Treatment of acute (cardio- and cerebro-) vascular syndromes

1. Treatment of acute (cardio- and cerebro-) vascular syndromes David Kent, MD, MS Institute for Clinical Research and Health Policy Studies Tufts-New England Medical Center, Boston

2. Average results of clinical trials do not apply to all patients.

3. Even in trials with well-defined inclusion/exclusion criteria, there is often considerable variation in outcome-risk.

5. Avg mortality risk = ~ 1%

6. Avg mortality risk = ~ 16% Avg mortality risk = ~ 1%

7. Summary result reflects arithmetic mean

8. Summary result reflects arithmetic mean Typical “median-risk” patient

9. The Thrombolytic Predictive Instrument • Predicts patient-specific outcomes in acute myocardial infarction in real time. • Based on several validated logistic regression equations.

10. Easily obtainable variables • Clinical • age • systolic blood pressure • diabetes • thrombolytic therapy • time from symptom onset to ECG • Electrocardiographic • right bundle branch block • heart rate • number of leads with ST segment elevation • amount of ST-segment elevation • leads with abnormal q-waves and no ST elevation • infarct location

13. tPA versus Streptokinase in STEMI

14. GUSTO • Mortality with t-PA: 6.3% • Mortality with streptokinase: 7.3% • Thrombolytic-related brain hemorrhages: • t-PA: 0.72% • SK: 0.52% • Cost: • t-PA: $2,750 • SK: $320

15. Hypothesis • Most of the incremental benefit of t-PA compared to SK can be obtained by treating a subgroup of high-risk (high-benefit) patients.

18. Thrombolytic-related ICH-risk in Myocardial Infarction(Gurwitz et al) • Age • sex, • race (white, black or other) • history of prior stroke • systolic blood pressure • diastolic blood pressure • interaction term: age* gender * history of prior stroke

21. Distribution of Marginal Cost-Effectiveness of t-PA Relative to Streptokinase 300000 250000 200000 Cost per Year of Life Saved (dollars) 150000 100000 50000 0 0 10 20 30 40 50 60 70 80 90 100 Percentile Composite Benefit (in Life Years, including mortality and ICH)

22. Conclusion • Population-wide treatment of STEMI patients with tPA is effective and cost-effective.

23. Conclusion • Population-wide treatment of STEMI patients with tPA is effective and cost-effective. • For many patients tPA is highly unlikely to provide incremental mortality benefit (and it may cause net harm for some).

24. Conclusion(methodology) • Conventional sub-group analysis was unable to identify patients most likely or unlikely to benefit from t-PA.

25. PCI versus thrombolysis in STEMI

26. Primary PCI yields superior outcomes to thrombolytic therapy in acute myocardial infarction. • Composite outcome: death, non-fatal reinfarction and stroke. • 22 trial meta-analysis (Lancet, 2003): • mortality: 5% vs 7%; p=0.0003

27. Methods • We modified the TPI to predict--in individual patients--the incremental mortality benefit of primary PCI compared to thrombolytic therapy.

28. Methods(cont’d) • Developmental Database • 3006 patients with complete data • 1378 received primary angioplasty; • 1628 received thrombolytic therapy. • Validation Dataset • Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) trial

29. Results: Model Validation(C-PORT)

30. C-PORT (validation) dataset

31. Predicted versus Observed BenefitsC-PORT Trial

32. DANAMI-2

33. DANAMI-2

34. Treatment of ACS

35. ACS • Greater relative and absolute benefit found in TIMI-high risk patients • the low molecular weight heparin enoxaparin (compared to unfractionated heparin), • the glycoprotein IIb/IIIa inhibitor tirofiban • an early invasive strategy (compared to conservative approach)

36. Thrombolysis in Acute Stroke

37. The NINDS tPA trial • The NINDS tPA study demonstrated that tPA improved outcomes in patients with stroke treated within 3 hours of symptom onset. • Absolute benefit was from 11% to 15% • likelihood of a normal or near-normal 90-day outcome • Despite a 6% increase in the risk of intracranial hemorrhage.

38. Based on these results, FDA approved the use of tPA in stroke, in the 0 to 3 hour time window, in 1996.

39. Currently, about 2% of patients with acute stroke receive thrombolytic therapy.

40. Other trials • ECASS 1 • dose: 1.1 mg/kg • time window 0 to 6 hours • ECASS 2 • time window 0 to 6 hours • primary outcome: mRS < 2 • ATLANTIS A • time window 0 to 6 hours • ATLANTIS B (after NINDS completed) • time window: 3 to 5 hours (mostly)

41. Global Outcome: p=0.70

42. Thrombolytic-related ICH-risk in Myocardial Infarction(Gurwitz et al) • Age • sex, • race (white, black or other) • history of prior stroke • systolic blood pressure • diastolic blood pressure • interaction term: age* gender * history of prior stroke

43. Rate of intracranial hemorrhage with thrombolytic therapy

44. Global Outcome: p=0.10 Treatment-by-risk: p=0.03

47. Summary • On average, tPA does not benefit stroke patients overall when given after 3 hours. • However, individual risk-benefit patient profiling suggests that more than half of patients might benefit from therapy.

48. Summary • Average results of clinical trials do not apply to all patients in the trial. • Conventional analysis of trials can lead harmfully to both over and under-treatment of important subgroups. • Combining variables into risk scores predicting outcome risk or treatment-related harm can uncover patients with dramatically different risk-benefit treatment profiles.