Prof. Freek Verheugt,
After ACC 2011 three interesting studies have been published on the efficacy and safety of the oral platelet thrombin receptor blocker atopaxar in patients with stable and unstable coronary disease treated with dual antiplatelet therapy. In an earlier study with vorapaxar promising results were obtained in patients undergoing elective PCI.1 In that 1,030 patients trial there was a strong trend of efficacy against ischemic endpoints without a significant increase in bleeding.
In the LANCELOT-CAD trial2 patients with stable coronary artery disease (n = 720) were randomized double-blind to 50, 100, or 200 mg daily of atopaxar or placebo for 24 weeks on top of regular therapy They were followed up for an additional 4 weeks. Overall CURE bleeding was higher with atopaxar (3.9% overall and 3.9%, 1.7% and 5.9% for 50, 100 and 200 mg respectively) compared with placebo (0.6%, RR 6.82, p = 0.03, p for trend = 0.01). By TIMI criteria these figures were also higher: atopaxar (10.3% overall, and 9.9%, 8.1% and 12.9% for 50, 100 and 200 mg respectively, figure) compared with placebo (6.8%, RR 1.52, p for trend = 0.07). Major bleeding was similar, but there was a trend to less ischemic events with atopaxar.
Bleeding in LANCELOT-CAD
Atopaxar achieved high levels of platelet inhibition with the 3 doses , but ALAT levels were increased and dose-dependent QTc prolongation was seen with higher-dose atopaxar.
In the LANCELOT-ACS trial 603 patients with non–ST-elevation ACS were randomized to 1 of 3 doses of atopaxar (400mg loading dose followed by 50, 100, or 200 mg daily) or placebo on top of aspirin and clopidogrel.3 The incidence of TIMI major or minor bleeding did not differ significantly between the combined atopaxar and placebo groups (3.1% versus 2.2%, respectively; p = 0.63). Major bleeding tended to be higher in the atopaxar groups compared with the placebo group (1.8% versus 0%; p = 0.12).
Bleeding in LANCELOT-ACS in the safety population
Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia were similar (8.0% versus 7.8%; p = 0.93). CV death, MI, or stroke was 5.6% in the placebo group and 3.3% in the atopaxar groups (p = 0.20). Atopaxar significantly reduced ischemia on Holter at 48 hours compared with placebo (RR 0.67, p = 0.02). Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar.
In a Japanese study 241 patients with ACS and 263 with high-risk CAD (J-LANCELOT) received 50, 100, or 200 mg atopaxar or placebo once daily for 12 weeks (ACS) or 24 weeks (CAD) on top regular antiplatelet therapy.4 TIMI major, minor, and minimal bleeds requiring medical attention was similar in the placebo and the atopaxar groups. There were no TIMI major bleeds and three CURE major bleeds (two with placebo; one with 100 mg atopaxar). There was a numerical increase in any TIMI bleeding (figure) with 200 mg atopaxar (16.4% placebo versus 23.0% ATOPAXAR for ACS, p = 0.40, and 4.5% placebo versus 13.2% atopaxar, p = 0.08 for CAD).
Bleeding in J-LANCELOT
Major cardiovascular adverse events with atopaxar were not significantly different from placebo (6.6% placebo versus 5.0% atopaxar, p = 0.73 for ACS, and 4.5% placebo versus 1.0% atopaxar, p = 0.07 for CAD). There was a statistically significant dose-dependent increase in liver function abnormalities and QTc prolongation with atopaxar. At trough levels in both populations, mean inhibition of platelet aggregation was 90% with 100 and 200 mg atopaxar, and 20–60% with 50 mg atopaxar.
Thus, the oral platelet thrombin receptor blocker atopaxar significantly inhibits platelet aggregation in patients with stable and unstable coronary artery disease already on regular antiplatelet therapy, but is associated with increased overall, but not major bleeding in 3 phase-II trials. Also asymptomatic liver enzyme elevation and QT prolongation were observed. Whether this additional class of antiplatelet therapy is safe and efficacious, is currently tested in 2 megatrials of vorapaxar: TRACER (n = 13,000) in acute coronary syndromes without ST-elevation (completed early 2011 and to be presented at AHA 2011) and TRA-2P TIMI 50 (n = 26,500) in secondary prevention after MI, stroke or PAD diagnosis. Inclusion in the latter study is also complete, but study medication was discontinued early 2011 in patients with prior stroke because of complications. TRA-2P TIMI 50 will be presented in 2012.
The most important results at ESC 2011 held in Paris came from the ARISTOTLE trial, which compared the oral direct Xa blocker apixaban with warfarin in stroke prevention in atrial fibrillation, and was simultaneously published.5 Patients with atrial fibrillation and a CHADS2 score of 2.0 were randomized double blind to warfarin (INR 2-3) or apixaban 5 mg bid (2.5 mg bid for patients with kidney failure). Analysed on an intention-to-treat basis, stroke or systemic embolism was 1.3% per year with apixaban and 1.6% per year with warfarin (HR 0.79, 95% CI 0.66 - 0.95, p < 0.001 for noninferiority, p = 0.01 for superiority, figure).
Stroke and systemic embolism in ARISTOTLE (ITT analysis)
Major bleeding was 2.1% per year on apixaban and 3.1% on warfarin (HR 0.69, 95% CI 0.60 - 0.80, p < 0.001). Mortality was also lower with apixaban: 3.5% as compared to warfarin: 3.9% (HR 0.89, 95% CI 0.80 - 0.99, p = 0.047). The rate of hemorrhagic stroke was 0.2% per year with apixaban and 0.5% per year with warfarin (HR 0.51, 95% CI 0.35 - 0.75, p < 0.001). After the SPORTIF trials, the RE-LY and the ROCKET studies ARISTOTLE is the fifth megatrial to show that novel oral anticoagulants are at least as effective as warfarin for stroke prevention in atrial fibrillation and have a better safety profile, especially with regard to intracerebral bleeding. The probably last and largest of this type of studies is the ENGAGE-TIMI 48 trial that compares 2 doses of the Xa blocker edoxaban once daily to warfarin in over 21,000 patients. Results are expected in 2012.
Finally, an interesting study was presented, but not published, on the optimal duration of clopidogrel therapy after coronary stenting: the PRODIGY trial by Marco Valgimigli (Ferrara, Italy). In 1,970 all-comers patients undergoing PCI with various stents clopidogrel was given in a randomized way for 6 months versus 24 months. The patients were followed for 2 years after stent implantation. In the patients randomized to 6 months clopidogrel the primary outcome (death, MI or stroke at 2 years) was seen in 10.0% versus 10.1% in patients randomized to 24 months (HR 0.98, 95% CI 0.74 - 1.29, p = 0.91, figure). Death and MI were not different either, nor were mortality and stent thrombosis. Landmark analysis at 6 months did not show any benefit for longer treatment duration either. Bleeding according to the BARC criteria II, III and V was very significantly reduced by stopping clopidogrel at 6 months versus continuation till 24 months: HR 0.46, 95% CI 0.10- 0.51, p = 0.00018).
Death/MI/stroke in PRODIGY
Thus, after the randomized studies from Korea6 and the not yet published EXCELLENT trial PRODIGY is the third one showing no benefit of clopidogrel duration beyond 6 to 12 months after stent implantation. Stent thrombosis was not increased, but bleeding was. Even the three studies together will not change practice, because the sample sizes and event rates do not allow definitive answers. In the largest trial6 only patients eligible for interruption were included (excluding bleeders, patients with reintervention and patients at risk because of diabetes or stent in the left main). They will come from the huge American DAPT study comparing 1 year clopidogrel to 3 year clopidogrel (n = 20,000) and the ISAR-SAFE trial (n = 6,000) from Germany comparing 6 to 12 months of clopidogrel.
Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 2009;373:919-928
Wiviott SD, Flather MD, O'Donoghue ML, et al. Randomized trial of atopaxar in the treatment of patients with coronary artery disease. Circulation 2011;123:1854-1863
O’Donoghue ML, Bhatt DL, Wiviott SD, et al. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes. Circulation 2011;123;1843-1853
Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL. Double-blind, placebo-controlled phase-II of the protease-activated receptor-1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur Heart J 2010;31:2601-2613
Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992
Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;362:1374-1382
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