Thrombolysis and the elderly

1. Thrombolysis and the elderly Eugene Braunwald MD Professor of Medicine Harvard University Robert Califf MD Professor of Cardiology Duke University Eric Peterson MD Associate Professor of Cardiology Duke University

2. Thrombolysis and the elderly Lack of benefit for thrombolysis in patients > 75 years This retrospective cohort was taken from a database compiled by the Health Care Financing Administration (HCFA) for the Cooperative Cardiovascular Project (CCP) detailing a nationwide sample of elderly patients with MI. From 210 996 original patients, a cohort of 5191 patients aged 65-75 and 2673 patients aged 76-86 was obtained. Among exclusion criteria were the following: direct admission to hospitals with on-site angioplasty capabilities, inappropriate ECG criteria on presentation, and contraindications to thrombolysis. Thiemann DR, et al. Circulation 2000;101:2239-2246

3. An increase in mortality? Observed 30-day mortality Thiemann DR, et al. Circulation 2000;101:2239-2246

4. Multivariate adjustment Adjusted hazard ratios for 30-day mortality after receiving thrombolysis Thiemann DR, et al. Circulation 2000;101:2239-2246

5. Increasing hazard with age Hazard ratios for thrombolytic therapy increase with increasing age Age Hazard ratio 95% CI 65 0.60 0.44-0.82 74.3 ~ 1.00 80 1.36 1.13-1.64 Thiemann DR, et al. Circulation 2000;101:2239-2246

6. Thrombolysis and the elderly Observational studies This study is observational in nature, and not a substitute for a randomized, controlled, clinical trial. In observational studies it is difficult to adjust for all possible variables and to control bias. Observational studies are, when well designed, able to raise and highlight important questions. The safety and efficacy of thrombolytics in an older population (76-86 years old) is indeed an important question. Thiemann DR, et al. Circulation 2000;101:2239-2246

7. Thrombolysis and the elderly Observation vs randomization Real-world experiences (observational studies) often tell us things that a randomized clinical trial cannot. However, real world experiences can't compare treatments in high risk groups of patients where treatment selection is based on major prognostic factors that are difficult to quantify. One concern is that such observational studies may impact clinical practice “beyond reasonableness”. In the world's compilation of placebo vs active treatment there is a trend toward benefit for those > 75 (approximately 2000 patients ).

8. Thrombolysis and the elderly Need for additional studies? An observational study is notable because of the lack of information in > 75 age group in prior randomized trials. Although a trend toward benefit exists in those > 75 under active treatment (world data), this trend is a lot less than that seen in younger age groups. Earlier thrombolytic trials used different agents than those studied today. In performing a randomized controlled trial, sufficient numbers of patients of age greater than 75 need to be enrolled.

9. The role of observation “If you think about how we accumulate medical evidence, we first make an observation…from that observation you set up a design to study a large number of patients prospectively. Sometimes the first observation that you’ve made bears out in a trial, and at other times it does not.” Dr Eugene Braunwald Professor of Medicine Harvard University

10. The role of databases Approach databases in a manner similar to that for the unusual or interesting patient. You may not be able to draw many conclusions, but you may glean some hints. eg, analysis of the database for patients with rheumatoid arthritis revealed that patients on ASA had a lower incidence of death from MI large number of ASA trials in MI prevention and treatment ASA accepted in MI management

11. The ideal patient Placebo controlled trials can no longer be performed with patients who are otherwise ideal candidates for thrombolytic therapy.

12. Thrombolysis and the elderly CCP database Characteristics of the CCP database: comorbidity some functional status data dementia variables Variables often provided as yes/no. Subtleties are not available in any database, hence unmeasured confounding is possible.

13. SHOCK trial Methodology Patients with MI and left ventricular failure were randomized to emergency revascularization (n=152) or initial medical stabilization (n=150). Revascularization was defined as either coronary artery bypass grafting or coronary angioplasty. The primary endpoint was all-cause 30-day mortality. All-cause 6-month mortality and additional subgroup analyses were investigated. Mean age of the patients was 66 + 10 years and 32% were women. Hochman JS, et al. New Engl J Med 1999;341:625-634

14. SHOCK trial Results Hochman JS, et al. New Engl J Med 1999;341:625-634

15. GUSTO-I trial data Outcomes in the elderly Analysis of the GUSTO-I trial data revealed that 30-day mortality increased markedly with age: <65 n=24 708 3.0% 65 to 74 n=11 201 9.5%30-day 75 to85 n=4625 19.6% mortality >85 n=412 30.3% Combined death or disabling stroke appeared to occur less often with TPA than with streptokinase in all but the oldest patients who demonstrated a weak trend suggesting a lower incidence with streptokinase and s/c heparin: odds ratio 1.13; 95% CI 0.6, 2.1. White HD, et al. Circulation 1996;94:1826-1833

16. Clinical trials in the elderly Importance in health policy The need for ongoing clinical trials in the elderly is apparent, especially given the aging of the baby-boomer population. Although current evidence supports the idea of giving thrombolysis, specific trials in this age group become ethical and very important. The role of percutaneous intervention is also at issue. Patients > 75 make up 1/3 of all patients with MI, but over 1/2 of all deaths.

17. Clinical trials in the elderly Early hazard with thrombolytics 30-day mortality data in a thrombolytic trial of the elderly may reflect an early hazard due to an increase in both intracranial hemorrhage and cardiac rupture. Benefit might therefore not be seen for 6-12 months.

18. Clinical trials in the elderly General implications The establishment of randomized controlled trials in thrombolysis might aid in informing the medical community that the elderly are being undertreated. Practicing physicians should STOP undertreating the elderly, and SHOULD continue to look for opportunities to participate in clinical trials.