title: Prospective validation of a composite end point in thrombolytic trials of acute myocardial infarction (TIMI 4 and 5). Thrombosis In Myocardial Infarction.
abstract: Although the use of composite end points in clinical trials has increased in recent years, few data are available on the validity of such an approach. In the Thrombolysis In Myocardial Infarction (TIMI) 4 and 5 trials, we set out to validate prospectively the nonfatal components of the "unsatisfactory outcome" end point. This end point consisted of the in-hospital occurrence or observation of new-onset severe congestive heart failure/shock, left ventricular ejection fraction <40% (or <30% for patients with prior myocardial infarction), reinfarction, reocclusion by sestamibi perfusion imaging, TIMI flow grade <2 at 90 minutes or 18 to 36 hours, intracranial hemorrhage, major spontaneous hemorrhage, or anaphylaxis. Among 576 patients in TIMI 4 and 5 with 1-year follow-up, a nonfatal unsatisfactory outcome end point was reached in hospital in 45% of patients. Compared with patients without such an end point, patients with an end point had a relative risk of 1-year mortality of 2.5 (95% confidence interval 1.4 to 5.6, p = 0.001). For individual components, new-onset severe congestive heart failure/shock had a relative risk of 4.6 (p = 0.001), left ventricular ejection fraction <40% had a relative risk of 3.5 (p = 0.006), recurrent myocardial infarction had a relative risk of 2.2 (p = 0.047), and TIMI flow grade <2 at 90 minutes had a relative risk of 2.2 (p = 0.005). Our findings show that these nonfatal in-hospital end points and the composite end point are associated with an increased risk of 1-year mortality and as such are valid predictive survival markers for use in clinical trials.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Cannon
authors.forename: P J
authors.initials: PJ
authors.lastname: Sharis
authors.forename: M J
authors.initials: MJ
authors.lastname: Schweiger
authors.forename: C H
authors.initials: CH
authors.lastname: McCabe
authors.forename: D J
authors.initials: DJ
authors.lastname: Diver
authors.forename: P K
authors.initials: PK
authors.lastname: Shah
authors.forename: R F
authors.initials: RF
authors.lastname: Sequeira
authors.forename: R M
authors.initials: RM
authors.lastname: Greene
authors.forename: R L
authors.initials: RL
authors.lastname: Perritt
authors.forename: W K
authors.initials: WK
authors.lastname: Poole
authors.forename: E
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D000368:Aged; D002986:Clinical Trials as Topic / Q000379:methods; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006331:Heart Diseases / Q000401:mortality*; D006333:Heart Failure / Q000209:etiology; D006439:Hemodynamics; D024764:Hirudin Therapy; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D010960:Plasminogen Activators / Q000627:therapeutic use; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D015203:Reproducibility of Results; D012306:Risk; D015912:Thrombolytic Therapy; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000209:etiology
chemical_list: D005343:Fibrinolytic Agents; D010960:Plasminogen Activators