Therapeutic Interventions AND THE SULFINPYRAZONE IN THE PREVENTION OF CARDIAC DEATH AFTER MYOCARDIAL INFARCTION. NEJM 1978 Onofre Morán MD, MSc. Professor, Faculty of Medicine, Universidad Autónoma de San Luis Potosí, S.L.P. México. PhD Candidate University of British Columbia, Vancouver, Canada. 30/11/2018

Questions to ask in Therapeutic interventions studies WHY: Justified? Hypothesis/purpose of the study? Efficacy or effectiveness? HOW: Controlled, Randomized, Clinical trial? Blinding: (1,2,3)? Prognostic factors comparable? 30/11/2018

Questions to ask in Therapeutic interventions studies WHO: Inclusion & Exclusion criteria? Author account for eligible patients who did not enter the study? WHAT: Intervention defined and replicable? Compliance? Contamination/Co-intervention? Were all clinically relevant outcomes reported? 30/11/2018

Questions to ask in Therapeutic interventions studies HOW MANY? Was statistical significance considered? Was clinical significance considered to calculate sample size? Were all patients who entered the study accounted for? Were non compliers & withdrawals Contamination/Co-intervention analyzed appropriately? 30/11/2018

Questions to ask in Therapeutic interventions studies SO WHAT? Clinical significance discussed? Were benefits and adverse effects considered? Is the therapeutic intervention feasible in your practice? Were the patients similar to your own? 30/11/2018

THE TRIAL (NEJM, 1978) BACKGROUND: One million persons in US experience a first acute myocardial infarction every year. Of the 400,000 patients who survive, 47,000 die during the first year after infarction. 30/11/2018

THE TRIAL RATIONALE: Sulfinpyrazone (Anturane), is a potent uricosuric agent which has been shown to inhibit in vitro and in vivo platelet adhesion, aggregation and prostaglandin synthesis. Other agents with antiplatelet properties are under study for the same purpose. 30/11/2018

THE TRIAL PURPOSE: SITES: Secondary prevention of myocardial infarction and coronary death. To reduce cardiac mortality after Myocardial infarction. SITES: 21 affiliated University Hospitals in US and 5 Canadian University Medical Institutions. Coordinated by Ciba-Geigy Co. 30/11/2018

THE TRIAL DESIGN: Randomized, double-blind, parallel study comparing Sulfinpyrazone (200 mg/day) with a placebo control group. 30/11/2018

THE TRIAL INCLUSION CRITERIA: Male & Female patients 45-70 years of age. At least one Myocardial infarction (MI), the most recent within 25-25 days before enrollment. MI diagnosed with ECG changes, typical chest pain and serum enzyme elevation. Only patients Killip Class I or II. 30/11/2018

THE TRIAL EXCLUSION CRITERIA: Previous cardiac surgery. Cardiomegaly. Demonstrated untreated Hypertension. On anticoagulants or agents known to affect the platelet function. 30/11/2018

THE TRIAL MEASUREMENTS: History, Physical and Lab: 1, 2, 6, 12, 18 & 24 m. ECG: 1, 12 & 24 m. Toxicity and compliance: 4, 8, 10, 14, 16, 20 & 22 m. 30/11/2018

THE TRIAL MEASUREMENTS: Data recorded without knowledge of medication being taken by patient. Compliance assessed by tablet counts and serum uric acid levels. Patients with unexplained compliance by tablet count less than 80% on 3 consecutive visits are dropped from the trial. 30/11/2018

THE TRIAL ENDPOINTS: Deaths categorized as: “Analizable” events: More than 7 days after initiation of therapy or less than 7 days after withdrawal of therapy “Nonanalyzable” events. Analyzed separately. By a trial committee without knowledge of medication received. 30/11/2018

THE TRIAL STATISTICAL METHODS: Mortality expected: 10% Reduction of mortality to 5%. Alpha = 0.05 Power = .90. N= 1200 patients (allowing for dropouts and exclusions). 30/11/2018

THE TRIAL STATISTICAL METHODS: Numerical Randomization Schedules were developed separately for each center. Drug assignment in blocks of 10, with equal number of patients receiving placebo or Sulfinpyrazone in each block (computer generated). Treatment efficacy comparisons were based on Cox’s regression models and Life-time methods. 30/11/2018

THE TRIAL RESULTS Patients entered 814 806 1,620 Patients excluded 51 CATEGORY PLACEBO SPN TOTALS Patients entered 814 806 1,620 Patients excluded 51 50 Baseline visit only 21 23 Accepted for analysis 742 733 1,475 Dropouts 114 100 Medical 63 30/11/2018

PATIENT CARACTERISTIC THE TRIAL RESULTS PATIENT CARACTERISTIC PLACEBO % SPN P VALUE Mean exposure (mo) 8.1 8.4 Sex: Male 86.7 86.1 0.8 Age: Mean 56.6 56.8 0.5 Myocardial infarction 22.4 19.5 0.2 Angina 34.1 32.7 0.6 Hypertension 33 32.3 30/11/2018

PATIENT CARACTERISTIC THE TRIAL RESULTS PATIENT CARACTERISTIC PLACEBO % SPN P VALUE Claudication 4.4 3.5 0.4 Diabetes 10.9 9.7 0.5 Left-bundle- branch block 10.1 8 0.2 Abnormality of rhythm 15 11.3 0.05 30/11/2018

THE TRIAL RESULTS ANALYZABLE CARDIAC MORTALITY All cardiac 44 24 0.025 CAUSES OF DEATH PLACEBO SPN P VALUE NNT All cardiac 44 24 0.025 22 Sudden Death 29 13 0.018 28 Myocardial Inf. 12 9 0.4 769 Other 3 30/11/2018

THE TRIAL RESULTS COMPLIANCE: 87% OF THE TOTAL SAMPLE, DEMONSTRATED AN OVERALL THERAPY COMPLIANCE RATE OF >80%. IN SPN GROUP, THERE WAS A REDUCTION TO <70% OF BASELINE URIC ACID LEVELS, IN 89% OF PATIENTS 30/11/2018

THE TRIAL CONCLUSION: SULFINPYRAZONE APPEARS TO BE EFFECTIVE IN REDUCING CARDIAC DEATH DURING THE FIRST YEAR AFTER MYOCARDIAL INFARCTION. 30/11/2018

Therapeutic Interventions SULFINPYRAZONE IN THE PREVENTION OF SUDDEN DEATH AFTER MYOCARDIAL INFARCTION NEJM 1980 Onofre Morán 30/11/2018

THE TRIAL RESULTS ANALYZABLE CARDIAC MORTALITY AT 24 MONTHS CAUSES OF DEATH PLACEBO SPN P VALUE All cardiac 62 43 0.058 Sudden Death 37 22 0.041 Myocardial Inf. 18 17 Other 7 5 30/11/2018

Annualized death rates in % THE TRIAL RESULTS ANALYZABLE CARDIAC MORTALITY AT 24 MONTHS Annualized death rates in % TREATMENT GROUPS SUDDEN DEATHS Up to 6 mo 7 to 24 mo NONSUDDEN DEATHS Placebo 7.0 2.0 3.2 2.1 SPN 1.8 2.3 1.4 30/11/2018

THE TRIAL CONCLUSION: SULFINPYRAZONE PREVENTS SUDDEN CARDIAC DEATH DURING THE HIGH-RISK PERIOD SHORTLY AFTER AN ACUTE MYOCARDIAL INFARCTION, BUT THERE IS NO FURTHER APPARENT EFFECT BEYOND THE SEVENTH MONTH AFTER INFARCTION. 30/11/2018

Therapeutic Interventions SULFINPYRAZONE IN THE PREVENTION OF SUDDEN DEATH AFTER MYOCARDIAL INFARCTION NEJM 1980 Onofre Morán 30/11/2018

THE FDA’S CRITIQUE FDA STATEMENTS: We are aware that it is unusual for an FDA critique of a clinical trial to be published in the medical literature. However we believe that it is important, because of the wide interest in the trial and because illustrates so clearly the problems that may arise from subgroup analysis and exclusion of patients from analysis after they have completed the study. 30/11/2018

THE FDA’S CRITIQUE FDA STATEMENTS: We audited about half the case records of the patients who died and the basis for the assigned cause of death. We also examined all reports of patients entered into the trial who died but were subsequently excluded from analysis. On the basis of this review, we do not believe that either reported outcome can be accepted for the following reasons. 30/11/2018

THE FDA’S CRITIQUE FDA STATEMENTS: The errors in assigning cause of death nearly all favored the conclusion that SPN decreased sudden death. The assignment criteria are ambiguous. Cause of death classification was hopelessly unreliable. The reported statistically significant reduction in sudden death is thus invalid. 30/11/2018

THE FDA’S CRITIQUE FDA STATEMENTS: The reported effect on overall mortality, which is nearly statistically significant, depends heavily on exclusion from analysis of certain patients who had participated fully in the study and died while receiving therapy. The exclusions virtually all favored Sulfinpyrazone. These exclusions were clearly planned in advance and were based on a plausible rationale. 30/11/2018

THE FDA’S CRITIQUE FDA STATEMENTS: The apparently significant P value must be adjusted upward to correct for the multiple comparisons associated with subgroup analysis. One lesson from our review seems to be clear: editors and readers are entitled to have a full accounting of all patients who entered a randomized trial. 30/11/2018

THE FDA’S CRITIQUE FDA STATEMENTS: We do not intend to obscure the fact that the trial did show favorable trend toward increased overall survival in patients treated with SPN in the first 6 months after myocardial infarction. There are therefore good grounds for conducting another, similar study, to learn whether this trend represents a real effect or a chance occurrence. The trend seen, however, was judged to be insufficient basis for FDA approval of SPN as effective in reducing mortality in patients with prior myocardial infarction. 30/11/2018

THE CIBA GEIGY’S AFTERTHOUGHTS 30/11/2018