Key Points:
- Though primary PCI for coronary obstruction is first-line therapy in acute myocardial infarction (AMI), many patients experience impaired myocardial perfusion despite vessel patency (no-reflow phenomenon), worsening morbidity and mortality post-AMI
- Current guidelines recommend using GP IIb/IIIa inhibitors to manage no-reflow phenomenon; however, this is based on expert consensus alone, as there are no randomized clinical trials assessing the efficacy and safety of this approach
- The REVERSE-FLOW study compared use of GP IIb/IIIa inhibitors for no-reflow phenomenon in ACS patients by comparing infarct size and microvascular obstruction (MVO) on CMR as well as assessing safety of this therapy regarding bleeding risk
- The study did not find significant difference between infarct size with GP IIb/IIIa treatment but did find decreased presence and extent of MVO on CMR; however, this study also found increased bleeding risk with GP IIb/IIIb therapy, though this was limited to non-life-threatening bleeding
Timely and total restoration of flow of a coronary obstruction with primary PCI is the first line reperfusion strategy in patients presenting with acute myocardial infection (AMI). However, in many patients (estimates of 10-20% of AMI patients), myocardial perfusion remains impaired despite vessel patency (known as “no-reflow phenomenon”), a major challenge for further reducing morbidity and mortality rates post-AMI. The pathophysiology of no-reflow is complex but is thought to involve coronary microvasculature and multiple mechanisms, including individual susceptibility, ischemic damage, distal embolization, and perfusion injury. Currently, the only recommended therapy for no-reflow phenomenon is glycoprotein (GP) IIb/IIIa inhibitors; however, this is only based on expert recommendations, and there is no clinical trial data to guide this decision. The REVERSE-FLOW trial hypothesis was that GP IIb/IIIa inhibitors were superior to standard therapy with respect to infarct size assessed by CMR imaging. The authors aimed to evaluate the impact of bailout GP IIb/IIIa inhibitors in AMI patients with angiographic no-reflow post-PCI and the safety of GP IIb/IIIa inhibitors with respect to increased bleeding risk. The study investigators hypothesized that that GP IIb/IIIa inhibitors would improve no-reflow phenomenon by reducing thrombus burden and distal thrombus embolization, thereby improving myocardial perfusion, as evidenced by smaller infarct size and less microvascular obstruction (MVO) on CMR imaging, resulting in improved clinical outcomes.
Across 3 centers in Switzerland, the REVERSE-FLOW enrolled adult STEMI or NSTEMI patients with TIMI grade ≤ 2 flow after primary PCI, ultimately including 120 patients randomized to either GP IIb/IIIa inhibitor therapy or no therapy, with 102 patients included in final analysis (51 per arm). Notable exclusion criteria were symptom onset > 48 hours before revascularization, contraindication to GP IIb/IIIa inhibitors, contraindication for CMR imaging, or stroke within the past 2 years. A standardized CMR protocol was used to assess infarct size (primary endpoint) and MVO (secondary endpoint), based on previous research recommendation that these parameters are optimal standard for assessing myocardial perfusion with CMR.
The study cohort was overall well-balanced with an average age of 64 in the experimental arm and 68 in the control arm; the only significant difference was a higher proportion of males in the control arm (42/62 vs 50/58, p=0.017). Between both arms, most PCI used radial access (46/62 vs 47/58, p=0.37), and the LAD was most likely to be the culprit vessel (30/62 vs 25/58, p =0.707). Regarding the number of vessels involved, there was a higher proportion of patients with 2-vessel disease in the experimental arm than the control arm, but this was ultimately calculated to be non-significant (28/62 vs 15/58; overall p=0.081).
The study found that there was no significant difference in the primary endpoint of CMR infarct size between those treated with GP IIb/IIIa inhibitors and those not (p=0.386). However, for the secondary endpoint of MVO, the study found both significantly less MVO present (38 out of 51 patients vs 47 out of 51 patients; p=0.017) and lower extent of MVO (2.1% vs 3.4%; p=0.025) with GP IIb/IIIa inhibitors therapy and optimal medical therapy (OMT) compared to OMT alone. With respect to bleeding, there was a significantly higher rate of any bleeding with GP IIb/IIIa therapy (14/62 vs 4/58; p=0.016); however, notably these were largely limited to non-life-threatening bleeding events and minor bleeding. The study authors also found no significant difference in all-cause death between arms (3/62 vs 2/58; p=0.703), though importantly the study was not powered to assess clinical endpoints.
This study notes specific limitations. First, the REVERSE-FLOW trial was not powered for clinical endpoints, but they use CMR-derived surrogates known to be strong independent prognostic indicators. In addition, both interventionalists and patients were not blinded to treatment allocation, though all endpoint analyses were performed by blinded investigators. Finally, time between index event and CMR imaging is important as there was a delay of 3 days, though the investigators argue that this is consistent with current management guidelines.
In conclusion, the study investigators argue that given the role of MVO in CMR as a strong surrogate predictor of clinical outcomes (including heart failure hospitalization, reinfarction, and death), GP IIb/IIIa should be considered in the event of no-reflow phenomenon after primary PCI for AMI, while incorporating each individual patient’s bleeding risk. The authors also suggest the need for further investigation regarding optimal timing of GP IIb/IIIa therapy as well as optimal patient selection for this therapy.