The Cardiac Arrythmia Suppression Trial

Transcription

1 The Cardiac Arrythmia Suppression Trial 1

2 The Cardiac Arrythmia Suppression Trial Background and significance Methods Statistical Analysis Results Discussion Summary on Therapy 2

3 Background and significance Study organization for multicenter trials Pilot Study (CAPS) identify effective agents Multicenter trial with Coordinating center Data and Safety Monitoring Board: periodic review of ongoing results with a view to stopping the trial early if if definitive differences found 3

4 Methods Patient population Assignment to treatment Endpoints Evaluation of endpoints & blinding Reasons for discontinuance Methods 4

5 Assignment to treatment Choice of active drug Based on response; not randomized Three possible active drugs: encainide, flecanainide, moricizine Placebo/active allocation: = randomization to active vs placebo 5

6 Endpoints Primary: death or cardiac arrest due to arrythmia Secondary: Death from all causes Cardiac death or arrest Other cardiac performance measures All defined prospectively not selected after the fact 6

7 Methods Patient population Assignment to treatment Endpoints Evaluation of endpoints & blinding Reasons for discontinuance 7

8 Statistical Analysis Intention to treat The outcome for each patient was analyzed solely on the basis of of the group to to which the patient was (randomly) assigned, regardless of of Compliance Intervening adverse cardiac events Survival estimates: Kaplan-Meier survival curves Censored data By cardiac arrest (no second events) April 18, 1989 (end of of followup) Statistical Analysis 8

9 Statistical Analysis P-values 2 sided Nominal = using standard methods' But, no adjustment has been made for multiple comparisons Interpretation of morbidity (nonfatal adverse events) data Interpret cautiously because of of large differences in in mortality Could consider death as an adverse event; if if lumped with others 9

10 Results Mortality What if if it it had been different? 10

11 Mortality Significantly greater deaths/arrests due to arrythmia among those receiving active drug rather than placebo Significant: Statistical? P-value addresses this question Clinical? Relative risk looks at this How big could the effect be? 95%CI Death from all causes 11

12 What if it had been different? E.g., no difference in cardiac deaths, but difference in total mortality? Possible explanations explored: Different rate of detecting Vfib? [No] Nature of fatal arrythmia? [No] Morbidity: similar in both groups Adverse effects: similar in both groups Compliance: similar in both groups 12

13 Discussion Potential mechanisms Clinical implications What works in in the morbidly ill ill need not work in in the mildly symptomatic Need for placebo-controlled trials What if if encainide had just been compared to to flecainide? Ans: chisquared=4.47 (1 (1 df), p=0.034, against encainide. Clinical implication: use flecainide instead (!) (!) Need for safety and data-monitoring board in in clinical trials 13

14 Summary on Therapy Are the results valid? What were the results? How will the results help my patients? 14