FRISC-II

Published

FRISC Investigators. "Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study". The Lancet. 1999. 354(9180):708-15.
PubMed • Full text • PDF

Clinical Question

In patients with UA/NSTEMI, does early invasive management reduce MI recurrence and mortality compared to a non-invasive approach?

Bottom Line

Among intermediate- to high-risk patients with UA/NSTEMI, an early invasive strategy is associated with fewer recurrent MIs and improved long-term survival compared to a non-invasive strategy.

Major Points

A challenge in modern cardiology is distinguishing between which patients with unstable angina will progress to myocardial infarction, which patients with NSTEMI will benefit from revascularization, and which of these patients will stabilize on optimal medical therapy alone. As a result, two approaches have come to the fore: conservative and early invasive strategies. The former approach begins with optimal medical management and limits coronary catheterization to patients with refractory or recurrent angina or a positive stress test. The latter approach uses early cardiac catheterization within 24-48 hours and revascularization, if appropriate. (Of note, this differs from the emergent coronary angiography and reperfusion via thrombolysis or primary PCI indicated in STEMI.) In addition, risk assessment tools, such as the TIMI or GRACE risk scores have been developed in an attempt to determine prognosis and identify patients at high risk for complications such as recurrent MI and death.

The 1999 Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC)-II trial randomized 2,457 patients with UA/NSTEMI or NSTE-ACS after 48 hours to receive either an early invasive (coronary angiography followed by revascularization within 7 days) or non-invasive management strategy (coronary angiography for a positive exercise stress test, recurrent or refractory angina, or MI). All patients were treated with aspirin, statin, beta-blockers, and ACE inhibitors according to treatment guidelines. At 6 months, the composite of death or MI was significantly lower in the invasive group (9.4% vs. 12.1%), driven by a reduction in recurrent MIs (7.8% vs. 10.1%). These benefits were maintained at 5-year followup (19.9% vs. 24.5%). The greatest benefit was observed in high-risk patients who had ST-depressions on EKG and/or elevated cardiac biomarkers.

The results of FRISC-II were included in a large meta-analysis in 2006 of seven large RCTs, including RITA-3, TACTICS-TIMI 18, and ICTUS, that randomized patients with UA/NSTEMI to an early invasive strategy compared to a conservative strategy. Among 8,375 patients, an early invasive strategy within 24-48 hours improved long-term survival, reduced recurrent MIs and rehospitalization for unstable angina compared to a conservative approach, particularly in intermediate- to high- risk patients. Interestingly, in contrast to the other 6 RCTs in the meta-analysis, the ICTUS trial demonstrated no benefit from an early invasive strategy. It is not clear why ICTUS conflicted with the other trials, but given the large number of patients in the meta-analysis, current guidelines recommend an early invasive strategy in patients with UA/NSTEMI with an elevated risk for clinical events.

Guidelines

ACC/AHA NSTE-ACS (2014, adapted)

• An urgent/immediate invasive strategy is indicated in patients with NSTE-ACS who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures) (class I, Level of Evidence: A)
• An early invasive strategy is indicated in initially stabilized patients with NSTE-ACS (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events (class I, Level of Evidence: B)
• It is reasonable to choose an early invasive strategy (within 24 hours of admission) over a delayed invasive strategy (within 25 to 72 hours) for initially stabilized high-risk patients with NSTE-ACS. For those not at high/intermediate risk, a delayed invasive approach is reasonable (class IIa, Level of Evidence: B)
• An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is not recommended in patients with:
  • Extensive comorbidities in whom the risks of revascularization and comorbid conditions are likely to outweigh the benefits (Class III, Level of Evidence: C)
  • Acute chest pain and a low likelihood of ACS who are troponin-negative (Class III, Level of Evidence: C), especially women (Class III, Level of Evidence: B)

Design

• Multicenter, prospective, 2x2 factorial design, randomized controlled trial
• N= 2,457 patients with unstable angina
  • Early invasive arm (n= 1,222) vs. Non-invasive arm (n= 1,235)
  • Dalteparin BID x 3 months (n= 1,232) vs. Placebo (n= 1,225)
• Setting: 58 centers in Scandinavia
• Enrollment: 1996-1998
• Follow-up: 24 months directly and 5 years via national registry data
• Analysis: Intention-to-treat
• Primary outcome: 5-year mortality, MI or both

Population

Inclusion Criteria

• Unstable angina (worsening chest pain or chest pain at rest) within 48 hours
• Ischemia verified by at least one of following:
  • EKG changes (ST depressions >0.1 mm or TWI >0.1 mm)
  • Elevated cardiac biomarkers (CK-MB >6 ug/L, troponin-T >0.10 ug/L, etc.)

Exclusion Criteria

• Thrombolysis indicated or treated within 24 hours
• Angioplasty within the prior 6 months
• Prior open-heart surgery
• Age > 75 years
• High risk of bleeding, anemia
• Other acute or severe cardiac disease
• Renal or hepatic insufficiency
• Clinically relevant osteoporosis

Baseline Characteristics

• Median age: 65 years
• Male: 70%
• Hypertension: 31%
• Hypercholesterolemia: 57%
• Diabetes mellitus: 12%
• Current smoker: 31%
• Prior MI: 22%
• Angina >48 hours: 68%
• Angina at rest: 81%
• ST depression at entry: 46%
• Troponin-T ≥0.03 μg/L: 68%
• LVEF <45%: 13%
• FRISK score: 54% medium risk, 30% high risk

Baseline Medications

• Aspirin: 35%
• Beta-blockers: 32%
• ACE-inhibitors: 12%
• Calcium channel blockers: 17%
• Long-acting nitrates: 19%
• Diuretics: 15%
• Statin 10%

Interventions

• Randomized to either early invasive or non-invasive strategy
• Early Invasive strategy
  • Coronary angiography (96%) within a few days
  • Revascularization (71%) within 7 days of admission (median 4 days). PCI with BMS for one or two bloodflow-limiting lesions (≥70% stenosis). CABG for 3 vessel or left main disease.
  • Open-label dalteparin every day until evening prior to revascularization.
• Non-invasive strategy
  • Coronary angiography (10%) and revascularization (9%) if (1) recurrent or refractory symptoms despite maximal medical management or (2) severe ischemia on pre-discharge exercise stress test (defined as ST depressions≥0.3mm; exertional chest pain or hypotension; ST elevation without Qw or TWI).
• All patients received maximal medical management, which included ASA, statin, ACE-inhibitor and β-blocker according to treatment guidelines. Open-label dalteparin for at least 5 days, if not contraindicated.
• Once randomized, all patients received open-label dalteparin for 5 days or until all procedures were done. Then half the patients in each group were also randomized to continued treatment with subcutaneous dalteparin vs. placebo for 3 months
• After 24 months, all information on events taken from national registries run by Swedish, Danish, or Norwegian health authorities.

Outcomes

Comparisons are invasive vs. non-invasive therpay groups.

Primary Outcome

Mortality

• 6-mo: 1.9 vs. 2.9% (P=0.10)
• 5-yr: 9.7% vs. 10.1% (P=0.693)

MI

• 6-mo: 7.8 vs. 10.1% (P=0.045)
• 5-yr: 12.9% vs.17.7% (P=0.002)

MI and/or mortality

• 6-mo: 9.4 vs. 12.1% (RR 0.78; 95% CI 0.62-0.98; P=0.031)
• 5-yr: 19.9% vs. 24.5% (RR 0.81; 95% CI 0.69–0.95; P=0.009)

Secondary Outcomes

Late revascularization after index hospitalization, either by PCI or CABG

12·7% vs. 40·3% (RR 0·32; 95% CI 0·27–0·37; P<0·0001)

Subgroup Analysis

Male gender, smoking, and patients with two or more risk indicators showed significant interaction with the effects of invasive strategy on primary outcome at 5 years.

Criticisms

• After 6 months, the diagnosis of MI was established based on clinical determination. After 2 years, the diagnosis of MI was established based on discharge diagnoses from national registries on hospital admission. This could have caused underestimation of peri-procedural MI in the non-invasive strategy group.
• There was no drug-eluting stents nor clopidogrel during the study period. The availability of glycoprotein IIb/IIIa inhibitors was also very limited.
• The risk stratification tool The FRISC score was not prospectively verified in other studies.
• Invasive strategy was delayed in this study.
• Patients with markedly positive stress tests (up to 2.9-mm exercise-induced ST depression) were randomized to noninvasive or invasive therapy.

Funding

Supported by Pharmacia, Upjohn and the Swedish Heart-Lung Foundation.