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Transcatheter Cardiovascular Therapeutics 2014
At the 26th annual Transcatheter Cardiovascular Therapeutics (TCT) conference in Washington, D.C., from September 13 to 17, a key focus (as with the European Society of Cardiology) included medications that may help reconcile the opposing goals of stroke prevention and lower bleeding risk among various populations. Attendance was 10,318.
TRANSLATE-ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment Of Treatment Patterns and Events After Acute Coronary Syndrome)
While randomized clinical trials of postmyocardial infarction use of adenosine diphosphate (ADP) receptor inhibitors have established prasugrel’s efficacy, data on the comparative effectiveness and safety of prasugrel versus the older standard agent clopidogrel in routine U.S. clinical practice are limited. To assess those, investigators for TRANSLATE-ACS, a multicenter, prospective observational study, enrolled 12,227 ST-segment-elevation and non–ST-segment-elevation myocardial infarction (MI) patients treated with percutaneous coronary intervention (PCI) at 233 U.S. hospitals.
Prasugrel was used in 25.5% of patients and clopidogrel in 72.3%. Patients receiving prasugrel were significantly (P < 0.0001) more likely to be younger, male, and have ST-segment-elevation MI and to receive drug-eluting stents. Prior MI, prior bypass surgery, prior stroke, and multivessel disease were more common (P < 0.0001) among patients receiving clopidogrel, as was diabetes (P = 0.003).
Unadjusted composite major adverse clinical events (MACE) were higher for clopidogrel (intention-to-treat) at 17.3% versus 13.5% for prasugrel (P < 0.0001). After adjustment for baseline risk, however, an as-treated analysis of MACE showed the HR for clopidogrel treatment to be 1.03 (P = 0.59).
Stent thrombosis rates were lower with prasugrel (0.98% versus 1.33%; adjusted HR, 0.63 [0.42–0.97]; P = 0.04), while unadjusted bleeding was higher for clopidogrel (2.7% versus 3.9%, P = 0.007). After adjustment among all comers, however, bleeding was higher with prasugrel (adjusted HR, 1.30; 95% CI, 1.04–1.63; P = 0.02). “When you focus on those who in routine practice are more likely to be treated with prasugrel, then that difference is no longer significant,” Dr. Wang noted. She called the results “somewhat reassuring” in that they show that interventionalists are actually paying attention to the data and are using prasugrel in patients who are younger, male, and have ST-elevation MI and who are likely to benefit the most from more potent antiplatelet therapy—and are less likely to bleed.
“One of the things that clinicians are most afraid of in the U.S.,” said the TCT moderator of the session, Roxana Mehran, MD, Professor of Medicine at Mount Sinai Hospital, New York, New York, “is that because of cost, patients will not fill the prescription for the more potent agent or they will discontinue it early.”
TRANSLATE-ACS, Dr. Wang commented, is the largest prospective longitudinal study of acute MI patients undergoing PCI in contemporary community practice.
The TRANSLATE-ACS trial was funded by Lilly USA and Daiichi Sankyo.
Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation
When patients who already have an indication for oral anticoagulation therapy—such as those with AF, pulmonary embolism, deep vein thrombosis, or mechanical valves—undergo coronary stenting, coronary interventionalists generally add dual antiplatelet therapy (usually consisting of clopidogrel and aspirin). The resulting “triple therapy,” however, entails elevated bleeding risk. The dilemma is that leaving out oral anticoagulation therapy risks stroke and thromboembolism, and leaving out dual antiplatelet therapy risks stent thrombosis and ischemic events.
The ISAR TRIPLE trial tested whether shortening the duration of triple therapy after stenting would reduce major bleeding events or increase ischemic events. It is the largest randomized trial to date investigating triple therapy and the first to examine duration of therapy. It included 614 patients at three European centers undergoing drug-eluting stent implantation. They were randomized, after aspirin and a vitamin K antagonist, to six weeks of clopidogrel (n = 307) or six months of clopidogrel (n = 307), with clinical follow-up at nine months.
Combined MI, stent thrombosis, stroke, or TIMI major bleeding at nine months, the primary endpoint, was reported at 8.8% for the six-month triple therapy group and 9.8% for the six-week group (HR, 1.14; 95% CI, 0.68–1.91; P = 0.63). The secondary endpoint analysis, separating out major bleeding, revealed no differences for the combined ischemic components (4.0% versus 4.3%, respectively, for the six-month and six-week groups; P = 0.87) or for major bleeding (4.0% and 5.3%, respectively; P = 0.44).
“The main finding is that six-week triple therapy is not superior to six-month triple therapy with regard to net clinical outcomes,” Dr. Fiedler said, “and that shortening the duration of triple therapy neither reduced the incidence of major bleeding nor increased the incidence of ischemic events.” When choosing the shorter or longer duration of triple therapy, the physician should weigh the trade-off between ischemic risk and bleeding risk, Dr. Fiedler concluded.
Predictors of Stent Thrombosis After Primary PCI And Risk for 30-Day Mortality: Analysis From the Pooled Patient-Level Data From the HORIZONS-AMI and EUROMAX Trials
The risk of early (30 days or less) stent thrombosis is considerable after primary PCI for non–ST-segment MI. The impetus for the current analysis arose out of the observation that patients in the HORIZONS-AMI, EUROMAX, and HEAT-PPCI trials treated with bivalirudin compared with unfractionated heparin ± GP2b/2a inhibitors uniformly showed an increased risk of acute (less than 24 hours) stent thrombosis, but did not show any significant stent thrombosis risk thereafter.
The current analysis covered 5,800 ST-segment MI patients; 100 of them (1.7%) developed early stent thrombosis, and within that group, 20 (20%) died within 30 days. Sixty of the stent thromboses occurred in patients receiving bivalirudin and 40 occurred in those receiving heparin ± GP2b/2a inhibitor.
The predominant stent thrombosis risk in the bivalirudin group, a one-day landmark analysis showed, was in the first day (bivalirudin, 1.3%; heparin ± GP2b/2a inhibitor, 0.2%; P < 0.0001). From day 2 to day 30, risk was similar (bivalirudin, 0.9%; heparin ± GP2b/2a inhibitor, 1.2%; P = 0.271) for both agents. Closer analysis showed the higher risk with bivalirudin to be limited to the first four hours post-procedure.
A further observation was that subacute stent thrombosis (occurring from day 2 to day 30) has higher subsequent mortality than acute stent thrombosis. Mortality at 30 days among patients with acute stent thrombosis was 16.7% with heparin ± GP2b/2a inhibitors and 2.8% with bivalirudin (P = 0.125). For subacute stent thrombosis patients, mortality rates were 44.1% for heparin ± GP2b/2a inhibitor and 12.0% for bivalirudin (P = 0.01). Combined 30-day mortality for all stent thrombosis patients was 6.7% for bivalirudin and 40% for heparin ± GP2b/2a inhibitor (RR, 0.19; 95% CI, 0.7–0.52; P = 0.0002).
The significant predictors of acute stent thrombosis were randomization to bivalirudin (odds ratio [OR], 6.94 [2.71–17.75]; P < 0.0001) and pre-procedure TIMI flow of 0 or 1 (OR, 2.35 [1.04–5.35]; P = 0.041). At 30 days after stent thrombosis, however, bivalirudin was an inverse predictor of mortality (OR, 0.17 [0.04–0.63]; P = 0.008). Age greater than 65 years also predicted mortality (OR, 5.13 [1.48–17.73], P = 0.010).
“Thirty-day mortality after early stent thrombosis is substantially less common in patients randomized to bivalirudin compared to heparin ± GP2b/2a inhibitor. This finding is consistent for both acute and subacute stent thrombosis,” Dr. Dangas concluded.
“The explanation for this finding is not yet clear,” coinvestigator Professor Philippe Gabriel Steg, MD, Hôpital Bichat, Paris, France, said in an interview, “and more data and analyses are required—but it is quite striking.” He speculated, “A possibility among others is that very early stent thrombosis occurring while patients are still in the cath lab or close proximity to it may be less dangerous than later stent thrombosis.
“With approximately a 1% absolute excess incidence and no increased reinfarction or mortality, I think the acute stent thrombosis issue in bivalirudin-treated ST-elevation myocardial infarction patients is important, but has been to some extent overblown,” Dr. Steg added. “It can be addressed by prolonged bivalirudin infusion.”
Extended Follow-Up of Multicenter Trial Demonstrates Continued Superiority of Bivalirudin to Heparin With and Without Glycoprotein IIb/IIIa Inhibition in Patients With Acute Myocardial Infarction: Results of Bright Trial
Conflicting findings from clinical trials have fueled recent controversy over strategies for optimal anticoagulation in patients undergoing PCIs. While a recent trial demonstrated superiority for heparin monotherapy over bivalirudin alone, with a disturbing increased rate of stent thrombosis among bivalirudin-treated patients, prior multicenter trials have demonstrated bivalirudin superiority over heparin plus GP2b/2a inhibition.
The BRIGHT trial included acute MI patients at 82 Chinese sites, 735 randomized to bivalirudin, 729 to heparin monotherapy, and 730 to heparin plus tirofiban, a GP2b/2a inhibitor, said Dr. Han. Most (about 78%) PCI procedures were performed transradially, and 99% of patients received drug-eluting stents. The primary endpoint, 30-day net adverse clinical events (NACE), was a composite of major adverse cardiac and cerebral events (MACCE) or BARC (Bleeding Academic Research Consortium bleeding).
In the bivalirudin group, NACE incidence was lower compared with the heparin and heparin plus tirofiban groups (8.8%, 13.2%, and 17.0%, respectively; P < 0.001). The bivalirudin group also had fewer NACE events at one year (12.8%, 16.5%, and 20.5%, respectively; P < 0.001). Bivalirudin reduced major bleeding (P = 0.04) and minor bleeding (P < 0.001), with similar rates of adverse ischemic events compared with the heparin and heparin plus tirofiban groups. Importantly, overall and acute (less than 24 hours) stent thrombosis rates were similarly low in both groups. The overall rate was 0.6% with bivalirudin, 0.6% with heparin, and 0.3% with heparin plus tirofiban (P < 0.77). Acute stent thrombosis incidence was 0.3% in each group.
Dr. Han suggested that the mandated routine after a PCI bivalirudin infusion in BRIGHT might account for the similar rate of stent thrombosis with bivalirudin in BRIGHT, unlike earlier trials in which bivalirudin had a higher stent thrombosis rate.
At the TCT press conference where Dr. Han presented her data, Rod Stables, MD, Liverpool Heart and Chest Hospital, United Kingdom, whose HEAT-PCI trial had shown higher rates of stent thrombosis with bivalirudin and no bleeding advantage, commented: “I’m very impressed by the emerging data on the use of prolonged infusion, which I think would solve the problem really well, as suggested in this trial.” He added, “Bivalirudin has many theoretical and practical advantages. One is that it has a well-established dose ratio with predictable pharmacodynamics … you certainly can’t say that about heparin.”
The BRIGHT trial was funded by a research grant from Salubris Pharmaceutical Co. Ltd. and research funds from China’s National Key Science and Technology R&D project of the 12th Five-Year Plan.
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