ACUTE CORONARY SYNDROME

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1 A supplement to MONTHLY PRESCRIBING REFERENCE April 2014 Issue #18 Intervention & Prevention: Keeping Current with ACUTE CORONARY SYNDROME JOURNAL CLUB Pretreatment with prasugrel in non-st-segment elevation acute coronary syndromes. Montalescot G, Bolognese L, Dudek D, et al. N Engl J Med. 2013;369: Background Although P2Y 12 antagonists are effective in patients with non ST-segment elevation (NSTE) acute coronary syndromes, the effect of the timing of administration before or after coronary angiography is not known. We evaluated the effect of administering the P2Y 12 antagonist prasugrel at the time of diagnosis versus administering it after the coronary angiography if percutaneous coronary intervention (PCI) was indicated. Methods We enrolled 4033 patients with NSTE acute coronary syndromes and a positive troponin level who were scheduled to undergo coronary angiography within 2 to 48 hours after randomization. Patients were randomly assigned to receive prasugrel (a 30-mg loading dose) before the angiography (pretreatment group) or placebo (control group). When PCI was indicated, an additional 30 mg of prasugrel was given in the pretreatment group at the time of PCI and 60 mg of prasugrel was given in the control group. Results The rate of the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy (glycoprotein IIb/IIIa bailout) through day 7, did not differ significantly between the two groups (hazard ratio with pretreatment, 1.02; 95% confidence interval [CI], 0.84 to 1.25; P = 0.81). The rate of the key safety end point of all Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, whether related or not related to coronary-artery bypass grafting (CABG), through day 7 was increased with pretreatment (hazard ratio, 1.90; 95% CI, 1.19 to 3.02; P = 0.006). The rates of TIMI major bleeding and life-threatening bleeding not related to CABG were increased by a factor of 3 and 6, respectively. Pretreatment did not reduce the rate of the primary outcome among patients undergoing PCI (69% of the patients) but increased the rate of TIMI major bleeding at 7 days. All the results were confirmed at 30 days and in prespecified subgroups. Conclusions Among patients with NSTE acute coronary syndromes who were scheduled to undergo catheterization, pretreatment with prasugrel did not reduce the rate of major ischemic events up to 30 days but increased the rate of major bleeding complications. Current guidelines of the American College of Cardiology/American Heart Association (ACC/AHA) recommend pretreatment with the P2Y 12 inhibitor clopidogrel in patients with non-stsegment elevation myocardial infarction (NSTEMI) acute coronary syndromes (ACS) scheduled to undergo percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and this strategy has become common clinical practice. The recommendation is based on two randomized studies suggesting that clopidogrel pretreatment could reduce ischemic events, albeit with an increased risk for major bleeding. The practice of pretreatment has been extended to include the use of the more potent and rapidly acting P2Y 12 inhibitors prasugrel and ticagrelor, which were shown in two comparative clinical trials to be more effective than clopidogrel in patients with ACS, but also increased the risk for bleeding complications. In one trial, the P2Y 12 inhibitors were administered only after the coronary anatomy was confirmed by angiography to deem an indication of PCI, whereas the protocol for the other called for pretreatment before cardiac catheterization. To evaluate the effects of the timing of prasugrel administration, Montalescot and colleagues designed the ACCOAST (Comparison of Prasugrel at the Time of Sponsored by Albert Einstein College of Medicine of Yeshiva University This CME activity was supported by an educational grant from Daiichi Sankyo, Inc. and Lilly USA, LLC Produced by

2 April Percutaneous Coronary Intervention [PCI] or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction) trial, a phase-3, randomized, double-blind, event-driven study conducted at 171 centers in 19 countries. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction (MI), stroke, urgent revascularization, or GP IIb/IIIa inhibitor rescue therapy at 7 days. The primary safety end point was all Thrombolysis in Myocardial Infarction (TIMI)-defined major bleeding, both coronary artery bypass grafting (CABG)-related and non-cabg-related at 7 days. Both primary end points were confirmed at day 30 and within prespecified subgroups. After randomization, 2037 patients were pretreated with prasugrel (30-mg loading dose) prior to coronary angiography; those for whom PCI was indicated received a second 30-mg dose at the time of the procedure. The control group of 1996 patients received placebo before coronary angiography, and those undergoing PCI received a 60-mg loading dose of prasugrel. PCI was performed in 69% of all patients; another 6% underwent CABG, and 25% were managed medically. Through day 7, there was no difference in the occurrence of the primary efficacy end point between the pretreatment group (10.0%) and the control group (10.0% vs 9.8%, P=.81; Figure) nor in any of the components of the primary efficacy end point (P>.44). Identical rates of the primary efficacy end point through day 7 occurred in the two groups within the cohort of patients who underwent PCI (13.1% in each, P=.93). Similarly, rates of the primary efficacy end point in the pretreatment and control groups were not significantly different at day 30 (10.8% in each, P=.98). Pretreatment with prasugrel did not decrease the rate of ischemic events during the period prior to coronary angiography (0.8% vs 0.9% with no pretreatment, P=.93). For the primary safety end point, however, patients in the pretreatment group had significantly higher rates of CABGrelated or non-cabg-related TIMI major bleeding than those in the control group (2.6% vs 1.4%, P=.006; Figure). A Primary Efficacy End Point Patients with End-Point Event (%) B All TIMI Major Bleeding The incidence of all non-cabg-related TIMI major bleeding in the pretreatment group was three times that in the control group (1.3% vs 0.5%, P=.003), and the incidence of non-cabg-related lifethreatening bleeding was increased by a factor of 6 (0.8% vs 0.2%, P=.002). Pretreatment with prasugrel, however, was not associated with an increased rate of fatal bleeding, and no instances of 15 Hazard ratio at day 7, 1.02 Hazard ratio at day 30, (95% CI, ) (95% CI, ) P=.81 P=.98 Pretreatment No pretreatment 5 No. at Risk No pretreatment 1996 Pretreatment 2037 Patients with End-Point Event (%) No. at Risk No pretreatment 1996 Pretreatment Hazard ratio at day 7, 1.90 (95% CI, ) P=.006 Days since First Loading Dose Pretreatment Hazard ratio at day 30, 1.97 (95% CI, ) P= No pretreatment Days since First Loading Dose MI = myocardial infarction; GP = glycoprotein; TIMI = Thrombolysis in Myocardial Infarction; CABG = coronary artery bypass grafting; NSTEMI = non-st-segment elevation myocardial infarction; ACS = acute coronary syndromes; PCI = percutaneous coronary intervention Figure. Comparison of outcomes for primary efficacy end point (A; cardiovascular death, MI, stroke, urgent revascularization, or GP IIb/IIIa inhibitor rescue therapy) and primary safety end point (B; all TIMI major bleeding, both CABG-related and non- CABG-related) between patients with NSTEMI ACS receiving pretreatment with prasugrel before PCI and those not receiving pretreatment (control group), at day 7 and through day 30. Reprinted with permission from N Engl J Med. 2013;369: Copyright 2013 Massachusetts Medical Society. All rights reserved. 2.9

3 3 Intervention & Prevention: Keeping Current with Acute Coronary Syndrome intracranial hemorrhage occurred in either group through day 7. Similar patterns in bleeding episodes in the two groups were observed through day 30. The P2Y 12 inhibitor currently recommended for pretreatment in NSTEMI ACS, clopidogrel, does not become biologically and clinically active until several hours after administration, while the newer P2Y 12 inhibitors have a more rapid onset of action. In the ACCOAST trial, a pharmacodynamic study showed that when administered as pretreatment, prasugrel was biologically effective at the time of cardiac catheterization, yet pretreatment did not reduce the risk for ischemic events in the overall patient population or in the PCI cohort. Thus, the results of the ACCOAST trial suggest that the use of prasugrel in patients with NSTEMI ACS be reserved until coronary angiography confirms an indication for PCI. COMMENTARY: SHOULD WE PRETREAT WITH P2Y 12 INHIBITORS PRIOR TO PCI IN PATIENTS WITH NON-ST ELEVATION ACS? Few areas in contemporary ACS management generate as much confusion and controversy as the optimal timing of P2Y 12 inhibitor loading relative to performance of cardiac catheterization and PCI. Two strategies are available: 1) a pretreatment strategy in which the P2Y 12 inhibitor is loaded upstream of cardiac catheterization as soon as possible after presentation, or 2) a deferred strategy in which the P2Y 12 inhibitor is loaded on the cath lab table after the coronary arteries have been visualized and the decision has been made to pursue PCI. The pretreatment strategy offers the potential for protection against ischemia in the waiting period prior to PCI, enhanced antiplatelet coverage during the PCI procedure, and more flexibility to use bivalirudin and avoid GP IIb/IIIa antagonists during PCI, but may expose patients to increased bleeding risks and prolonged hospitalization if CABG is required. The cath lab strategy is logistically simpler and avoids delays for CABG, but could expose patients to increased risks for pre- and periprocedural ischemic complications. The data surrounding this question have been very difficult to reconcile due to a wide variation in the timing of initiation of the three P2Y 12 inhibitors in the pivotal studies demonstrating their efficacy, and heretofore the absence of adequately powered clinical trials comparing pretreatment vs deferred initiation of P2Y 12 inhibitors. Current practice guidelines provide strong support for pretreatment with clopidogrel or ticagrelor, but not with prasugrel. 1 This difference reflects the design of the pivotal clinical trials: in TRITON-TIMI 38, P2Y 12 inhibitors were largely administered at the time of PCI, 2 whereas pretreatment was utilized in the PCI-CURE 3 and PLATO 4 trials. Thus, while clopidogrel and ticagrelor are recommended for pretreatment, prasugrel is recommended to be initiated in the cath lab. 1 The ACCOAST investigators stepped bravely into this data-free zone, randomizing 4033 patients with NSTEMI to either a prasugrel pretreatment strategy (prasugrel 30 mg given upstream and 30 mg at the time of PCI) or a cath lab initiation strategy (prasugrel 60 mg at the time of PCI). 5 Enrollment in the trial was stopped slightly early because the pretreatment arm had an increased risk of TIMI major bleeding (HR 1.90, 95% CI ) and more than a fivefold increase in life-threatening bleeding, with no benefit seen with regard to the primary end point of cardiovascular death, MI stroke, urgent revascularization, or GP IIb/IIIa inhibitor bailout through 7 days (HR 1.02, 95% CI ). The absence of benefit on the efficacy end point occurred despite stronger platelet inhibition seen at the time of PCI in the pretreatment group. This finding adds to a growing list of observations that cast doubt on the hypothesis that greater inhibition of platelet function will improve ACS outcomes. The ACCOAST trial provides definitive and unambiguous direction for the use of prasugrel: This agent should not be initiated until the coronaries have been visualized. Pretreatment with prasugrel exposes patients to a doubling in periprocedural bleeding risks, as well as long delays to CABG, without providing any benefit. Beyond the clear directive for prasugrel, there may also be indirect implications for pretreatment with ticagrelor or clopidogrel. Given the similar high potency and rapid onset of action of ticagrelor, and current recommendations for delaying at least 5 days after ticagrelor discontinuation before CABG, it is tempting to speculate that ticagrelor loading should also be deferred until the time of PCI for invasively managed patients. More difficult to determine is the optimal time to initiate clopidogrel for invasively managed patients. On the one hand, the studies purporting to show a benefit of clopidogrel pretreatment are not applicable to modern ACS management, as the pretreatment period averaged more than a week. 3 As highlighted in ACCOAST, ischemic events occur in fewer than 1% of patients waiting for PCI in the contemporary era, and are not influenced by P2Y 12 inhibitor pretreatment. 5 On the other hand, due to its prolonged onset of action, cath lab initiation of clopidogrel may expose patients to higher risk for periprocedural complications, including stent thrombosis. For these reasons, cath lab initiation of the second-generation P2Y 12 inhibitors (ticagrelor or prasugrel) appears to be emerging as the best strategy for high-risk NSTE ACS patients in whom bleeding risks and cost considerations are not prohibitive. James A. de Lemos, MD REFERENCES: 1. Jneid H, Anderson JL, Wright RS, et al ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60(7): Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001; 358(9281): Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-st-segment elevation acute coronary syndromes. N Engl J Med. 2013; 369(11):

4 April Association between bleeding and mortality among women and men with high-risk acute coronary syndromes: Insights from the Early versus Delayed Provisional Eptifibatide in Acute Coronary Syndromes (EARLY ACS) trial. Kaul P, Tanguay J-F, Newby K, et al. Am Heart J. 2013;166: Background Female sex is an established risk factor for bleeding, which is an important safety end point in patients presenting with non ST-segment elevation acute coronary syndromes (NSTE ACS). However, it is unknown whether the association between bleeding and mortality is modulated by sex in this patient population. Methods We examined the interaction between sex and bleeding and 30-day mortality outcomes among 2,975 women and 6,431 men with high-risk NSTE ACS enrolled in the EARLY ACS trial. The Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria were used to identify moderate or severe bleeds. Results Women were older and had more comorbid disease compared with men. Bleeding rates were higher among women (8.2%) than among men (5.5%; P <.01). However, the association of bleeding and 30-day mortality was stronger among men (odds ratio 5.8, 95% CI ) than among women (odds ratio 1.5, 95% CI ; sex * bleeding interaction P <.01). Sex differences in the association of bleeding and mortality persisted in a landmark analysis of 120-hour survivors. Conclusions In a contemporary high-risk NSTE ACS cohort, women had higher bleeding rates than did men. Paradoxically, the association between bleeding and mortality was worse among men than among women. Bleeding is independently associated with mortality among patients with acute coronary syndromes (ACS), and female sex is an established risk factor for bleeding. Previous studies have suggested that a higher mortality rate among women than men with non-st-segment elevation ACS (NSTE ACS) can be explained by older age and comorbid diseases; however, no sex-modulated association between bleeding and mortality had been established until the recent analysis of EARLY ACS (Early versus Delayed Provisional Eptifibatide in Acute Coronary Syndromes) trial data by Kaul et al, which included 6431 male and 2975 female EARLY ACS patients undergoing percutaneous coronary intervention (PCI). Since the EARLY ACS trial found no differences between the two treatment groups in either the primary or secondary end points, Kaul and colleagues pooled the data for the analysis of bleeding and mortality. Bleeding was defined as any bleeding event that occurred within 120 hours of randomization and met moderate or severe Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria. Data were analyzed according to sex in the overall population and a subset of patients who did not undergo CABG (coronary artery bypass grafting). Thirty-day mortality was significantly higher among patients who had a bleeding event than those who did not, both in the entire population (10.6% vs 2.1%, P<.01) and in those without CABG (12.8% vs 2.1%, P<.01). Ironically, although the rates of GUSTO bleeding were higher in women, the 30-day mortality rates were higher in men, in both the overall population and the subsets of patients who underwent CABG. Bleeding rates were higher among women than men in the entire population (8.2% vs 5.5%), those who underwent CABG (27.3% vs 22.3%, respectively), and women who did not undergo CABG (6.4% vs 2.9%). For all patients with bleeding events, the 30-day mortality rate was 6.7% among women and 13.5% among men; the respective rates among women and men with bleeding events who did not undergo CABG were 6% and 20%. Thus, there was a stronger association of bleeding with 30-day mortality among men than women, with odds ratios (OR) about four times higher in men than women (P<.01 for sex * bleeding). This association persisted in a landmark analysis of 120-day survivors for all patients (OR 2.4 for men vs. OR 0.7 for women; P<.02 for sex * bleeding) and patients who did not undergo CABG (OR 2.6 for men and 0.4 for women; P<.04 for sex * bleeding). The investigators suggested possible explanations for this paradoxical finding, including surveillance bias in favor of women based on their baseline health characteristics (eg, increased age, more comorbidities), more access-site bleeding to be easily identified and treated, a lower rate of clopidogrel discontinuation, and more subjective bleeding assessments among patients not undergoing CABG. COMMENTARY: SEX, BLEEDING, AND DEATH IN ACS The debate continues. In patients with ACS, is bleeding associated with worse outcomes? Or are the patients who are most likely to bleed also the most likely to do poorly, just because they are older and have more comorbidities? It is extremely difficult to tease out the complex interplay between bleeding and death in clinical trials or registries. Not surprisingly, the risk factors for bleeding and poor cardiovascular outcomes (eg, age, renal function, vascular disease, shock) overlap substantially, such that bleeding and general clinical risk scores look very similar. As there will never be a randomized trial of bleeding vs no bleeding, we are left with these imperfect anal-

5 5 Intervention & Prevention: Keeping Current with Acute Coronary Syndrome yses to understand the clinical implications of bleeding and, we hope, improve care. The report from the EARLY ACS trial by Kaul and colleagues confirms some things we already knew while offering new observations that require further explanation. Consistent with other studies, women with ACS are older, have more comorbidities, and are more likely to have a bleeding event compared with men. What was interesting in EARLY ACS is that a bleeding event was significantly more likely to be associated with death in men, whereas there was no excess mortality risk in women. It is not entirely clear why this paradoxical relationship would exist. The authors provide several reasonable hypotheses. Women may be more likely to be classified with a severe bleed due to lower baseline hematocrit levels. Access-site bleeds, which are more common in women, are easier to identify and control, and therefore less likely to lead to death. Also, dual antiplatelet therapy interruption is common after bleeds and associated with worse outcomes (see article by Mehran and colleagues in this issue), but in women the risk may be lower because they have more nonobstructive disease that never required a stent. All these hypotheses require further exploration. There are also some observations from EARLY ACS that do not make intuitive sense and, therefore, raise the possibility that this gender difference was a chance observation. For example, upstream use of eptifibatide reduced death and myocardial infarction in women, but not men, which has not been seen in other ACS trials. Regardless, bleeding will remain a necessary evil as long as we need antithrombotic therapy. Strategies to minimize bleeding by using radial artery access, choosing intravenous agents with short half-lives, appropriately dosing drugs, and minimizing the duration of potent intravenous agents will help mitigate the risk of bleeding and benefit all parties involved, especially patients. Benjamin M. Scirica, MD, MPH, FACC A direct comparison of intravenous enoxaparin with unfractionated heparin in primary percutaneous coronary intervention. Collet J-P, Huber K, Cohen M, et al. Am J Cardiol. 2013;112: Intravenous enoxaparin did not reduce significantly the primary end point (p = 0.06) compared with unfractionated heparin (UFH) in the randomized Acute Myocardial Infarction Treated with primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short- and Long-term follow-up (ATOLL) trial. We present the results of the prespecified per-protocol analysis excluding patients who did not receive the treatment allocated by randomization or received both enoxaparin and UFH. We evaluated all-cause mortality, complication of myocardial infarction, procedural failure, or major bleeding (primary end point) and all-cause mortality, recurrent acute coronary syndrome, or urgent revascularization (main secondary end point). Baseline and procedural characteristics were well balanced between the 2 treatment groups. Of 910 randomized patients, 795 patients (87.4%) were treated according to the protocol with consistent anticoagulation using intravenous enoxaparin (n=400) or UFH (n=395). Enoxaparin reduced significantly the rates of the primary end point (relative risk [RR] 0.76, 95% confidence interval [CI] 0.62 to 0.94, p=0.012) and the main secondary end point (RR 0.37, 95% CI 0.22 to 0.63, p<0.0001). There was less major bleeding with enoxaparin (RR 0.46, 95% CI 0.21 to 1.01, p=0.050) contributing to the significant improvement of the net clinical benefit (RR 0.46, 95% CI 0.3 to 0.74, p=0.0002). All-cause mortality was also reduced with enoxaparin (RR 0.36, 95% CI 0.18 to 0.74, p=0.003). In conclusion, in the per protocol analysis of the ATOLL trial, pertinent to >87% of the study population, enoxaparin was superior to UFH in reducing ischemic end points and mortality. The protocol for the ATOLL (Acute Myocardial Infarction Treated with primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short- and Long-term follow-up) study was unique in that it was designed to achieve a head-tohead comparison between enoxaparin and unfractionated heparin (UFH) in patients undergoing percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI) by excluding patients who had received any anticoagulant before randomization, as well as stipulating no crossover to a different anticoagulant after randomization. During the trial, the patients in both groups received similar antiplatelet therapy, and 9 of 10 were treated with the same anticoagulant throughout the treatment period. Although an intent-to-treat (ITT) analysis found a 17% reduction of the composite primary end point (all-cause mortality, complication of myocardial infarction [MI], procedural failure, or major bleeding) in the enoxaparin-treated group, the difference did not reach statistical significance. This publication by Collet et al reports the results of a per-protocol analysis of a population comprised of patients who had not received an anticoagulant at the time of randomization, were administered at least one dose of the randomized treatment before PCI, and received the same anticoagulant treatment after PCI when applicable. Patients who did not receive any anticoagulant at the time of PCI, did not receive the randomized treatment, or were switched to another anticoagulant after PCI were excluded from this analysis. The per-protocol analysis used the same

6 April composite primary end point, composite secondary end point (any death, recurrent acute coronary syndrome [ACS], or urgent revascularization), and main safety end point (major bleeding unrelated to coronary artery bypass graft [CABG] during hospitalization). This per-protocol analysis provided for a true head-to-head comparison of enoxaparin and UFH in patients undergoing PCI. In the ATOLL trial, none of the 910 patients with acute STEMI received an anticoagulant prior to randomization. After excluding patients for protocol violations, a total of 400 patients were treated with enoxaparin (0.5 mg/kg IV bolus and 40 mg/day subcutaneously after PCI) and 396 with UFH (according to current guidelines). All patients received aspirin (75 to 500 mg/day), a thienopyridine, and a glycoprotein (Gp) IIb/IIIa inhibitor according to local practices. At 30 days after PCI, treatment with enoxaparin reduced the composite primary end point by 24% compared with UFH (26.3% vs 34.4%, P=.012). In addition, there were significant reductions in the secondary efficacy end points of allcause mortality (64%, P=.0034) and death or resuscitated cardiac death (67%, P=.001). For the net clinical benefit end point of death, complication of MI, or major bleeding, there was a highly significant reduction with enoxaparin compared with UFH (7.3% vs 15.7%, P=.0002). In addition, fewer enoxaparinthan UFH-treated patients experienced major bleeding (4.9% vs 2.3%, P=.05), the main safety end point. This refined, per-protocol analysis reinforced the findings of the earlier ITT analysis to show that the differences in outcomes after treatment with enoxaparin are significantly better than after treatment with UFH, including all ischemic end points, major bleeding, and net clinical benefit. COMMENTARY: IS ENOXAPARIN A REASONABLE ALTERNATIVE TO UFH IN PRIMARY PCI? Current American College of Cardiology/ American Heart Association (ACC/ AHA) STEMI guidelines list a class I indication for the use of UFH as the periprocedural anticoagulant of choice for patients undergoing primary PCI. 1 Similarly, bivalirudin use carries a class I indication in this patient subset. A direct factor Xa inhibitor, fondaparinux, carries a class III recommendation (suggestion of harm) for use as a sole anticoagulant based on results of the OASIS-6 trial. The role of low-molecular-weight heparins such as enoxaparin remains unclear. One of the inherent attractions of using enoxaparin is lack of need for serial monitoring with activated clotting times (ACTs), similar to bivalirudin. In patients undergoing elective PCI, the STEEPLE trial demonstrated superiority of a single dose of intravenous enoxaparin (both 0.5 and 0.75 mg/kg doses) over UFH for major bleeding; the lower dose was also associated with a significant reduction in all non-cabg related bleeding. 2 No differences in ischemic end points were noted. On the other hand, in the SYNERGY trial of patients with highrisk non-st-elevation acute coronary syndrome undergoing PCI, subcutaneous enoxaparin was similar to intravenous UFH for the primary ischemic end point, but associated with a higher rate of bleeding. 3 Finally, in the ExTRACT-TIMI 25 trial, patients with STEMI undergoing fibrinolysis demonstrated superior ischemic outcomes but higher bleeding rates with subcutaneous enoxaparin for 7 days compared with intravenous UFH for 2 days. 4 The ATOLL trial was conducted to assess the role of enoxaparin in patients with STEMI undergoing primary PCI. In this open-label trial, 910 patients with STEMI undergoing primary PCI were randomized to receive either intravenous enoxaparin (0.5 mg/kg) or intravenous UFH, with target ACT levels in the UFH arm contingent on concomitant Gp IIb/IIIa inhibitor use. The primary results of this trial were published in the Lancet in Enoxaparin failed to demonstrate superiority over UFH for the primary end point of 30-day death, complication of MI, procedure failure, or major bleeding (P=.06), although death, complication of MI, and major bleeding were reduced with enoxaparin. Protocol violations (no anticoagulation, crossover to the other anticoagulant) were observed in 14% of patients in this trial. Thus, while the initial results were presented as intention-to-treat, the authors seek to present the results of the per-protocol analysis in the current analysis. This analysis thus includes 795 patients who were treated exactly as per study protocol. Radial access was utilized in more than two-thirds of all patients, and Gp IIb/ IIIa inhibitors were used in nearly 80% of all patients, with a statistically higher rate of use in patients in the UFH arm. The primary end point of 30-day death, complication of MI, procedure failure, or major bleeding was significantly lower in the enoxaparin arm compared with UFH (26.3% vs 34.4%, P=.012). The primary safety end point of STEEPLE, major bleeding, was also significantly lower in the enoxaparin arm (2.3% vs 4.9%, P=.05), as was all-cause mortality at 30 days (2.5% vs 7.0%, P=.003). These results need to be considered in the light of a negative overall ITT analysis, which is less prone to biases than a per-protocol analysis. The temporal relationship between switching of anticoagulants/crossover and end point ascertainment was also unclear from this analysis. Further randomized controlled trials on this topic, as well as cost-effectiveness analyses, are necessary. Overall, though, these per-protocol results suggest that enoxaparin might be a reasonable alternative to UFH in the management of patients undergoing primary PCI. Based on the results of the ATOLL trial, the updated 2012 European Society of Cardiology (ESC) STEMI guidelines list enoxaparin use (with or without a concomitant Gp IIb/IIIa inhibitor) as a class IIb indication in patients with STEMI undergoing primary PCI; the use of UFH remains a class I indication. 6 The 2013 ACC/AHA STEMI guidelines provide no recommendations for or against enoxaparin use. 1 Dharam J. Kumbhani, MD, SM, MRCP, FACC REFERENCES: 1. American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions, O Gara PT, Kushner FG, Ascheim DD, et al ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of

7 7 Intervention & Prevention: Keeping Current with Acute Coronary Syndrome Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e Montalescot G, White HD, Gallo R, et al; STEEPLE Investigators. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med. 2006;355(10): Ferguson JJ, Califf RM, Antman EM, et al; SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-st-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292(1): Antman EM, Morrow DA, McCabe CH, et al; ExTRACT- TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354(14): Montalescot G, Zeymer U, Silvain J, et al; ATOLL Investigators. Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet. 2011; 378(9792): Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20): Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Mehran R, Baber U, Steg PG, et al. Lancet. 2013;382: Background Dual antiplatelet therapy (DAPT) cessation increases the risk of adverse events after percutaneous coronary intervention (PCI). Whether risk changes over time, depends on the underlying reason for DAPT cessation, or both is unknown. We assessed associations between different modes of DAPT cessation and cardiovascular risk after PCI. Methods The PARIS (patterns of non-adherence to anti-platelet regimens in stented patients) registry is a prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the USA and Europe between July 1, 2009, and Dec 2, Adult patients (aged 18 years or older) undergoing successful stent implantation in one or more native coronary artery and discharged on DAPT were eligible for enrollment. Patients were followed up at months 1, 6, 12, and 24 after implantation. Prespecified categories for DAPT cessation included physician-recommended discontinuation, brief interruption (for surgery), or disruption (non-compliance or because of bleeding). All adverse events and episodes of DAPT cessation were independently adjudicated. Using Cox models with time-varying covariates, we examined the effect of DAPT cessation on major adverse events (MACE [composite of cardiac death, definite or probable stent thrombosis, myocardial infarction, or target-lesion revascularization]). Incidence rates for DAPT cessation and adverse events were calculated as Kaplan-Meier estimates of time to the first event. This study is registered with ClinicalTrials.gov, number NCY Findings We enrolled 5031 patients undergoing PCI, including 5018 in the final study population. Over 2 years, the overall incidence of any DAPT cessation was 57.3%. Rate of any discontinuation was 40.8%, of interruption was 10.5%, and of disruption was 14.4%. The corresponding overall 2 year MACE rate was 11.5%, most of which (74%) occurred while patients were taking DAPT. Compared with those on DAPT, the adjusted hazard ratio (HR) for MACE due to interruption was 1 41 (95% CI ; p=0.10) and to disruption was 1 50 ( ; p=0 004). Within 7 days, 8 30 days, and more than 30 days after disruption, adjusted HRs were 7 04 ( ), 2.17 and 1.3 ( ), respectively. By contrast with patients who remained on DAPT, those who discontinued had lower MACE risk (0.63 [ ]). Results were similar after excluding patients receiving bare metal stents and using an alternative MACE definition that did not include target lesion revascularisation. Interpretation In a real-world setting, for patients undergoing PCI and discharged on DAPT, cardiac events after DAPT cessation depend on the clinical circumstance and reason for cessation and attenuates over time. While most events after PCI occur in patients on DAPT, early risk for events due to disruption is substantial irrespective of stent type. Discontinuation of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with stent implantation whether permanent or temporary is associated with an increased risk for major adverse cardiovascular events (MACE). Until Mehran and colleagues published the results of the PARIS (patterns of nonadherence to antiplatelet regimens in stented patients) registry, however, no associations between the incidence, timing, and reason for DAPT cessation and subsequent cardiac risk had been documented. The PARIS registry was a prospective, multinational observational study in 5018 patients who were followed at 1, 6, 12, and 24 months after PCI for DAPT cessation and any ischemic or bleeding events. DAPT cessation occurred at a rate of 57.3% over 2 years, primarily physicianrecommended discontinuation (40.8%), followed by interruption for surgery (10.5%), and disruption (for 0 to 30 days) due to noncompliance or bleeding (14.4%). Most physician-recommended discontinuations (87%) were for a thienopyridine only aspirin was almost always continued but both agents were discontinued in 70% of DAPT interruptions and 50% of DAPT disruptions. DAPT cessations were less likely to occur in younger patients, patients with drugeluting stent implantation, and patients with a previous myocardial infarction (MI) or coronary artery bypass graft (CABG). Disruptions occurred more often in patients undergoing PCI for acute coronary syndromes. The cumulative incidence of MACE was 11.5%, and most events (74%) occurred in patients while on DAPT. MACE rates for DAPT discontinuation, interruption, or disruption were remarkably lower: 9%, 5%, and 12%, respec-

8 April Despite years of experience, dozens of well-performed clinical trials, and persistent clinical need, we still do not know the optimal duration of DAPT after stenting. tively. The occurrence of each of the MACE components (spontaneous MI, definite or probable stent thrombosis, target lesion revascularization, or cardiac death) followed similar patterns in the on-dapt, discontinuation, interruption, and disruption cohorts. Recommended DAPT discontinuation was associated with a significantly reduced MACE risk (hazard ratio [HR] 0.63, P=.004), whereas the risk was increased with DAPT interruption (HR 1.41, not significant) or disruption (HR 1.50, P=.004). With disruption, the MACE risk was highest during the first 7 days (HR 7.04, P=.004) and was attenuated thereafter. Additional analyses found that 5.4% of the overall MACE events were statistically attributed to interruption or disruption of DAPT, and with any type of DAPT cessation the risk was highest during the first 6 months after stent implantation. In the PARIS registry, which was designed to capture real-world clinical practice, the highest incidence of MACE occurred during DAPT. These findings suggest that the overall contribution of DAPT cessation to cardiac risk is small and not uniform and should prompt further study of DAPT-cessation patterns and clinical outcomes. COMMENTARY: READDRESSING OPTIMAL DAPT DURATION Despite years of experience, dozens of well-performed clinical trials, and persistent clinical need, we still do not know the optimal duration of DAPT after stenting. Most clinicians choose the duration of DAPT based on the type of stent (eg, bare metal vs drug-eluting, or stent generation), clinical scenario (eg, acute vs stable coronary syndromes), and patient comorbidities (eg, risk of bleeding, required concomitant anticoagulation). Even the two ongoing pivotal randomized trials (PEGASUS 1 and DAPT 2 ) will leave several questions unanswered, as many clinical scenarios were excluded from these studies. Further complicating DAPT management is the uncertainty about the safety of interrupting DAPT for required procedures and understanding the degree of risk associated with the cessation of DAPT before the recommended time. The PARIS registry provides important real-world insight into contemporary DAPT practice patterns. Over 2 years, more than half of all patients stopped DAPT. The PARIS Investigators wisely chose to predefine several different clinical scenarios associated with stopping DAPT. The most common was discontinuation, which indicated the treating physician chose to stop DAPT (40.8%). The next most common scenario was cessation of DAPT due to patient adherence or bleeding, which was termed disruption (14.8%), followed by procedural-related temporary interruption (10.5%). Not surprisingly, the risk of subsequent cardiac events was highest among patients who had unplanned disruptions of DAPT. For these patients, the risk was highest within 1 week of premature disruption. Interruption for intercurrent procedures was associated with a nonsignificant increased risk. Most importantly, there was no increased risk after physician-directed discontinuation, regardless of clinical scenario or stent type. What s interesting about this registry is that more than 40% of physicians continued DAPT for at least 2 years, which is twice as long as the longest recommended treatment duration. The question remains, therefore, how long should DAPT last? Most likely, physicians prolong DAPT in patients at highest risk, but discontinue DAPT at recommended times for lower risk patients. Based on the PARIS registry, it looks like clinical intuition is working, since patients with planned DAPT discontinuation were not at least at increased risk. We can t know, however, if they would have been at even lower risk with extended DAPT, which has been studied in another antiplatelet trial with longer follow-up. 3 It is also reassuring that temporary interruption did not appear to increase the risk of MI or stent thrombosis, presumably because physicians are appropriately timing procedures requiring DAPT interruption. The key messages from this study are, first, to follow the guidelines and second, to stop DAPT only when indicated. Efforts to improve patient adherence will likely have the greatest impact on reducing cardiovascular complications, but the question of how long to treat with DAPT still remains unanswered. Benjamin M. Scirica, MD, MPH, FACC REFERENCES: 1. PEGASUS Trial. Prevention of Cardiovascular Events (eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke) in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS). Accessed February 20, Mauri L, Kereiakes DJ, Normand SL, et al. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am Heart J. 2010;160(6): Scirica BM, Bonaca MP, Braunwald E, et al; TRA 2 P-TIMI 50 Steering Committee Investigators. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2 P-TIMI 50 trial. Lancet. 2012;380(9850): For additional perspective on the question of optimal duration of dual antiplatelet therapy in patients with stents, please see a report on the OPTIMIZE trial, page 12.

9 9 Intervention & Prevention: Keeping Current with Acute Coronary Syndrome Anticoagulation with otamixaban and ischemic events in non-st-segment elevation acute coronary syndromes. The TAO randomized clinical trial. Steg PG, Mehta SR, Pollack CV Jr, et al. JAMA. 2013;310: Importance The optimal anticoagulant for patients with non ST-segment elevation acute coronary syndromes (NSTE-ACS) managed with an invasive strategy remains controversial. Objective To compare the clinical efficacy and safety of otamixaban, a novel intravenous direct factor Xa inhibitor, with that of unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS undergoing a planned early invasive strategy. Design, Setting, And Participants Randomized, double-blind, active-controlled superiority trial that enrolled patients with NSTE-ACS and a planned early invasive strategy, at 568 active sites in 55 countries and conducted between April 2010 and February A planned interim analysis was conducted for otamixaban dose selection. Interventions Eligible participants were randomized to otamixaban (bolus and infusion, at 1 of 2 doses) or unfractionated heparin plus, at the time of percutaneous coronary intervention, eptifibatide. The otamixaban dose selected at interim analysis was an intravenous bolus of mg/kg followed by an infusion of mg/kg per hour. Main Outcomes And Measures The primary efficacy outcome was the composite of all-cause death or new myocardial infarction through day 7. Results Rates of the primary efficacy outcome were 5.5% (279 of 5105 patients) randomized to receive otamixaban and 5.7% (310 of 5466 patients) randomized to receive unfractionated heparin plus eptifibatide (adjusted relative risk, 0.99 [95%CI, ]; P=.93). There were no differences for the secondary end points, including procedural thrombotic complications. The primary safety outcome of Thrombosis in Myocardial Infarction major or minor bleeding through day 7 was increased by otamixaban (3.1% vs 1.5%; relative risk, 2.13 [95%CI, ]; P<.001). Results were consistent across prespecified subgroups. Conclusions And Relevance Otamixaban did not reduce the rate of ischemic events relative to unfractionated heparin plus eptifibatide but did increase bleeding. These findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention. Outcomes following non-st-segment elevation myocardial infarction (NSTEMI) acute coronary syndromes (ACS) have improved greatly with the increasing use of percutaneous coronary intervention (PCI) and combination therapy with potent oral antiplatelet agents and injectable anticoagulants. Nonetheless, a substantial risk for death, myocardial infarction (MI), and thrombotic complications remains. Guidelines recommend unfractionated heparin (UFH), combined with a glycoprotein (GP) IIb/IIIa inhibitor at the time of PCI, despite several disadvantages, including the risk for bleeding. In a phase 2 trial in patients with NSTEMI ACS and a planned invasive strategy, the synthetic intravenous direct factor Xa inhibitor otamixaban reduced the combined outcome of death or MI compared with UFH plus eptifibatide, and with similar rates of bleeding at midrange doses. Steg et al recently reported the results of the TAO (Treatment of Acute Coronary Syndromes with Otamixaban) trial, comparing the efficacy and safety of otamixaban with UFH plus eptifibatide. At randomization, patients undergoing PCI were treated with otamixaban (intravenous [IV] bolus of mg/kg followed by an infusion of mg/kg/h) or UFH (IV bolus of 60 IU/kg followed by an infusion of 12 IU/kg). The active control group received an IV bolus of 180 mcg/kg of eptifibatide immediately before PCI, followed by an infusion of 2.0 mcg/kg/min and a second 180-mcg/kg bolus 10 minutes later. All patients also received aspirin and an approved P2Y 12 inhibitor. Efficacy and safety data accrued at day 7 did not support the use of otamixaban for patients with NSTEMI ACS and planned early PCI. The primary efficacy outcome (death or MI at 7 days) occurred in 5.5% of patients in the otamixaban group and 5.7% in the UFH plus eptifibatide group, for a relative risk (RR) of Rates of the components of the primary efficacy outcome and their RRs also were similar between the groups. When stroke was added to death and MI at day 7 for a secondary outcome, the rates in the otamixaban and UFH plus eptifibatide groups were 5.8% and 5.9%, respectively (RR 0.98). The primary safety outcome, major or minor bleeding meeting the TIMI (Thrombolysis in Myocardial Infarction) criteria, occurred in 3.1% of otamixabantreated patients and 1.5% of UFH plus eptifibatide-treated patients (RR 2.13). Otamixaban was not superior to UFH plus eptifibatide in reducing the risk for ischemic outcomes in patients with NSTEMI ACS undergoing early planned PCI and doubled the risk for bleeding across patient subgroups. COMMENTARY: CAN WE IMPROVE ON CURRENT ADP INHIBITION? The TAO study shows how difficult it is to improve early outcomes in ACS with new antithrombotic regimens. Despite encouraging results of the well-conducted phase 2 study, otamixaban, a direct Xa inhibitor, not only failed to reduce the risk of MI or death, but more than doubled the risk of bleeding when compared with UFH and eptifibatide. This is surprising since there tend to be positive correlations between efficacy and bleeding. There are several potential explanations for the lack of efficacy. Most patients received a nonstudy injectable anticoagulant before randomization; the time from randomization to angiography

10 April was relatively short; and 85% received an oral adenosine diphosphate (ADP) receptor agonist before randomization. These factors might have mitigated the potential benefit of an IV agent with more predictable pharmacodynamics and a shorter half-life than UFH. Explaining the increased bleeding is more difficult, but could be due to the fact that the investigators chose higher doses of otamixaban to offset the periprocedural thrombotic events observed in the lower doses in the phase 2 study. 1 As with fondaparinux, another Xa inhibitor, procedural anticoagulation appears to require some anti-iia activity to prevent contact thrombosis, unless higher doses of Xa inhibitors are used. The final TAO dose may have prevented thrombosis, but at the price of more bleeding. Another important consideration was the comparator treatment: UFH plus a doublebolus eptifibatide regimen at the time of PCI. Over the past 5 years, Gp IIb/IIIa inhibitor use has declined precipitously. The widespread use of early oral ADP inhibition in general, and the availability of more potent ADP inhibitors in particular, together with the increased bleeding seen in the ACUITY 2 and EARLY ACS 3 trials with routine eptifibatide use, has led to a steady decline in eptifibatide administration. More clinicians choose the direct thrombin (IIa) inhibitor bivalirudin, alone or with provisional Gp IIb/IIIa antagonists, together with a more potent oral ADP antagonist. If approved, cangrelor, an IV ADP inhibitor that was superior to placebo when used with heparin or bivalirudin in the CHAMPION PHOENIX study, 4 will likely further erode Gp IIb/IIIa inhibitor use. Thus, even if TAO had demonstrated some efficacy, or even better safety, it was against an infrequently used regimen. After 2 decades of intense study, it remains a challenge to identify new antithrombotic regimens that can amplify the benefit beyond the currently recommended therapies of ADP inhibition, antithrombotics with heparin or bivalirudin, and provisional Gp IIb/IIIa inhibitors. As seen in the TAO study, promising new drugs must be tested in properly powered trials with carefully adjudicated end points to ensure that the complete risk/benefit profile of any investigational antithrombotic agent is fully understood. Benjamin M. Scirica, MD, MPH, FACC REFERENCES: 1. Sabatine MS, Antman EM, Widimsky P, et al. Otamixaban for the treatment of patients with non-stelevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2009;374(9692): Stone GW, McLaurin BT, Cox DA, et al; ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355: Giugliano RP, White JA, Bode C, et al; EARLY ACS Investigators. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med. 2009;360(21): Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368: Bivalirudin started during emergency transport for primary PCI. Steg PG, van t Hof A, Hamm CW, et al. N Engl J Med. 2013;369: Background Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y 12 inhibitors, and radial-artery PCI access use is unknown. Methods We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-cabg major bleeding. Results Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P = 0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P = 0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P = 0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients. Conclusions Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis. In 2008, the investigators of the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial 1 reported that in patients undergoing percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction, adjunctive treatment with bivalirudin reduced rates of death and major bleeding at 30 days compared with administration of unfractionated heparin (UFH) and glycoprotein (Gp) IIb/IIIa inhibitors; there was, however, an increased rate of acute stent thrombosis associated with bivalirudin treatment. Since that time, clinical practice has evolved with the availability of newer P2Y 12 inhibitors (ticagrelor or prasugrel), a decrease in the use of Gp IIb/IIIa inhibitors, increased use of radial artery access for PCI, and earlier initiation of intravenous anticoagulation therapy often during transport to the hospital. To evaluate whether the improved outcomes with bivalirudin persisted in contemporary clinical practice and after initiation of treatment during transport, Steg and colleagues designed the EUROMAX (European Ambulance