ORBITA: PCI BETTER OR MEDICAL THERAPY?
The ORBITA trial1 was the first blinded randomized multicenter clinical trial designed to assess the effect of PCI versus placebo on exercise time, in patients with stable ischemic symptoms. Accordingly, the primary endpoint was the difference in exercise time at 6 weeks after the procedure, as compared to baseline assessment, between the two groups of patients. Secondary endpoints were change in peak oxygen uptake, change in exercise time to 1 mm ST segment depression, angina severity, physical limitation, angina stability, angina frequency and quality of life, Duke treadmill score and change in wall motion score index with dobutamine stress echocardiography (DSE).
The study included patients with single vessel stenosis of at least 70% diameter reduction and with less than 50% stenosis in non-target vessels, visually assessed at angiography. Two hundred patients were randomized 1:1 to undergo PCI (n = 105), with placement of drug eluting stent, or placebo (n = 95), consisting of a sham intervention, which was a coronary angiography without performing any procedure.
The study protocol was comprised of two phases. The first one, pre-randomization, consisted of 6 weeks of antianginal medical therapy optimization, more intense than in standard clinical practice, involving several interactions per week between patients and their referring physicians. Afterwards, baseline assessment was performed. This comprised assessment of angina symptoms burden by CCS class and Seattle Angina questionnaire, myocardial ischemia burden via DSE, functional capacity cardiopulmonary exercise testing (CPET) and quality of life with EQ-5D-5L questionnaire. CPET was continued until patients developed limiting symptoms (angina, dyspnea or fatigue), abnormalities in heart rhythm or blood pressure or marked ST-segment deviation. Blinded randomization and treatment were then carried out with FFR and iFR being assessed during the procedure (but not revealed neither to the patient or to their medical care providers). The second phase of the study consisted of the follow-up at 6 weeks after the blinded randomized procedure, when the same tests done at baseline were performed. Subsequently, the unblinding for patients and physicians to treatment group allocation occurred. Patients in the placebo group could decide in consultation with their referring physicians to undergo PCI.
The most surprising result….was the statistically non-significant difference between change in exercise time of PCI and placebo groups
In a previous unblinded study it has been shown that PCI by balloon angioplasty (no stenting) increased exercise time by 96 s more than the medical therapy alone. Therefore, the most surprising result for the entire scientific community, including the authors of the study, was the statistically non-significant difference between change in exercise time of PCI (28.4 s, 95% CI 11.6 to 45.1 s) and placebo (11.8 s, 95% CI 7.8 to 31.3 s) groups as compared to the respective baseline assessment (difference PCI – placebo: 16.6 s, 95% CI 8.9 to 42 s, p = 0.200). Also, no difference in secondary endpoints was found between the two groups except for a slightly greater improvement in terms of peak stress wall motion score for PCI patients (p < 0.0001). Of note, no change in CCS class was reported in about 50% of both PCI and placebo group at follow-up as compared to baseline.
The authors concluded that a large placebo effect may underlie the clinical observation of symptom improvement after PCI.
SCIENTIFIC DEBATE ON THE RESULTS OF ORBITA
The surprising results of ORBITA have intensified the discussion on the diagnostic and therapeutic approach in stable angina patients. Some investigators have raised criticisms concerning the size of the ORBITA population, being relatively small (n = 200), as a possible cause for not achieving statistically significant differences between PCI and placebo study arms, thereby questioning the study’s statistical power2, 3. Other comments pointed out the fact that 29% of the ORBITA trial patients had FFR above the 0.80 threshold therefore not in need of PCI, according to current guidelines, implying that this may have confounded the expected beneficial effect of PCI3-5.
PHYSIOLOGY STRATIFIED ANALYSIS OF ORBITA
A subsequent physiology stratified analysis of the ORBITA trial data by Al-Lamee et al.6, investigated the association of pre-randomization FFR and iFR with the placebo-controlled efficacy of PCI.
An initial FFR-guided PCI strategy has superior long term beneficial effects as compared to medical therapy alone and lesions with FFR > 0.80 show favorable outcome with medical therapy alone
FFR and iFR were not dichotomized, but treated as continuous variables (n = 196 patients: 103 PCI and 93 placebo). Pre-randomization FFR and iFR predicted the placebo controlled effect of PCI on stress echocardiography. PCI caused large improvements in terms of anatomic and hemodynamic stenosis severity and greater angina relief as compared to placebo (p = 0.006). Moreover, the lower the iFR or the FFR and greater the magnitude of the beneficial effect of PCI in terms of ischemia burden as assessed by DSE (p < 0.00001 for both).
FAME 2: PCI, WHAT HAPPENS AFTER 5 YEARS?
The FAME 2 trial7 was designed to investigate whether the treatment of significant stenoses, as assessed by FFR cutoff of 0.80, with PCI plus medical therapy is more effective than medical therapy alone.
The study included 1220 patients and randomized 888 patients with FFR £ 0.80 in at least one large coronary artery to PCI plus medical therapy (n = 447) or medical therapy alone (n = 441). Drug eluting stents were placed for patients undergoing PCI. The remaining 332 patients with FFR > 0.80 were included in the trial registry and half of them were randomly selected for follow-up. The primary endpoint was a composite of death, myocardial infarction or urgent revascularization.
Importantly, recruitment was stopped earlier than the originally intended 1632 patients, following advice of the data and safety monitoring board, due to a significant difference in the rate of primary endpoint in favor of the PCI group.
Taken together, ORBITA and FAME 2 support current guidelines recommending PCI deferral and medical therapy alone for lesions with FFR > 0.80.
These trials highlight that the smaller the FFR (< 0.80 threshold), the greater the benefit of PCI.
Pressure-only assessment may result in residual risks that remain unnoticed for patients with exhausted coronary flow reserve but non-significant stenosis.
At 5 years follow-up, the cumulative incidence of the primary end-point was larger for the medical therapy group (27.0 %) as compared to the PCI group (13.9 %) (HR: 0.46, 95% CI 0.34 to 0.63, p < 0.001). This difference was driven by the higher urgent revascularization rate for the medical therapy group (21.1 % vs 6.3 %, p < 0.001). The rate of primary endpoint was significantly higher in the medical therapy group than in the registry cohort (15.7 %) (HR: 1.91, 95% CI 1.25 to 2.91, p = 0.003), while it was similar between the PCI group and the registry cohort (HR: 0.88, 95% CI 0.55 to 1.39, p = 0.57).
It should be noted that by the end of the 5 years follow-up period, 51% of the patients initially assigned to the medical therapy group had to undergo to at least one PCI. This large subgroup of patients crossing over from medical therapy to PCI group may underlie the non-significant difference in angina reports at 5 years, in contrast to the 3-year follow-up, when less angina was reported by patients in the PCI group.
The authors of the study concluded that an initial FFR-guided PCI strategy has superior long term beneficial effects as compared to medical therapy alone and lesions with FFR > 0.80 show favorable outcome with medical therapy alone.
FAME 2 RESULTS: ANOTHER POINT OF VIEW
Despite showing significant differences in terms of primary endpoint between the two groups, the FAME 2 results also showed that the majority of the lesions (> 70 %) in the medical therapy group did not suffer from adverse events, while deferring PCI with FFR ≤ 0.80. van de Hoef et al.8, suggested that this occurrence may be due to preserved coronary flow reserve in that subgroup of patients. The authors of this study also highlighted that the primary endpoint rate being > 10 % in the “normal” FFR group (trial registry) may point to the fact that vessels with FFR > 0.80 are not necessarily healthy and reduced coronary flow reserve due to microvascular dysfunction might have been overlooked, due to the fact that only pressure was measured.
ORBITA vs FAME 2
Differences and similarities can be identified between these two trials. The ORBITA trial was blinded and placebo-controlled, visual assessment of lesion severity was performed and the study had a relatively short follow-up period. In the FAME 2 trial patients and referring physicians were aware of diagnosis and treatment selection, lesions severity was assessed by FFR, follow-up period was longer and the patient recruitment had to be stopped prematurely. The results of ORBITA and FAME 2 taken together support current guidelines recommending PCI deferral and medical therapy alone for lesions with FFR > 0.80. These two trials also highlight that the smaller the FFR, below the 0.80 threshold, the larger the benefit of PCI. Residual risks for patients with exhausted coronary flow reserve but non-significant stenosis may still be present and remain unnoticed with pressure-only assessment. Results of the DEFINE-FLOW trial (NCT02328820), expected soon, may provide more insights into this aspect.
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Author: Lorena Casadonte