Reported from TCT 2021
Examination of the study methodology and results according to the PICOT principle, SWOT analysis and real-world applicability of the FAME 3 trial presented at TCT 2021.
Examination of the study methodology and results according to the PICOT principle
Population of interest:
- 1500 patients with three vessel coronary artery disease (at least 50% stenosis by visual assessment in each of the 3 major epicardial or major side branches) not involving the left main were randomly assigned to FFR guided PCI or CABG.
- All lesions were evaluated as amenable to treatment with either PCI or CABG by the local Heart Team.
- The mean age was 65 years, the majority were male (>80%) and 29% had diabetes.
- 39% of patients presented with ACS.
- The mean SYNTAX score was 26 with a mean of 4.3 stenoses per patient, CTO’s were present in 22% and 68% had at least one bifurcation lesion.
- Exclusion criteria included: recent ST-segment elevation myocardial infarction, cardiogenic shock, a left ventricular ejection fraction of less than 30%.
Intervention of interest:
- FFR assessment of all stenosis, (excluding subtotal or total occlusions); 24% of the evaluated lesions had an FFR >0.80.
- PCI with durable polymer zotarolimus eluting stents in stenoses with an FFR <0.80.
- Intracoronary imaging at the operators discretion, ultimately performed in 12% of PCI procedures. Post-PCI FFR was performed in 60% of cases with a median value of 0.88.
Control:
- CABG as per standard practice in the centre with complete arterial revascularisation strongly recommended. (24.5% had multiple arterial grafts, 97% had LIMA used as a graft).
- If FFR was obtained in the diagnostic procedure (10% of cases), this information could be used to guide CABG at surgeons discretion.
Outcomes of interest:
- Composite endpoint of all-cause death, any MI, stroke, and repeat revascularization did not meet non-inferiority for FFR guided PCI; 10.6% (FFR-PCI) vs 6.9% (CABG) (HR 1.5 [CI 1.1-2.2], P = 0.35 for noninferiority).
- There was no difference between PCI and CABG in the rates of any of the individual components of the primary endpoint.
- Periprocedural complications including atrial fibrillation, acute kidney injury, major bleeding, and ultimately 30-day rehospitalization rate, were more frequent in the CABG group.
Time frame of interest:
- Follow-up was 12 months for all endpoints.
Strengths – Weaknesses – Opportunities – Threats (SWOT) analysis
Strengths
- Investigator-initiated, high-quality randomized clinical trial, funded through research grants from Stanford University, comparing contemporary myocardial revascularization techniques, percutaneous versus surgical, for three-vessel coronary artery disease without left main stem involvement.
- Stenting was guided by FFR, this reflects previous evidence demonstrating improved outcomes of FFR-guided over angiography-guided PCI.
- CABG was performed according to the standard practice at each participating centre, thus reflecting daily practice.
- hom*ogeneity of the baseline patient characteristics.
- Assuming a 10% or lower range of 1-year MACCE in the CABG arm (including repeat revascularization), a clinically acceptable non-inferiority margin was expressed as a hazard ratio of 1.65. This underscores the solidity of the results obtained in favour of CABG and minimizes the risk of bias towards non-inferiority by not using a) absolute difference in event rates or b) a narrow margin, to define non-inferiority (View example of a trial including a non-inferiority analysis: FUTURE II)
- The definitions of periprocedural myocardial infarction were in line with the CABG-related periprocedural MI in the Third Universal Definition. This allowed for a conservative perspective on periprocedural MI, which likely reduced the rate of periprocedural MI in the PCI group. This once again underscores the overall beneficial outcomes of CABG.
- FFR was used in >80% of lesions to assess their functional significance (the remainder were either subtotal or total occlusions), in the CABG arm 97% of patients received a LIMA and 24% multiple arterial grafts, as per standard practice in the investigating centres.
- The primary composite endpoint all-cause death, myocardial infarction, stroke and repeat revascularisation reflects daily practice, with near complete 1-year follow up (99.7%).
Weaknesses
- The incidence of events in the control group (CABG) was lower than originally assumed (6.9% versus 10.0%).
- Lesions of at least 50% at angiography were considered for inclusion, which may have resulted in selection bias given the ambiguity of angiography in eccentric and diffuse CAD.
- Limited use of intravascular imaging (12%). Although this may reflect real world practice, evidence is mounting that increased use of intracoronary imaging is associated with improved outcomes.
- Low numbers of female patients included in both arms of the trial.
- In 22% of patients, at least one vessel was chronically occluded, it is unclear what proportion of CTO’s were treated in the PCI arm. Completeness of revascularisation is unclear in both arms, given that complete revascularisation conferred a benefit in the SYNTAX trial this is of interest.
- Events leading to repeat revascularization were not defined. The type of event, i.e. angina, MI etc, leading to repeat angiography and/or revascularization would provide more insights into the trial’s results.
- The lesions requiring repeat revascularization, within stent (e.g., target lesion revascularization: in-stent restenosis or thrombosis) or de novo disease progression (target vessel revascularization) are not defined.
- One-year follow-up limits comparability with previous investigations, 5-10 year follow-up is available for the majority of previous trials comparing PCI vs. CABG . However, of note, the early differences between PCI and CABG seen in the FAME III trial have not been usually demonstrated in prior trials.
- Repeat revascularisation was included in the primary endpoint whilst major bleeding or the need for rehospitalization was not. Both of the latter event types were document more frequently in the CABG arm.
Opportunities
- CABG remains the treatment of choice for three-vessel coronary artery disease with moderate-to-severe anatomic complexity as defined by the SYNTAX score.
- In the trial, rates of major adverse cardiovascular events after PCI and CABG were lower than those reported in previous trials comparing myocardial revascularization techniques, likely highlighting improvements in both fields over time.
- Differences in the key individual secondary endpoints between myocardial revascularization techniques were attenuated, though the trial is not powered for individual outcomes a numerical reduction in death and myocardial infarction after coronary artery bypass grafting was observed.
- PCI in the subgroup of patients with three-vessel disease and a SYNTAX score <23 seems to be safe and effective compared with CABG. With the caveat that the trial did not meet its primary endpoint, therefore this is hypothesis generating.
- Extension of the long-term follow-up from 3 years to 5 years will be critical in understanding the clinical implications of any differences between the two treatment strategies.
- It may be necessary to reconsider the current recommendations in patients with angiographic three-vessel coronary artery disease, irrespective of the SYNTAX score, as FFR-guided PCI did not meet the criterion of non-inferiority in the overall population.
Threats
- The CABG group had significantly higher rates of periprocedural atrial fibrillation, acute kidney injury and bleeding. This, together with the individual patient´s frailty and co-morbidities, needs to be considered when deciding between PCI and CABG for multivessel disease in everyday practice.
- In light of the FLOWER-MI (STEMI) and FUTURE (all-comer) trials, which did not show a benefit of FFR over angiography guidance, further analyses may be warranted to define the role of FFR outside stable CAD (as documented in the FAME and FAME 2 trials). See Figure 2.
- The large difference observed between revascularization techniques, within the first year of the procedure, may warrant a more detailed evaluation of the reasons leading to repeat revascularization in both study groups.
- The periprocedural myocardial infarction definition used may have partially influenced the results. However, it should be noted that the relationship between periprocedural MI definitions and mortality is a topic of ongoing research.
- The SYNTAX score has shown some inconsistencies in predicting outcomes following myocardial revascularization. Moreover, the primary end point of the study was not reached, therefore the sub-group interpretation of possible PCI benefits in low SYNTAX score patients may be perceived as hypothesis generating alone.
Figure 2: FFR-guided PCI via CABG - a comparison of clinical trials
Reviewers
- Daniel Faria
- Emanuele Gallinoro
- Daniele Giacoppo
- Breda Hennessey
- Jean Marco
- Dejan Milasinovic
- Nicola Ryan
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