Fame 2 Update

FAME 2 (published online at NEJM.org August 28, 2012) was a randomized clinical trial sponsored by St. Jude Medical comparing FFR-guided PCI plus best available medical therapy (PCI group) or best available medical therapy alone (medical-therapy group) in patients with stable coronary artery disease (CAD) who were referred on clinical grounds for cardiac catheterization and had at least one major coronary artery stenosis with a fractional flow reserve (FFR) <0.80. Patients in whom all stenoses had an FFR of more than 0.80 were entered into a registry and received the best available medical therapy. The primary endpoint was a composite of death, MI, or urgent revascularization.

Recruitment was halted prematurely after enrollment of 1220 patients (888 randomized and 332 enrolled in the registry) because of a significant between-group difference in the percentage of patients who had a primary endpoint event: 4.3% in the PCI group and 12.7% in the medical-therapy group (hazard ratio [HR] with PCI, 0.32; 95% confidence interval [CI], 0.19 to 0.53; P<0.001). The difference was driven by a lower rate of urgent revascularization in the PCI group than in the medical-therapy group (see Table). Half of the patients undergoing urgent revascularization had no objective evidence of ischemia (i.e., no elevated cardiac biomarkers or ischemic ECG changes). The mean follow-up was only 7 months, even though the original design was to follow patients for 1 year.

 

Endpoints

PCI + Medical Therapy

Medical Therapy Alone

P value

Composite of death, MI, or urgent revascularization

4.3%

12.7%

<0.001

Cardiac Death

0.2%

0.2%

0.98

Myocardial infarction

3.4%

3.2%

0.89

Urgent revascularization

1.6%

11.1%

<0.001

There are important similarities and differences between the FAME 2 and COURAGE. Like COURAGE, all FAME 2 patients were randomized after cardiac catheterization. Therefore, patients were clinically referred for cath and neither the physicians nor investigators were blinded to the coronary anatomy of patients randomized to the medical-therapy group. Knowing the coronary anatomy may have been a driver of early revascularization procedures in the medical therapy groups of both trials. In COURAGE approximately 16% of the medical therapy group underwent PCI (urgent and non-urgent) during the first year. In FAME 2, 19.5% of the medical therapy group underwent PCI (urgent and non-urgent) during the first year. In both trials there was no difference between treatment groups in the incidence of death or MI. The primary endpoint in COURAGE was the composite of death or MI. The primary endpoint in FAME 2 was the composite of death, or MI, or urgent revascularization. If COURAGE had included revascularization procedures as part of its primary endpoint, there would have been significantly more endpoint events in the medical therapy group at a comparable time period. It appears that this would be the same for the BARI 2D trial of revascularization in stable CAD. In other words, the results of FAME 2 are entirely predictable from COURAGE and BARI 2D. On the basis of FAME 2, one would need to perform PCI in 100 stable patients to prevent 9 urgent revascularizations — only 4 of which have positive biomarkers or ECG changes — without reducing the incidence of death or MI.

What is particularly newsworthy about the FAME 2 results is that there was no difference in the rates of death or MI between treatment groups. These are the most important components of the FAME 2 primary endpoint composite. This is entirely consistent with a recently published nuclear substudy from COURAGE (Am Heart J 2012; 2012;164:243-250). This analysis of outcomes by treatment assignment in 468 patients with at least moderate ischemia at baseline found no reduction in death or MI among patients assigned to PCI + optimal medical therapy (OMT) as compared with OMT alone (HR 1.08 [95% CI 0.71,1.65], p=0.72).

As noted by Dr. Hillis on CardioExchange, the definition of peri-PCI MI required 10-fold elevation of CK-MB or 5-fold elevation with other evidence of MI, e.g., angiographic or ECG. He questioned:“Doesn’t this minimize the rate of peri-PCI MI?” The ISCHEMIA primary endpoint definition has engendered substantial debate and uses a similarly stringent definition of peri-PCI MI as FAME 2. The 2012 International Consensus document—Third Universal Definition of MI—was recently published and specifies a more conservative definition of peri-PCI MI than their prior version, but a more liberal definition than FAME 2 or ISCHEMIA. Ultimately the most important outcome is mortality, but ISCHEMIA is not adequately powered for mortality as the sole endpoint.

The design of ISCHEMIA is fundamentally different from FAME 2, COURAGE, and BARI 2D in that study-eligible patients are being randomized prior to cardiac catheterization (have not been referred for catheterization based on clinical status), and only the anatomy of patients randomized to the invasive strategy will be unblinded. This randomization process will reduce referral bias.  The trial protocol and consent were finalized after FAME 2 announced its decision to halt recruitment. This report in NEJM does not change our understanding of the findings since that time, and FFR was already incorporated in ISCHEMIA, hence there is no new impact on our protocol.  With an anticipated 8,000 subjects followed for an average of 3.5-4 years, ISCHEMIA is powered to answer the question whether an initial strategy of ischemia-guided revascularization plus medical therapy reduces cardiovascular death or MI as compared with an initial strategy of medical therapy alone.

Date: 
Thursday, September 13, 2012 - 09:00