, y Chlorthalidone Amlodipine Lisinopril RR (95%CI)P value A/C1.08 (0.82-1.42)0.59 L/C1.06 (0.78-1.44)0.72 ALLHAT

30. Post-HF Mortality With Preserved Systolic Function (EF >50) 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 Cumulative Post HF Mortality Rate 01234 Time to event, y Doxazosin Chlorthalidone RR (95% CI)P value D/C0.86 (0.47-1.58)0.62 ALLHAT

31. Post-HF Mortality With Impaired Systolic Function (EF<50) 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 Cumulative Post-HF Mortality Rate 01234 Time to event, y Doxazosin Chlorthalidone RR (95% CI)P value D/C0.73 (0.47-1.14)0.17 ALLHAT

32. Post-HF Mortality By Systolic Function 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 Cumulative ALLHAT#1 HF to Death Rate 0123456 Time to Event, y Preserved Systolic Function (EF >50) Impaired Systolic Function (EF <50) ALLHAT

33. Heart Failure with preserved left ventricular systolic function is common in treated patients with hypertension (compared to heart failure with impaired systolic function). Heart Failure with preserved left ventricular systolic function is common in treated patients with hypertension (compared to heart failure with impaired systolic function). Heart Failure with preserved left ventricular systolic function is associated with more edema while heart failure with impaired left ventricular systolic function is associated with signs of ventricular dilatation. Heart Failure with preserved left ventricular systolic function is associated with more edema while heart failure with impaired left ventricular systolic function is associated with signs of ventricular dilatation. Heart Failure with preserved left ventricular systolic function is associated with lower case fatality (than heart failure with impaired systolic function). Heart Failure with preserved left ventricular systolic function is associated with lower case fatality (than heart failure with impaired systolic function). Heart Failure with preserved left ventricular systolic function is common in treated patients with hypertension (compared to heart failure with impaired systolic function). Heart Failure with preserved left ventricular systolic function is common in treated patients with hypertension (compared to heart failure with impaired systolic function). Heart Failure with preserved left ventricular systolic function is associated with more edema while heart failure with impaired left ventricular systolic function is associated with signs of ventricular dilatation. Heart Failure with preserved left ventricular systolic function is associated with more edema while heart failure with impaired left ventricular systolic function is associated with signs of ventricular dilatation. Heart Failure with preserved left ventricular systolic function is associated with lower case fatality (than heart failure with impaired systolic function). Heart Failure with preserved left ventricular systolic function is associated with lower case fatality (than heart failure with impaired systolic function). Conclusions HF With Preserved And Impaired Systolic Left Ventricular Function ALLHAT