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FRagmin and Fast Revascularization during InStability in coronary artery disease - FRISC II
Description:
Early invasive vs. conservative strategy and dalteparin vs placebo for unstable CAD.
Hypothesis:
In patients with unstable CAD: 1. Is the use of the low molecular weight heparin dalteparin superior to placebo? 2. Is an invasive strategy better than conservative approach?
Study Design
Study Design:
Patients Screened: 3489/3048
Patients Enrolled: 2267(dalteparin vs placebo)/2457(invasive vs nonivasive)
NYHA Class: Not reported
Mean Follow Up: 6 months
Mean Patient Age: Median 67 years
Female: 32%
Mean Ejection Fraction: LVEF <45% in 14% of dalteparin and 17% of placebo patients (according to echocardiocardiography measured in 842 and 860 patients)
Patient Populations:
Patients from 3 Scandinavian countries with ischemic symptoms in previous 48 hours accompanied by ECG changes (ST depression or T wave inversion ≥0.1 mv) or elevated markers (e.g. CK-MB >6 mg/L, troponin T >0.10 mg/L). Unstable CAD, defined as 2 out of the following 3 symptoms: ST-segment depression or T wave inversion, elevated CPK-MB levels, or elevated troponin-T levels.
Exclusions:
Increased bleeding risk, anemiam, thrombolytic indication in past 24 hours, PTCA in previous 6 months, scheduled angiography/revascularization, other acute/severe cardiac disease, renal or hepatic insufficiency, known clinically relevant osteoporosis. Those with previous open heart surgery and age >75 years were not eligible for invasive strategy assignment but were assigned to dalteparin or placebo.
Primary Endpoints:
Death or MI at 3 months (dalteparin vs placebo) or 6 months (invasive vs noninvasive strategies)
Secondary Endpoints:
Death, MI, need for revascularization, death + MI + revascularization, bleeding complications
Drug/Procedures Used:
After 5 or more days of open-label dalteparin, patients were randomized to subcutaneous dalteparin 120 IU/kg twice daily or placebo for 3 months. Within 48 hours, patients were randomized to either invasive or noninvasive early treatment strategies (coronary angiography within 7 days performed in 96% and 10% and revascularization in first 10 days in 71% and 9%). After the 3-month dalteparin/placebo treatment, patients in the invasive group underwent angiography/PTCA/CABG within 2 to 7 days. Patients in the non-invasive group underwent exercise testing if stable and, if indicated, had angiography/PTCA/CABG.
Concomitant Medications:
All patients received aspirin (initial dose 300-600 mg then 75-320 mg once daily). Beta-blockers given unless contraindicated.
Principal Findings:
Dalteparin vs Placebo At 30 days, the incidence of death or MI was significantly lower in dalteparin compared to placebo group(3.1% vs 5.9%, p = 0.002), but at 3 months the reduction was no longer significant (6.7% vs 8.0%, p = 0.17). Dalteparin therapy was associated with a significant reduction in the 3 month incidence of death, MI, or revascularization (29.1% vs 33.4%, p = 0.031), but again this benefit did not persist at 6 months (38.4% vs 39.9%, p = 0.50). Patients treated with dalteparin had higher rates of severe bleeding (3.0 vs 1.8%) and intracranial hemorrhage (0.8% vs 0%) compared placebo-treated patients. Invasive vs Noninvasive Strategies Invasive strategy was associated with a significantly lower incidence of death or MI at 6 months (9.4% vs 12.1%, p = 0.031). There was also a significant reduction in MI alone (7.8% vs 10.1%, p = 0.045), while the decrease in mortality was not statistically significant (1.9% vs 2.9%, p = 0.10). Subgroup analysis found these benefits were restricted to men (RR 0.64 of death or MI at 6 months); this finding could have due to the higher incidence of normal coronary arteries among women. The invasive strategy was associated with a 50% reduction in the incidence of recurrent angina and hospital readmission.
Interpretation:
The FRISC II trial demonstrated no significant advantage of dalteparin therapy compared to placebo at 3 months in reducing death or MI in unstable CAD patients. In contrast, sigificant benefits were seen with the use of a different low-molecular weight heparin, enoxaparin, in the TIMI 11-B and ESSENCE trials. This suggests there may be differences between agents within this class of drugs, although direct comparative data are lacking. The FRISC II results suggest that early invasive should be the preferred management strategy of unstable CAD, a finding also by the TIMI-18/TACTICS study. The TIMI-18/TACTICS study was a more contemporary study with a higher rate of coronary artery stent placement, and all patients were treated with glycoprotein IIb/IIIa inhibitors upstream prior to the PCI.
References:
Lancet 1999; 354: 701-7. Dalteparin vs placebo. Lancet 2000; 354: 708-715. Invasive vs conservative Lancet 2000; 356: 9-16. 1 year follow-up (invasive vs conservative)
Keywords: Troponin T, Coronary Disease, Dalteparin, Electrocardiography, Stents, Intracranial Hemorrhages, Coronary Angiography, Patient Readmission, Enoxaparin, Myocardial Revascularization, Coronary Vessels
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