Heart Failure (HF) Findings: Are They Real? Stanley S. Franklin, MD, FACP, FACC Clinical Professor of Medicine University of California at Irvine Associate Medical Director UCI Heart Disease Prevention Program Irvine, California ALLHAT

Presenter Disclosure Information DISCLOSURE INFORMATION: The following relationships exist related to this presentation: Speakers bureau for: Boehringer Ingelheim, Bristol-Myers Squibb, Merck. Consultant for: AtCor Medical, Bristol-Myers Squibb, and Merck Stanley S. Franklin, MD, FACP, FACC, FAHA, FASN

HF Objectives Characterize HF in ALLHAT by its antecedent risk factors and underlying conditions. Characterize HF in ALLHAT by its antecedent risk factors and underlying conditions. Examine occurrence of HF by treatment groups overall, in subgroups, and over time. Examine occurrence of HF by treatment groups overall, in subgroups, and over time. Examine post-HF mortality overall and by treatment group. Examine post-HF mortality overall and by treatment group. Characterize HF in ALLHAT by its antecedent risk factors and underlying conditions. Characterize HF in ALLHAT by its antecedent risk factors and underlying conditions. Examine occurrence of HF by treatment groups overall, in subgroups, and over time. Examine occurrence of HF by treatment groups overall, in subgroups, and over time. Examine post-HF mortality overall and by treatment group. Examine post-HF mortality overall and by treatment group. ALLHAT Davis BH, et al. Circulation 2006;113:

Decision to Stop Doxazosin Arm  Futility of finding a significant difference for primary outcome compared to chlorthalidone  Statistically significant 25 percent higher rate of major cardiovascular events, including near twofold higher rate of HF (hospitalized, treated out-of-hospital, or fatal) ALLHAT

Blood Pressure Trial Design ALLHAT Randomized, practice –based Double-blind (not PROBE) Diagnoses assigned by clinic investigators guided by protocol-defined diagnostic criteria Randomization stratified by clinic Exclude: h/o symptomatic HF (stage C) and/or known LVEF <35%

Baseline Characteristics ALLHAT Hospitalized/Fatal HF During Trial YesNoDifferencep N1,77331,584 Age (mean) <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) <0.001 DBP (mean mm Hg) <0.001 Pulse (mean bpm) <0.001 Cigarette smoking, % 18.3%22.1%-3.8<0.001 Diabetes, % %<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) <0.001 Davis BH, et al. Circulation 2006;113:

Hospitalized/ Fatal HF by ALLHAT Treatment Group Cumulative Event Rate Years RR 95% CI A-C L-C A-L – 1.38 Chlorthalidone Amlodipine Lisinopril ALLHAT Davis BH, et al. Circulation 2006;113:

HF Before and After 1 Year 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 Davis BH, et al. Circulation 2006;113:

Cumulative Hosp/Fatal HF Rate Years to Hosp/Fatal HF Chlorthalidone Amlodipine Lisinopril Years to Hosp/Fatal HF 0 Baseline to Year 1 RR 95% CI A-C – 2.91 L-C – 2.74 A-L – 1.38 > Year 1 RR 95% CI A-C – 1.38 L-C – 1.10 A-L – 1.46 Hospitalized/ Fatal HF by ALLHAT Treatment Group Within 1 Year and >1 Year ALLHAT Davis BH, et al. Circulation 2006;113:

1.83 ( ) Non-Diabetic 2.71 ( ) Diabetic 2.17 ( ) Women 2.27 ( ) Men 2.37 ( ) Black 2.12 ( ) Non-Black 2.06 ( ) Age ≥ ( ) Age < ( ) Total 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 Davis BH, et al. Circulation 2006;113:

Hospitalized/fatal HF in Subgroups - Amlodipine / Chlorthalidone Relative Risks After 1 Year of Follow-up Favors Amlodipine Favors Chlorthalidone Relative Risk (95% CI) 1.21 ( ) Non-Diabetic 1.23 ( ) Diabetic 1.16 ( ) Women 1.28 ( ) Men 1.28 ( ) Black 1.20 ( ) Non-Black 1.17 ( ) Age ≥ ( ) Age < ( ) Total ALLHAT Davis BH, et al. Circulation 2006;113:

Hospitalized/fatal HF in Subgroups - Lisinopril / Chlorthalidone Relative Risks from Baseline to 1 Year of Follow-up 2.16 ( ) 1.99 ( ) 2.40 ( ) 1.80 ( ) 2.15 ( ) 2.04 ( ) 1.98 ( ) 2.53 ( ) 2.08 ( ) Relative Risk (95% CI) Favors Lisinopril Favors Chlorthalidone Non-Diabetic Diabetic Women Men Black Non-Black Age ≥ 65 Age < 65 Total ALLHAT Davis BH, et al. Circulation 2006;113:

Non-Diabetic Diabetic Women Men Black Non-Black Age ≥ 65 Age < 65 Total 0.93 ( ) 0.93 ( ) 1.01 ( ) 1.01 ( ) 0.89 ( ) 0.89 ( ) 1.02 ( ) 1.02 ( ) 1.10 ( ) 1.10 ( ) 0.90 ( ) 0.90 ( ) 0.97 ( ) 0.97 ( ) 0.95 ( ) 0.95 ( ) 0.96 ( ) 0.96 ( ) Relative Risk (95% CI) Favors Lisinopril Favors Chlorthalidone Hospitalized/fatal HF in Subgroups - Lisinopril / Chlorthalidone Relative Risks After 1 Year of Follow-up ALLHAT Davis BH, et al. Circulation 2006;113:

ALLHAT 1. Can the early divergence of HF curves in the treatment arms be explained by the preferential discontinuation of diuretics upon entry into ALLHAT? 4 Unanswered Questions

Potential Confounders Confounders by indication: why was the patient placed on a specific class of drug prior to participation in the study? Missing data: approximately one third of HF cases lacked information on specific drugs used prior to entry into ALLHAT ALLHAT Grimm R, et al J Am Cardiol Coll 2007;49:350A

Baseline Characteristics of Participants with HF within First Year Following Randomization ALLHAT With Prior BP Med Data Without Prior BP Med Data P Value Hx of CHD, % NS Hx of cor. revasc., % NS Hx of diabetes, % NS Cigarette smoker,% NS LVH on ECG, % NS Tchol., mean, mg/dL NS Fast. trig.,mean, mg/dL NS Grimm R, et al J Am Cardiol Coll 2007;49:350A

Validation of Case-Only Analyses A technique know as case-only analyses was used to examine if there was interaction between prior drugs and treatment effects. Does “any prior meds (yes/no)” have the same interaction effect with treatment on outcomes in a “cases and non-cases” analysis versus a “case only analysis” ? ALLHAT Grimm R, et al J Am Cardiol Coll 2007;49:350A

Interaction OR between prior use of diuretic and treatment effects in HF Prior use of antihypertensive agents: 39% diuretics 37% ACEIs 47% CCBs Prior use of diuretic on “A” effect for new HF: A vs C: OR 1.08 ( , p=0.83) Prior use of diuretic on “L” effect for new HF: L vs C: OR 1.33 ( , p=0.44) ALLHAT Grimm R, et al J Am Cardiol Coll 2007;49:350A

Summary Patients on any prior BP med (vs. none) were at higher risk of developing HF. 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 These findings suggest that the type of BP drug at entry is not a major determinant of the HF results. ALLHAT Grimm R, et al J Am Cardiol Coll 2007;49:350A

2. How accurate is the diagnosis of HF? ALLHAT

Origin of the HF Validation Study HF endpoint defined as treated in hospital or out- of-hospital or fatal HF endpoint defined as treated in hospital or out- of-hospital or fatal A component of combined CVD (CHD, stroke, HF, PAD) – pre-specified secondary outcome A component of combined CVD (CHD, stroke, HF, PAD) – pre-specified secondary outcome Systematic central review of hospitalized HF events initiated in 2001, on advice of the DSMB Systematic central review of hospitalized HF events initiated in 2001, on advice of the DSMB HF endpoint defined as treated in hospital or out- of-hospital or fatal HF endpoint defined as treated in hospital or out- of-hospital or fatal A component of combined CVD (CHD, stroke, HF, PAD) – pre-specified secondary outcome A component of combined CVD (CHD, stroke, HF, PAD) – pre-specified secondary outcome Systematic central review of hospitalized HF events initiated in 2001, on advice of the DSMB Systematic central review of hospitalized HF events initiated in 2001, on advice of the DSMB ALLHAT Einhorn PT, et al. Am Heart J 2007;153:42-53

HF Validation Study Objectives ALLHAT Evaluate ALLHAT site physician-assigned diagnoses Evaluate ALLHAT site physician-assigned diagnoses Evaluate treatment effects reported in December 2002 ( Evaluate treatment effects reported in December 2002 ( JAMA. 2002;288: ) Compare RRs of validated HF between randomized treatment groups with RRs reported in 2002 Compare RRs of validated HF between randomized treatment groups with RRs reported in 2002 Evaluate incidence of validated HF and examine subsequent mortality rates as indicators of clinical significance of HF Evaluate incidence of validated HF and examine subsequent mortality rates as indicators of clinical significance of HF Evaluate ALLHAT site physician-assigned diagnoses Evaluate ALLHAT site physician-assigned diagnoses Evaluate treatment effects reported in December 2002 ( Evaluate treatment effects reported in December 2002 ( JAMA. 2002;288: ) Compare RRs of validated HF between randomized treatment groups with RRs reported in 2002 Compare RRs of validated HF between randomized treatment groups with RRs reported in 2002 Evaluate incidence of validated HF and examine subsequent mortality rates as indicators of clinical significance of HF Evaluate incidence of validated HF and examine subsequent mortality rates as indicators of clinical significance of HF Einhorn PT, et al. Am Heart J 2007;153:42-53

2850 hospital records for 1987 patients received records of 1935 patients suitable for review. Centrally abstracted by cardiology fellow blinded to treatment assignment. Each record independently reviewed by two reviewers. For algorithmic criteria (ALLHAT and Framingham), diagnoses were assigned by computer. Reviewers’ clinical judgment entered as yes, no, don’t know. ALLHAT HF Validation Study Einhorn PT, et al. Am Heart J 2007;153:42-53.

HF* 1.19 ( ) Hosp/Fatal HF 1.10 ( ) 1st Documented 1.13 ( ) ALLHAT ( ) ALLHAT 3 (CXR) 1.21 ( ) Framingham ( ) Framingham ( ) Reviewers agree 1.15 ( ) ALLHAT HF Validation Study ACEI versus diuretic Definition, Relative Risk and 95% Confidence Intervals Favors Lisinopril Favors Chlorthalidone * Pre-specified endpoint of treated in hospital or as outpatient or fatal

Percent agreement with investigator- assigned diagnosis of HF Einhorn PT, et al. Am Heart J 2007;153: ALLHAT ALLHAT Framingham1 Framingham 2 Reviewers % agreement

HF Outcome Verified Clinically Significant  ALLHAT site physician diagnoses confirmed in most patients  Treatment differences based on site physician reports corroborated when applying validation criteria sets RRs approximating these for the HF prespecified endpoint  6-year incidence rates of validated HF events comparable to those of stroke (5.6%) and to about half of non-fatal MI+CHD deaths (11.4%)  High mortality rates subsequent to validated hospitalized HF (55% at 5 years) ALLHAT Einhorn PT, et al. Am Heart J 2007;153:42-53.

3. How important are the blood pressure differences in the three treatment arms? ALLHAT

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, and in blacks ~4 mm Hg) Compared to chlorthalidone: DBP significantly lower in the amlodipine group (~1 mm Hg). ALLHAT

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 Davis BH, et al. Circulation 2006;113:

Exposure to different rates of BP Reduction u Early, inadequate blood pressure responses are never fully corrected (ALLHAT, Syst-Eur, SCOPE, ASCOT, VALUE) u The comparator was never able to catch up to the active drug after short differences in initial BP despite attempts to increase therapy. Time Benefit-Differences Persists Over Time

What we don’t and never will know! What we don’t and never will know! 24 hour blood pressure ? 24 hour blood pressure ? Night time blood pressure ? Night time blood pressure ? Central blood pressure ? Central blood pressure ? ALLHAT

4. How can differences in secondary endpoints be termed significant when primary endpoints are equal in all three treatment arms? ALLHAT

Drug comparisons for HF Chlorthalidone vs Amlodipine: RR 1.35 (95% CI , p<0.0013) and consistent with external data: Meta-analysis: RR 1.30 ( ) in favor of Diuretics/ß blocker over CCBs for preventing HF. (BPLTT Collaboration Lancet, 2003;362:1527 ) Chlorthalidone vs Amlodipine: RR 1.35 (95% CI , p<0.0013) and consistent with external data: Meta-analysis: RR 1.30 ( ) in favor of Diuretics/ß blocker over CCBs for preventing HF. (BPLTT Collaboration Lancet, 2003;362:1527 ) Yusuf SY, Circulation 2006;113:2166 ALLHAT

Drug comparisons for HF Chlorthalidone vs lisinopril: HF RR 1.19 (95% CI ), p<0.001 ―Pre-specified endpoint of treated in hospital or as outpatient or fatal (Einhorn PT, et al. Am Heart J 2007;153:42-53) and consistent with external data: Network meta–analysis: RR 0.88 ( ) p<0.01 in favor of a diuretic over ACEI for preventing HF. (Psaty BM, et al. JAMA 2003;289: ) ALLHAT

Final Conclusions Chlorthalidone was superior to amlodipine in both time periods in preventing HF in the aggregate and in all subgroups: age, race, sex, diabetic history. Chlorthalidone was superior to amlodipine in both time periods in preventing HF in the aggregate and in all subgroups: age, race, sex, diabetic history. Chlorthalidone was superior to lisinopril in preventing HF during the first year of treatment; thereafter, the 2 drugs were equally effective in preventing HF. Chlorthalidone was superior to lisinopril in preventing HF during the first year of treatment; thereafter, the 2 drugs were equally effective in preventing HF. The ALLHAT studies confirmed that thiazide- type diuretics should be a preferred first-step drug treatment for prevention of HF in high-risk patients with hypertension and/or post MI. The ALLHAT studies confirmed that thiazide- type diuretics should be a preferred first-step drug treatment for prevention of HF in high-risk patients with hypertension and/or post MI. Chlorthalidone was superior to amlodipine in both time periods in preventing HF in the aggregate and in all subgroups: age, race, sex, diabetic history. Chlorthalidone was superior to amlodipine in both time periods in preventing HF in the aggregate and in all subgroups: age, race, sex, diabetic history. Chlorthalidone was superior to lisinopril in preventing HF during the first year of treatment; thereafter, the 2 drugs were equally effective in preventing HF. Chlorthalidone was superior to lisinopril in preventing HF during the first year of treatment; thereafter, the 2 drugs were equally effective in preventing HF. The ALLHAT studies confirmed that thiazide- type diuretics should be a preferred first-step drug treatment for prevention of HF in high-risk patients with hypertension and/or post MI. The ALLHAT studies confirmed that thiazide- type diuretics should be a preferred first-step drug treatment for prevention of HF in high-risk patients with hypertension and/or post MI. ALLHAT

What constitutes optimal treatment of ACC/AHA stage A or B HF to prevent progression to stage C—overt symptomatic HF? Postscript:

Heart Failure: Causal Mechanisms Vasan RS and Levy D. Archives Int Med 1996 LVH Diastolic Dysfunction Obesity Diabetes MI Systolic Dysfunction HF Smoking Dyslipidemia Diabetes Hypertension Normal LV Structure and Function LV RemodelingSubclinical LV Dysfunction Overt Heart Failure ACC/AHA Stage AStage BStage C

Current ACC/AHA Guidelines: Management of HF as Applied to ALLHAT Patients ALLHAT patients were divided between stage A and B categories (Stage C patients were excluded). For the stage A patients (high risk without structural abnormalities), ACEIs and diuretics are recommended for treatment of HTN. For the stage B patients (structural heart disease), ACEIs and diuretics are recommended for treatment of HTN; ACEIs and BBs are recommended for post MI, LVH, and reduced LVEF. Therefore, poly-pharmacy will be necessary in the majority of patients for optimal control of HTN (Stage A and B) and for treatment of structural heart disease (Stage B). Hunt. et al. Circulation 2005;112:

JNC-7 Guidelines for HF Treatment “HF is a ‘compelling indication’ for the use of ACEI. Abundant evidence exists to justify their use with all stages of HF.” “Blood pressure targets in HF have not been firmly established. In most successful trials SBP were lowered to the range of mm Hg.” Therefore, ACEI (or ARB)/diuretic combinations, rather than single agents, are necessary in the majority of patients for achieving ‘optimal control’ of HTN, preventing and/or reversing structural heart damage, and preventing progression to overt HF. JNC- 7 Report. JAMA 2003;289: