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
Mortality Efficacy or Safety Efficacy Safety Both
Evidence to Practice Observation and Surrogates Scientific Discovery RCT Observation and Outcomes
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
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?
Sample Size Patients Randomized Chance of Comments Deaths (Risk = 10%) Type II Error* on Sample Size 0-50 < 500 > 0.9 Utterly inadequate 50-150 1000 0.7-0.9 Probably inadequate 150-350 3000 0.3-0.7 Possibly inadequate 350-650 6000 0.1-0.3 Probably adequate > 650 10000 < 0.1 Adequate *Probability of failing to achieve p <.01 if risk reduction = 25% Yusuf, Prog in CV Disease, 1985 9503CG01
Small Trials in CHF are Unreliable Trials N Deaths RRR P ELITE I 722 49 46%.035 ELITE II 3,152 530-14%.16 Vesnarinone 477 46 62%.002 VEST (60mg) 2,558 534-21%.02 PRAISE I* 421 119 46% <.001 PRAISE II 1,652 538-10%.28.50 1.0 1.5 * (non-ischemic only)
FIRST :Vasodilator and Mortality :Prostacyclin A Mortality Efficacy Trial Califf R, et al, AHF, 134(1), July 1997; 44-54
Endpoints Primary Endpoint All-cause mortality Major Secondary Endpoints Cardiovascular mortality Death (all-cause) + cardiovascular hospitalization
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
All-Cause Mortality As Randomized HR 0.86 (0.72, 1.04) P = 0.123 0.46 0.41
All-Cause Mortality As Randomized HR 0.86 (0.72, 1.04) P = 0.123 Adjusted HR 0.82 (0.68, 0.99) Adjusted P = 0.039 0.46 0.41
Cardiovascular Mortality As Randomized HR 0.81 (0.66, 1.00) P = 0.050 Adjusted HR 0.77 (0.62, 0.94) Adjusted P = 0.012 0.39 0.32
Time-varying Hazard Ratios As Randomized
All-Cause Mortality As Treated HR 0.70 (0.58 0.84) P < 0.001 0.49 0.38
All-Cause Mortality Per Protocol HR 0.76 (0.62, 0.92) P = 0.005 0.48 0.37
Unintended Targets t-pa Intracerebral Vessels Calcium Blockers Systolic Function? Neurohormones Inotropic Agents Arrhythmia Lidocaine Asystole
The OPTIME Trial :First Large Trial
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 24 72 hour infusion RANDOMIZED within 48 hours of admission 48-hour Milrinone Infusion 48-hour Placebo Infusion 60-day Follow-up
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;287:1541-1547.
Results: Complications Complications (%, in hosp) Placebo Milrinone (n=472) (n=477)p-value Ischemia/angina 2.5 2.1 0.648 Myocardial infarct 0.4 1.5 0.178 New atrial fib 1.5 4.6 0.004 VT 1.3 2.7 0.107 VF 0.6 1.7 0.127 Sustained hypotension 3.2 10.7 < 0.001
The ESCAPE Trial
Escape : Death or Hospitalization- No Difference Figure 1: A cumulative proportion plot of number not dead or hospitalized during 180 days 1 0.9 0.8 0.7 Cumulative proportion 0.6 0.5 0.4 0.3 PAC CLIN 0.2 0.1 0 0 30 60 90 120 150 180 Number of days not dead or hospitalized (days well) during 180 days
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%
PROTECT STUDY DESIGN Treatment phase Follow-up Screening AHF & fluid overload, need of iv loop diuretic CrCl, 20-80 ml/min Rolofylline 30 mg Placebo All cause Death CV/Renal hosp All cause death Days 1 2 3 4 5 6 7 14 60 180 Randomisation Rolofylline to placebo, 2:1 Kidney Function
Percent of Patients Primary Endpoint Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09) 100 80 60 40 20 0 36.0 44.2 19.8 Placebo 40.6 37.5 21.8 Ro 30 mg Treatment Success Patient Unchanged Treatment Failure p=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test
Cumulative Risk Time to Death or CV or Renal Rehospitalization - Day 60 0.4 0.3 Hazard Ratio (95% CI) = 0.98 (0.83, 1.17) P-value = 0.861 0.2 0.1 Placebo Rolofylline 30 mg 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 Study Day Study Day 7 14 30 55 65 No. of patients at risk Placebo (N=677) 657 633 566 489 74 Rolofylline (N=1356) 1322 1263 1134 1001 158 Death: Placebo 9.5% (64) versus Rolofylline 8.9% (120) Re-hospitalization: Placebo 25.6% (146) versus Rolofylline 25.7% (302)
DOSE : Death, Rehospitalization, or ED Visit Proportion with Death, Rehosp, or ED Visit 0.6 0.5 0.4 0.3 0.2 0.1 0 HR for Continuous vs. Q12 = 1.19 95% CI 0.86, 1.66, p = 0.30 Continuous Q12 0 10 20 30 40 50 60 Days Proportion with Death, Rehosp, or ED visit 0.6 0.5 0.4 0.3 0.2 0.1 0 HR for High vs. Low = 0.83 95% CI 0.60, 1.16, p = 0.28 High 0 10 20 30 40 50 60 Days Low
Risk of Nesiritide in ADHF JAMA Paper
ASCEND 3500 Nesiritide Acute HF Randomize <48 hours from hospitalization <24 hours from IV RX for HF 24-168 Hours Rx Co-Primary Endpoint Dyspnea index @ 6/24hrs Co-Primary Endpoint 30-day Death/HF rehosp Other Secondary endpoints 3500 Placebo All-cause Mortality @ 180 days
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 0.045 significance level Dyspnea tested at 0.005 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 0.0025 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
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
Baseline characteristics Placebo (n=3511) Nesiritide (n=3496) Age (yrs) 67 (56, 76) 67 (56, 76) Female (%) 34.9 33.4 Black or African American 15.0 14.7 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 60.8 59.5 Hypertension 72.6 71.8 Atrial fibrillation 37.7 37.4 Chronic respiratory disease 16.6 16.3 Diabetes 42.9 42.3 Continuous variables as median (IQR 25 th, 75 th ); MITT population 34
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) 10 8 10.1 9.4 Placebo Nesiritide % 6 6.1 6.0 4 4.0 3.6 2 0 30-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
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) 0.1 1 10 36
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)
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 < 123 123 <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=2913-10 -5 0 5 10 Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval 38
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=3410-10 -5 0 5 10 Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo Difference (%) and 95% Confidence Interval 39
Mortality Efficacy or Safety Efficacy : hard to achieve if we don t increase sample size to ACS levels 16000-25000 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
Every strike brings me closer to the next homerun Babe Ruth