Clinical Trial Result Information

Title of Study:
Combined angioplasty and pharmacological intervention versus thrombolysis alone in acute myocardial infarction (CAPITAL AMI Study).

Fast Facts:

Protocol number:	ML16358
Sponsor:	Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	TNKase
Generic name:	tenecteplase
Phase of development:	IV
Therapeutic area, approved indication:	Myocardial infarction
Date of report:	8/2/2005

Clinical study summary:
This was a randomized, multicenter study of the efficacy and safety of TNKase (tenecteplase)-facilitated angioplasty compared with tenecteplase alone in patients with acute myocardial infarction (MI). Tenecteplase was given by intravenous (iv) injection according to body weight and coronary angiography was performed as soon as possible after administration of tenecteplase on patients assigned to facilitated angioplasty. Patients were evaluated 30 days and 6 months after randomization.

Study center(s) :
4 Ottawa hospitals, with the interventional facility located at the University of Ottawa Heart Institute.

Objectives:
The primary endpoint was a composite of death, recurrent MI, recurrent unstable ischemia, or stroke at 30 days and 6 months after randomization.

Methodology:
Patients were randomly assigned to treatment with tenecteplase alone or to tenecteplase with immediate tenecteplase-facilitated angioplasty. All patients received 160 mg of chewable aspirin and 325 mg of aspirin daily thereafter. Tenecteplase was given according to body weight (30 mg for <60 g, 35 mg for 60–69 kg, 40 mg for 70–79 kg, 45 mg for 80–89 kg, and 50 mg if ≥90 kg) over 5 seconds plus weight-adjusted unfractionated iv heparin, based on the 2004 ACC/AHA Guidelines for ST-Elevation MI. After administration of tenecteplase, coronary angiography was performed as soon as possible on patients assigned to facilitated angioplasty. The heparin infusion was stopped on arrival at the catheterization laboratory, and the dose was adjusted to maintain an ACT at 250s. Routine use of GP 2b/3a inhibitors was discouraged. Patients who underwent angioplasty were prescribed clopidogrel 300 mg as a single dose at the time of the procedure and 75 mg daily thereafter for ≥1 month.

Number of patients (planned/analyzed):
170 enrolled.

Diagnosis and main criteria for inclusion:
Patients presenting within 6 hours of the onset of chest discomfort of ≥30 minutes’ duration and having ≥1 mm ST-segment elevation in ≥2 contiguous leads or left bundle branch block on a 12-lead electrocardiogram were eligible if they had one of the following high risk criteria: 1) anterior infarct 2) extensive non-anterior infarction 3) Killip 3 or 4, or 4) systolic blood pressure of <100mg.

Test product, dose and mode of administration or test procedure:
Tenecteplase iv according to body weight ( 30 mg for <60 kg, 35 mg for 60–69 kg, 40 mg for 70–79 kg, 45 mg for 80–89 kg, and 50 mg for ≥90 kg.). plus angioplasty.

Duration of treatment:
Single dose.

Reference therapy, dose and mode of administration or reference procedure:
Tenecteplase iv according to body weight (see above).

Criteria for evaluation (efficacy, safety):
The primary endpoint was a composite of death, recurrent MI, recurrent unstable ischemia, or stroke at 6 months after randomization.

Statistical methods:
It was anticipated that the occurrence of the primary endpoint would be 40% in the tenecteplase-alone group and 20% in the tenecteplase-facilitated PCI group at 6 months (a 50% reduction). With a 2-sided alpha of 5%, a power of 80%, and a non-adherence rate of 2%, a total of 170 patients (85 patients per group) were required. Statistical analysis was performed according to the intention-to-treat principle. Values for binary outcomes are reported as frequencies and percents with group comparisons using the Fisher exact test; values for continuous outcomes are reported as medians and interquartile ranges with group comparisons using the Mann-Whitney rank-sum test; and time-to-event outcomes are reported using Kaplan-Meier curves with group comparisons using the log-rank test. Two-sided tests and 95% confidence intervals were used. Analyses were performed with SAS statistical software (version 8.02; SAS Institute, Cary, North Carolina).

Summary (efficacy, safety, other results):
At 30 days, the primary endpoint was reached in 21.4% of patients in the tenecteplase-alone group compared with 9.3% in the tenecteplase-facilitated angioplasty group. At 6 months, the benefit was maintained: 23.8% vs 11.6%, respectively (P=0.045). The difference in the occurrence of the primary endpoint was driven by a reduction in the rate of recurrent unstable ischemia at 30 days, 17.9% vs 7.0% (P=0.037) and at 6 months, 17.9% vs 7.0% (P=0.037). There was trend toward a lower rate of re-infarction in the tenecteplase-facilitated angioplasty group at 30 days, 13.1% vs 4.7% (P=0.062) and at 6 months, 5.8% vs 14.2% (P=0.077). No differences were observed in the rates of death or stroke. One intracranial hemorrhage occurred in each group. Major bleeding was observed in 7.1% of the tenecteplase alone group, and in 8.1% of the tenecteplase-facilitated angioplasty group (P=0.44).

Conclusions:
In patients presenting with high-risk ST-elevation MI, tenecteplase plus immediate angioplasty reduced the risk of recurrent ischemic events and was superior compared with tenecteplase alone, and was not associated with an increase in major bleeding complications.

Publications (references, if available):
LeMay Mr, Wells GA, Labinaz M. et al. Combined angioplasty and pharmacological intervention versus thrombolysis alone in acute myocardial infarction. (CAPITAL AMI Study). J Amer Col Cardiol. 2005;46: 417-424.