Mortality as an Efficacy or Safety Endpoint : Lessons Learned from the Heart Failure Trials

Transcription

1 Mortality as an Efficacy or Safety Endpoint : Lessons Learned from the Heart Failure Trials Christopher M. O Connor, MD Professor of Medicine Director, Duke Heart Center Acting Chief, Division of Cardiology Chief, Division of Clinical Pharmacology Duke University Medical Center

2 Mortality Efficacy or Safety Efficacy Safety Both

3 Evidence to Practice Observation and Surrogates Scientific Discovery RCT Observation and Outcomes

4 Therapeutic Principles of Treatment of Chronic Disease Treatment effects usually modest Need large sample sizes Qualitative interactions uncommon Simple studies reasonable Quantitative interactions common No pain, no gain Unintended targets common Can t depend on pathophysiological reasoning Long term and short term effects may differ Combinations are unpredictable Class effect is dying 9709RC14

5 Definition of Useful Therapeutic Medical Product Improves longevity Reduces adverse events Improves quality of life Reduces cost Can we afford to accept that a medical product is useful based on theoretical as opposed to demonstrated health benefits?

6 Sample Size Patients Randomized Chance of Comments Deaths (Risk = 10%) Type II Error* on Sample Size 0-50 < 500 > 0.9 Utterly inadequate Probably inadequate Possibly inadequate Probably adequate > < 0.1 Adequate *Probability of failing to achieve p <.01 if risk reduction = 25% Yusuf, Prog in CV Disease, CG01

7 Small Trials in CHF are Unreliable Trials N Deaths RRR P ELITE I %.035 ELITE II 3, %.16 Vesnarinone %.002 VEST (60mg) 2, %.02 PRAISE I* % <.001 PRAISE II 1, % * (non-ischemic only)

8 FIRST :Vasodilator and Mortality :Prostacyclin A Mortality Efficacy Trial Califf R, et al, AHF, 134(1), July 1997; 44-54

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10 Endpoints Primary Endpoint All-cause mortality Major Secondary Endpoints Cardiovascular mortality Death (all-cause) + cardiovascular hospitalization

11 Statistical Assumptions and Analyses Statistical Assumptions MED mortality of 25% at 3 years CABG would reduce mortality by 25% 20% or fewer crossovers from MED to CABG 400 or more deaths Planned Analyses Intention to treat (as randomized) Covariateadjusted As treated Time-dependent Per protocol 90% power

12 All-Cause Mortality As Randomized HR 0.86 (0.72, 1.04) P =

13 All-Cause Mortality As Randomized HR 0.86 (0.72, 1.04) P = Adjusted HR 0.82 (0.68, 0.99) Adjusted P =

14 Cardiovascular Mortality As Randomized HR 0.81 (0.66, 1.00) P = Adjusted HR 0.77 (0.62, 0.94) Adjusted P =

15 Time-varying Hazard Ratios As Randomized

16 All-Cause Mortality As Treated HR 0.70 ( ) P <

17 All-Cause Mortality Per Protocol HR 0.76 (0.62, 0.92) P =

18 Unintended Targets t-pa Intracerebral Vessels Calcium Blockers Systolic Function? Neurohormones Inotropic Agents Arrhythmia Lidocaine Asystole

19 The OPTIME Trial :First Large Trial

20 Design A prospective, multicenter, double-blind, placebocontrolled trial of IV milrinone in addition to best medical therapy Patient with Exacerbation of Known Systolic Heart Failure No loading dose 0.5 mcg/kg/min Goal hour infusion RANDOMIZED within 48 hours of admission 48-hour Milrinone Infusion 48-hour Placebo Infusion 60-day Follow-up

21 OPTIME-CHF: Outcomes and Events with Milrinone Index hospitalization Control (n = 472) Milrinone (n = 477) Overall adverse events 2.1% 12.6% * Sustained hypotension 3.2% 10.7% * Outcome within 60 days post-discharge Days of hospitalization for CVrelated causes 5.9 (12.5) 5.7 (12.6) Rehospitalization or death 35.3% 35.0% Death 8.9% 10.3% * P <.001 OPTIME-CHF=Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure Cuffe MS, et al. JAMA. 2002;287:

22 Results: Complications Complications (%, in hosp) Placebo Milrinone (n=472) (n=477)p-value Ischemia/angina Myocardial infarct New atrial fib VT VF Sustained hypotension < 0.001

23 The ESCAPE Trial

24 Escape : Death or Hospitalization- No Difference Figure 1: A cumulative proportion plot of number not dead or hospitalized during 180 days Cumulative proportion PAC CLIN Number of days not dead or hospitalized (days well) during 180 days

25 60 Day Outcomes: Death and Rehospitalization Death or cardiovascular or renal hospitalization 1 Placebo (n=78) 10 mg (n=74) Rolofylline 20 mg (n=75) 30 mg (n=74) 33% 32% 24% 19% 1 30 mg vs placebo: HR 0.55 (95% CI = 0.28,1.04) Death 10% 12% 8% 5% Rehospitalization for cardiovascular or renal causes 30% 22% 17% 16%

26 PROTECT STUDY DESIGN Treatment phase Follow-up Screening AHF & fluid overload, need of iv loop diuretic CrCl, ml/min Rolofylline 30 mg Placebo All cause Death CV/Renal hosp All cause death Days Randomisation Rolofylline to placebo, 2:1 Kidney Function

27 Percent of Patients Primary Endpoint Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09) Placebo Ro 30 mg Treatment Success Patient Unchanged Treatment Failure p=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test

28 Cumulative Risk Time to Death or CV or Renal Rehospitalization - Day Hazard Ratio (95% CI) = 0.98 (0.83, 1.17) P-value = Placebo Rolofylline 30 mg Study Day Study Day No. of patients at risk Placebo (N=677) Rolofylline (N=1356) Death: Placebo 9.5% (64) versus Rolofylline 8.9% (120) Re-hospitalization: Placebo 25.6% (146) versus Rolofylline 25.7% (302)

29 DOSE : Death, Rehospitalization, or ED Visit Proportion with Death, Rehosp, or ED Visit HR for Continuous vs. Q12 = % CI 0.86, 1.66, p = 0.30 Continuous Q Days Proportion with Death, Rehosp, or ED visit HR for High vs. Low = % CI 0.60, 1.16, p = 0.28 High Days Low

30 Risk of Nesiritide in ADHF JAMA Paper

31 ASCEND 3500 Nesiritide Acute HF Randomize <48 hours from hospitalization <24 hours from IV RX for HF Hours Rx Co-Primary Endpoint Dyspnea 6/24hrs Co-Primary Endpoint 30-day Death/HF rehosp Other Secondary endpoints 3500 Placebo All-cause 180 days

32 Statistical methods Study population: modified intention-to-treat based on receiving study drug Primary analysis: Co-primary endpoints tested using Bonferroni approach Composite of HF rehospitalization and all-cause mortality tested at significance level Dyspnea tested at level using Hochberg method: Significant if both 6- and 24-hr assessment P values 0.005; or If either 6- or 24-hr assessment P values Sample size determination: Based on composite endpoint: 89% power with 7000 patients using chi-square test, assuming a placebo event rate of 14% and a relative risk reduction of 18.6% 32

33 Power Power (Assume 9.7% Event Rate) 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0,80 0,81 0,82 0,83 0,84 Relative Risk

34 Baseline characteristics Placebo (n=3511) Nesiritide (n=3496) Age (yrs) 67 (56, 76) 67 (56, 76) Female (%) Black or African American Systolic Blood Pressure (mmhg) 124 (110, 140) 123 (110, 140) Heart rate (beats/min) 82 (72, 95) 82 (72, 95) Respiratory rate (breaths/min) 24 (21,26) 23 (21, 26) Medical History (%) Ischemic heart disease Hypertension Atrial fibrillation Chronic respiratory disease Diabetes Continuous variables as median (IQR 25 th, 75 th ); MITT population 34

35 Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization 12 P=0.31 Hazard Ratio 0.93 (95% CI: 0.8,1.08) Placebo Nesiritide % day Death/HF Rehospitalization 30-day Death HF Rehospitalization Risk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0) 35

36 30-day mortality meta-analysis Odds Ratio (95% CI) Mills (N=163) 0.38 (0.05, 2.74) Efficacy (N=127) 1.24 (0.23, 6.59) Comparative (N=175) 1.43 (0.50, 4.09) PRECEDENT (N=147) 0.59 (0.18, 2.01) VMAC (N=498) 1.63 (0.77, 3.44) PROACTION (N=237) 6.93 (0.89, 53.91) COMBINED 30 day w/out ASCEND 1.28 (0.73, 2.25) ASCEND-HF (N=7007) 0.89 (0.69, 1.14) COMBINED with ASCEND 1.00 (0.76, 1.30)

37 Endpoint Rates Overall N=6825 North America N=3108 Latin Americ a N= 628 Asia- Pac N=1642 Central EU N=967 Western EU N=480 Lost to follow-up %(n) 1.1 (75) 0.8 (25) 1.5 (9) 2.1 (33) 0.1 (1) 1.5 (7) Withdrew consent (n) 1.1 (73) 0.9 (28) 0.5 (3) 2.2 (35) 0.2 (2) 1.1 (5) Death within 30 days (n) 3.9 (255) 3.5 (105) 6.9 (41) 3.7 (58) 3.1 (30) 4.6 (21) Death or rehosp for HF within 30 d 9.8 (629) 12.4 (366) 12.1 (70) 9.2 (138) 5.2 (50) 8.5 (37)

38 30 day death/hf readmission subgroups All Subjects N=6836 Baseline SBP (mmhg) Baseline Ejection Fraction (%) Renal function- MDRD GFR (ml/min/m 2 ) History of CAD History of Diabetes Mellitus < <40 40 <60 60 No Yes No Yes N=3346 N=3490 N=4362 N=1187 N=3395 N=3093 N=3092 N=3742 N=3923 N= Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval 38

39 30 day death/hf readmission subgroups All Subjects N=6836 Inotrope Use at Randomization Vasodilators Diuretics Study Drug Bolus Time from Hosp to Rand (hrs) No Yes None Any IV Vasodilators No IV Nitroglycerin IV Nitroglycerin No Yes No Yes >15.5 <=15.5 N=6556 N=280 N=5889 N=942 N=5943 N=892 N=691 N=6145 N=2609 N=4227 N=3426 N= Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval 39

40 Mortality Efficacy or Safety Efficacy : hard to achieve if we don t increase sample size to ACS levels pts. Efficacy: if achieved on softer endpoints then safety is must be ascertained on mortality Exclusion of a 1.3 upper limit of the CI Meta-analysis of mortality can help secure the safety signal

41 Every strike brings me closer to the next homerun Babe Ruth