ACUTE CORONARY SYNDROME

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1 A supplement to MONTHLY PRESCRIBING REFERENCE September 2014 Issue #19 Intervention & Prevention: Keeping Current with ACUTE CORONARY SYNDROME JOURNAL CLUB Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial Shahzad A, Kemp I, Mars C, et al; HEAT-PPCI trial investigators Lancet Jul 4. [Epub ahead of print] SUMMARY Background Bivalirudin, with selective use of glycoprotein (GP) IIb/IIIa inhibitor agents, is an accepted standard of care in primary percutaneous coronary intervention (PPCI). We aimed to compare antithrombotic therapy with bivalirudin or unfractionated heparin during this procedure. Methods In our open-label, randomised controlled trial, we enrolled consecutive adults scheduled for angiography in the context of a PPCI presentation at Liverpool Heart and Chest Hospital (Liverpool, UK) with a strategy of delayed consent. Before angiography, we randomly allocated patients (1:1; stratified by age [<75 years vs 75 years] and presence of cardiogenic shock [yes vs no]) to heparin (70 U/kg) or bivalirudin (bolus 0.75 mg/kg; infusion 1.75 mg/kg per h). Patients were followed up for 28 days. The primary efficacy outcome was a composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularisation. The primary safety outcome was incidence of major bleeding (type 3 5 as per Bleeding Academic Research Consortium definitions). This study is registered with ClinicalTrials.gov, number NCT Findings Between Feb 7, 2012, and Nov 20, 2013, 1829 of 1917 patients undergoing emergency angiography at our centre (representing 97% of trial-naive presentations) were randomly allocated treatment, with 1812 included in the final analyses. 751 (83%) of 905 patients in the bivalirudin group and 740 (82%) of 907 patients in the heparin group had a percutaneous coronary intervention. The rate of GP IIb/IIIa inhibitor use was much the same between groups (122 patients [13%] in the bivalirudin group and 140 patients [15%] in the heparin group). The primary efficacy outcome occurred in 79 (8.7%) of 905 patients in the bivalirudin group and 52 (5.7%) of 907 patients in the heparin group (absolute risk difference 3.0%; relative risk [RR] 1.52, 95% CI , p=0.01). The primary safety outcome occurred in 32 (3.5%) of 905 patients in the bivalirudin group and 28 (3.1%) of 907 patients in the heparin group (0.4%; 1.15, , p=0.59). Interpretation Compared with bivalirudin, heparin reduces the incidence of major adverse ischaemic events in the setting of PPCI, with no increase in bleeding complications. Systematic use of heparin rather than bivalirudin would reduce drug costs substantially. Funding Liverpool Heart and Chest Hospital, UK National Institute of Health Research, The Medicines Company, AstraZeneca, The Bentley Drivers Club (UK). COMMENTARY: TURNING UP THE HEAT ON BIVALIRUDIN Bivalirudin monotherapy has replaced unfractionated heparin (UFH) as the preferred anticoagulant to support primary percutaneous coronary intervention (PCI) for patients with acute ST-segment elevation myocardial infarction (STEMI) at many medical centers. This is based on data from the HORIZONS-AMI and EUROMAX trials reporting lower bleeding and similar efficacy with bivalirudin compared with UFH. 1,2 However, these trials were not direct comparisons of the Continued on page 3 This CME activity is posted on mycme.com. This CME activity is supported by an educational grant from Daiichi Sankyo, Inc. and Lilly USA, LLC Provided by In collaboration with

2 September two agents, since GP IIb/IIIa inhibitors were mandated in the UFH arm of HORIZONS-AMI and used more than 6 times as often in the UFH arm compared with the bivalirudin arm of EUROMAX. Thus, despite marked increase in the utilization of bivalirudin in STEMI, it is not clear whether this agent offers other advantages over UFH alone when GP IIb/IIIa inhibitors are not routinely administered, particularly if radial access is utilized. In a single-center, open-label trial, the How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) investigators randomized 1829 patients with STEMI undergoing primary PCI to either bivalirudin or UFH, which was administered at a lower dose (70 U/kg) than in many prior trials comparing those agents, including EUROMAX. GP IIb/IIIa inhibitors were not routinely administered, but were allowed as bailout for high thrombus burden or procedural complications. This bold trial incorporated several unique design features that have generated both praise and controversy. First, the investigators randomized patients without first obtaining informed consent, subsequently getting informed consent from survivors once the dust settled. This approach paid clear dividends, allowing for randomization of 100% of eligible participants (unheard of in contemporary clinical trials) and resulting in a widely generalizable study cohort. In contrast to most clinical trials that enroll a selected, lower-risk subset of patients, HEAT enrolled all comers, including patients with the highest acuity. Multiple ethics committees have approved deferral of consent, which is used regularly in resuscitation research, but it is not a standard approach in STEMI trials. While I believe this strategy was appropriate and ethical in this particular study, additional international debate is needed to clarify the situations under which modification of typical informed consent could be considered for comparative effectiveness trials of well-established therapies. The results of the study were quite surprising bivalirudin was clearly inferior to UFH for primary composite efficacy outcome of death, recurrent MI, stroke, or unplanned target lesion revascularization (8.7 vs. 5.7%; RR 1.52, P=.01). The difference in the efficacy end point was largely driven by stent thrombosis, which was notably increased in the bivalirudin group compared with the UFH group (3.4 vs. 0.9%; RR 3.91, P=.001), a finding also seen in HORIZONS-AMI and EUROMAX. 1,2 Rates of major and minor bleeding were similar between the two groups, a finding that differs notably from prior studies. Potential explanations for the similar bleeding rates between UFH and bivalirudin include the low use of GP IIb/IIIa inhibitors (15% in the UFH arm), high rates of radial access (>80%), and the lower dose of UFH used (70 U/kg). This trial should be interpreted in light of several limitations. It is a single-center study that enrolled only a modest number of patients. Moreover, a nonstandard technique was used to measure activated clotting times, although it is not likely that this had a major impact on the study results. Despite these caveats, the trial clearly raises highly relevant questions as to whether the current enthusiasm for bivalirudin is warranted. It highlights major design flaws in the previous trials comparing bivalirudin with UFH, namely that high use of GP IIb/IIIa inhibitors 1,2 or excess dosing of UFH 2 may have contributed to the excess bleeding in the UFH arms of these trials. An emerging theme from HEAT and other recent trials is that switching to lower doses of UFH (ie, 70 U/kg) and limiting GP IIb/ IIIa inhibitors to selective high-risk cases may be a simple strategy to lower bleeding risks with no apparent downside with regard to ischemic complications. Why is this study so important? Simply put, it s the money. In the current era of constrained health care resources, if low-dose UFH is as safe as and more effective than bivalirudin, it would represent exactly the sort of value purchase that health care systems seek. Indeed, it is not actually necessary for UFH to be superior to bivalirudin as was seen in the HEAT trial; with the cost of UFH ~400 times lower than the cost of bivalirudin, demonstrating noninferiority is sufficient. Given these important cost considerations, it is critical that additional studies follow the HEAT and attempt to validate these intriguing findings in additional comparative effectiveness studies. James A. de Lemos, MD REFERENCES 1. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358: Steg PG, van t Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013;369:

3 3 Intervention & Prevention: Keeping Current with Acute Coronary Syndrome Patterns and outcomes of red blood cell transfusion in patients undergoing percutaneous coronary intervention. Sherwood MW, Wang Y, Curtis JP, et al. JAMA. 2014;311: ABSTRACT Importance Studies have shown variation in the use of red blood cell transfusion among patients with acute coronary syndromes. There are no definitive data for the efficacy of transfusion in improving outcomes, and concerning data exist about possible association with harm. Current transfusion practices in patients undergoing percutaneous coronary intervention (PCI) are not well understood. Objective To determine the current patterns of blood transfusion among patients undergoing PCI and the association of transfusion with adverse cardiac outcomes across hospitals in the United States. Design, setting, and participants Retrospective cohort study of all patient visits from the CathPCI Registry from July 2009 to March 2013 that included PCI, excluding those with missing data on bleeding complications or who underwent in-hospital coronary artery bypass graft surgery (N = visits). Main outcomes and measures Transfusion rates in the overall population and by hospital (N = 1431) were the primary outcomes. The association of transfusion with myocardial infarction, stroke, and death after accounting for a patient s propensity for transfusion was also measured. Results The overall rate of transfusion was 2.14% (95% CI, 2.13%-2.16%) and quarterly transfusion rates slightly declined from July 2009 to March 2013 (from 2.11% [95% CI, 2.03%-2.19%] to 2.04% [95% CI, 1.97%-2.12%]; P <.001). Patients who were more likely to receive transfusion were older (mean, 70.5 vs 64.6 years), were women (56.3% vs 32.5%), and had hypertension (86.4% vs 82.0%), diabetes (44.8% vs 34.6%), advanced renal dysfunction (8.7% vs 2.3%), prior myocardial infarction (33.0% vs 30.2%), or prior heart failure (27.0% vs 11.8%). Overall, 96.3% of sites gave a transfusion to less than 5% of patients and 3.7% of sites gave a transfusion to 5% of patients or more. Variation in hospital riskstandardized rates of transfusion persisted after adjustment, and hospitals showed variability in their transfusion thresholds. Receipt of transfusion was associated with myocardial infarction ( events; 4.5% vs 1.8%; odds ratio [OR], 2.60; 95% CI, ), stroke (5011 events; 2.0% vs 0.2%; OR, 7.72; 95% CI, ), and in-hospital death ( events; 12.5% vs 1.2%; OR, 4.63; 95% CI, ), irrespective of bleeding complications. Conclusions and relevance Among patients undergoing PCI at US hospitals, there was considerable variation in blood transfusion practices, and receipt of transfusion was associated with increased risk of in-hospital adverse cardiac events. These observational findings may warrant a randomized trial of transfusion strategies for patients undergoing PCI. SYNOPSIS There is considerable uncertainty surrounding the practice of red blood cell transfusion (RBCT) in patients with acute coronary syndrome. On the one hand, recent evidence suggests that RBCT in patients with ACS or a history of coronary artery disease may increase the risk for myocardial infarction (MI) and death; in contrast, anemia, a known risk factor for exacerbation of ischemia, can be mitigated by increased oxygen delivery through RBCT. To complicate matters, current guidelines make no recommendations at all for patients with ACS in the absence of definitive evidence. Registry-based data indicate that current transfusion practices vary widely for patients with ACS, and transfusion practices for patients undergoing percutaneous coronary intervention (PCI), in particular, are not well-understood. Using the US-based CathPCI Registry, Sherwood et al. conducted a retrospective cohort study of transfusion practice patterns to determine the relationship between RBCT and patient factors and the association between RBCT and clinical outcomes in patients undergoing PCI. Data from 1431 hospitals that contribute to the registry yielded 48,430 of 2,258,711 patients who received RBCT (2.14%). Transfusion recipients were more likely to be older and female, and more often had comorbidities such as hypertension, diabetes, advanced renal dysfunction, a history of MI or congestive heart failure (CHF), and underwent urgent rather than elective PCI. Although the median rate of RBCT was 2.5%, the rates ranged widely across hospitals, from 0.3% to 9.3%. More patients who experienced a bleeding event received transfusions than those who did not, regardless of post-pci hemoglobin values; however, the rate of transfusion among patients who did not experience a bleeding event increased with postprocedural hemoglobin values <8 g/dl. An analysis of transfusion rates according to hospital characteristics found that hospitals with RBCT rates >2.79% had more beds and higher PCI procedural volume, were more likely to be teaching hospitals, and were more likely to use glycoprotein IIb/IIIa antithrombotics than hospitals with low (<1.78%) or medium (1.78% to <2.79%) transfusion rates. Compared with patients who did not receive transfusions, patients who received RBCT were more likely to experience an in-hospital MI, stroke, CHF, cardiogenic shock, or death. After adjustment for patient demographic and disease characteristics, comorbidities, and hospital characteristics, use of RBCT following PCI remained associated with increased risk for the composite of MI, stroke, or in-hospital death (17.4% vs. 3.07%; odds ratio [OR] 3.62). RBCT more than doubled the risk for MI alone (4.54% vs. 1.84%; OR 2.60), carried a nearly 8-fold risk for stroke (2.04% vs. 0.18%; OR 7.72), and increased the risk for in-hospital death by more than 4 times (12.5% vs. 1.17%; OR 4.63). Furthermore, the risk for MI, stroke, and in-hospital mortality increased with each increment of preprocedural hemoglobin value from >10 to <13 g/dl, >13 to

4 September <15 g/dl, and >15 mg/dl (OR 3.62, 5.86, and 8.12, respectively), while the risk was significantly decreased in patients with a preprocedural hemoglobin value <10 g/dl. Based on this retrospective analysis of PCI registry data, transfusion practices vary considerably in the US. Nevertheless, RBCT was significantly associated with adverse in-hospital outcomes, whether patients had or had not experienced a post-pci bleeding event and regardless of preprocedural hemoglobin level. The study authors called for randomized clinical trials of transfusion strategies to guide practitioners managing ACS patients with PCI. A LOT OF EFFORT IN VEIN: EXAMINING TRANSFUSION PRACTICES AND OUTCOMES IN PCI PATIENTS The National Cardiovascular Data Registry s CathPCI registry offers a wealth of information on percutaneous coronary intervention (PCI) practice patterns and outcomes in the United States. 1 The present study analyzes data from over 2 million patients drawn from the majority of US PCI centers, making these data particularly well-suited to capturing US practice patterns in a descriptive sense. It is important to note, though, that participation in the registry is voluntary, and nonparticipating hospitals tend to be smaller and may have fewer resources or choose to employ them differently, potentially impacting generalizability. An important descriptive finding in the present study was the marked variation in rates of transfusion across US PCI centers from nearly 0% to 10%. There was also a modest signal for more transfusion in teaching hospitals, which may reflect a lower threshold to transfuse by trainees than by more experienced clinicians. This type of variation is important because it points to the disproportionate impact of local practice patterns over national or international guidelines, highlighting either a lack of underlying consensus on best practice or a failure to educate and disseminate best practice. In the present case, unfortunately, optimal practice is not clear in the management of higher cardiovascular (CV)-risk patients with respect to transfusion. It is much more challenging, however, to try to understand outcomes associations from large registry studies. Since these are retrospective data, we can only examine associations and cannot draw causal inferences. Furthermore, the fact that the extent of data captured by the registry is limited by logistic constraints limits our ability to adjust for potential confounding. Although multivariable adjustment and propensity modeling using inverse probability weighting was used in this study to try and minimize the impact of differences between patient groups, it is impossible to statistically adjust for factors not captured in the registry. Randomized trials in higher-risk CV patients are lacking. One such trial, Conservative Versus Liberal Red Cell Transfusion in Acute Myocardial Infarction, or CRIT, randomized patients to a liberal (maintain hematocrit [HCT]>30%) vs conservative (maintain HCT>24%) transfusion strategy. 2 Although very small (<50 patients), CRIT did show an adverse signal in the liberal transfusion strategy with respect to heart failure (38% vs 8% in the conservative arm). This study at least raises concern about transfusion causing volume overload in patients with acute coronary syndrome. In the present study, receiving a transfusion was associated with significantly worse short-term outcomes. 3 This finding has been seen repeatedly in various observational contexts, although optimal transfusion thresholds are unclear. 4 The more important question whether transfusion plays a causal role in worse outcomes or is merely a marker for sicker patients who would have done poorly regardless cannot be answered by these data. It is very likely that transfusion acts in large part as a risk marker as seen by the massive differences in in-hospital death for transfused vs nontransfused patients that dwarf observed differences in adverse CV events. All we can say with certainty is that there is a clear need for larger randomized trials to help answer this important clinical question. Sandeep R. Das, MD, MPH REFERENCES 1. American College of Cardiology. National Cardiovascular Data Registry. Accessed June 24, Cooper HA, Rao SV, Greenberg MD, et al. Conservative versus liberal red cell transfusion in acute myocardial Infarction (the CRIT Randomized Pilot Study). Am J Cardiol. 2011;108(8): Sherwood MW, Wang Y, Curtis JP, et al. Patterns and outcomes of red blood cell transfusion in patients undergoing percutaneous coronary intervention. JAMA. 2014;311(8): Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2012; 4:CD

5 5 Intervention & Prevention: Keeping Current with Acute Coronary Syndrome Pharmacodynamic evaluation of switching from ticagrelor to prasugrel in patients with stable coronary artery disease. Results of the SWAP 2 study (Switching Anti Platelet 2). Angiolillo DJ, Curzen N, Gurbel P, et al. J Am Coll Cardiol. 2014;63: ABSTRACT Objectives The goal of this study was to evaluate the pharmacodynamic effects of switching patients from ticagrelor to prasugrel. Background Clinicians may need to switch between more potent P2Y 12 inhibitors because of adverse effects or switch to the use of a once-daily dosing regimen due to compliance issues. Methods After a 3- to 5-day run-in phase with a ticagrelor 180-mg loading dose (LD) followed by a ticagrelor 90-mg twice-daily maintenance dose (MD), aspirin-treated patients (N = 110) with stable coronary artery disease were randomized to continue ticagrelor or switch to prasugrel 10-mg once-daily MD, with or without a 60-mg LD. Pharmacodynamic assessments were defined according to P2Y 12 reaction unit (PRU) (P2Y 12 assay) and platelet reactivity index (vasodilator-stimulated phosphoprotein phosphorylation assay) at baseline (before and after the run-in phase) and 2, 4, 24, and 48 h and 7 days after randomization. Results Platelet reactivity was significantly greater at 24 and 48 h after switching to prasugrel versus continued therapy with ticagrelor, although to a lesser extent in those receiving an LD. Mean PRU remained significantly higher in the combined prasugrel groups versus the ticagrelor group (least-squares mean difference: 46 [95% confidence interval 25 to 67]) and did not meet the primary noninferiority endpoint (upper limit of the confidence interval <45), although PRU in the prasugrel cohort was lower at 7 days than at 24 or 48 h. Accordingly, rates of high on-treatment platelet reactivity were higher at 24 and 48 h in both prasugrel groups. At 7 days, there was no difference in high on-treatment platelet reactivity rate between the combined prasugrel and ticagrelor groups. Conclusions Compared with continued ticagrelor therapy, switching from ticagrelor to prasugrel therapy was associated with an increase in platelet reactivity that was partially mitigated by the administration of an LD. SYNOPSIS The addition of prasugrel or ticagrelor, potent platelet P2Y 12 receptor inhibitors, to aspirin improves the clinical efficacy of clopidogrel/aspirin therapy in patients with acute coronary syndrome (ACS). Both prasugrel and ticagrelor are approved for the management of patients with ACS based on their superiority to clopidogrel in reducing thrombotic events in clinical trials. The key pharmacodynamic differences between the two agents is that prasugrel, a prodrug, has an active metabolite that binds irreversibly to the P2Y 12 receptor and is administered once daily (QD), whereas ticagrelor binds reversibly to the P2Y 12 receptor and is administered twice daily (BID). Angiolillo et al. designed the Switching Anti Platelet 2 (SWAP 2) study to evaluate the effect on platelet reactivity when patients with ACS were switched from ticagrelor to prasugrel therapy, which may be a consideration in patients who experience adverse effects or when QD dosing may improve compliance. They hypothesized that a significant effect on high ontreatment platelet reactivity (HPR) after switching may suggest a pharmacodynamic interaction between the drugs resulting from competition for binding sites. In SWAP 2, patients with stable coronary artery disease (CAD) and on low-dose aspirin therapy received ticagrelor as a loading dose (LD) of 180 mg followed by a BID maintenance dose (MD) of 90 mg for 3 to 5 days. After the run-in phase, 110 patients were randomized to one of three treatment groups: prasugrel as a 60-mg LD followed by a 10-mg QD MD, prasugrel as a 10-mg QD MD, or continuation of the 90-mg QD MD of ticagrelor for 7 days. Platelet reactivity was evaluated before the run-in phase, immediately before the first randomized dose of prasugrel or ticagrelor, and at 2, 4, 24, and 48 hours and at 7 days after the first randomized dose. HPR was categorized as >208 P2Y 12 reaction units (PRU), >230 PRU, and >50% platelet reactivity index (PRI), cutoffs that correlate with established cardiovascular end points. At 7 days, the mean PRU in the combined prasugrel groups was significantly higher than that in the ticagrelor group (95.6 PRU vs PRU), with a betweentreatment difference of 46 PRU (P<.001) (Figure), which exceeded the predetermined limit for noninferiority of 45 PRU (the primary study objective). Similarly, the mean difference in PRI between the combined prasugrel group and the ticagrelor group was 46% (13.6% vs. 30.1%, respectively; P=.004). However, rates of HPR at 7 days were similar between the combined prasugrel and ticagrelor groups using a cutoff for PRU of >208 or >230 (1.5% vs. 3.0%, respectively, for both). Additional analyses showed that of HPR rates at 24 hours and 48 hours were higher for the combined prasugrel groups than the ticagrelor group for all HPR criteria, but there was a nonsignificant lower HPR for prasugrel at 7 days, suggesting that an increase in HPR associated with a switch from ticagrelor to prasugrel therapy in ACS patients may have been at least partially mitigated by administration of a prasugrel LD. The investigators suggested further investigations to determine the optimal timing for switching from ticagrelor to prasugrel and to further understand the pharmacodynamic interactions between these two classes of platelet receptor inhibitors. COMMENTARY: SWITCHING FROM TICAGRELOR TO PRASUGREL: A LITTLE MORE THAN MEETS THE EYE? Both ticagrelor and prasugrel are more potent inhibitors of the P2Y 12 receptor than clopidogrel, and these newer oral antiplatelet agents are more efficacious

6 September than clopidogrel in reducing thrombusmediated cardiovascular events in patients with acute coronary syndromes (ACS) (with revascularization in the case of prasugrel). 1,2 Ticagrelor and prasugrel, however, differ in three key ways: 1. The mechanism of binding on the P2Y 12 receptor differs in location and reversibility. 2. Ticagrelor is given twice daily, while prasugrel is once-daily. 3. Ticagrelor is occasionally associated with dyspnea. Thus, clinicians may want to switch from ticagrelor to prasugrel in some situations (eg, patients who wish to take once-daily medications, experience dyspnea, or have a recurrent event on ticagrelor). Angiolillo and colleagues performed a careful pharmacodynamic evaluation of the switch from ticagrelor to prasugrel in patients with stable coronary artery disease and observed that the platelet reactivity was generally lower with ticagrelor than with prasugrel through 7 days post switching; and a loading dose of prasugrel reduced the platelet reactivity in the early timepoints after switching as compared with a switch to prasugrel 10 mg daily with no loading dose. The explanations for these observations are not clear, but may be related to competition in binding the P2Y 12 receptor, particularly if no loading dose of prasugrel was given, and/or a greater reduction in platelet reactivity with ticagrelor as compared with prasugrel. Limitations of this study include the open-label administration of medications (greater potential for confounding due to other treatments/interventions), arbitrary cut points for the assessment of platelet reactivity, and exclusion of patients with ACS. In any case, it appears prudent to administer a loading dose of 60 mg prasugrel on day 1 of a switch and be aware that for a short time thereafter the level of platelet inhibition may not be maximal on prasugrel 10 mg daily. Whether this translates into an appreciable increase in thrombotic events is unknown. Robert P. Giugliano, MD, SM, FACC, FAHA REFERENCES 1. Wallentin L, Becker RC, Budaj A, et al; for the PLATO Investigators. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361: Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357: Coronary artery bypass graftingrelated bleeding complications in real-life acute coronary syndrome patients treated with clopidogrel or ticagrelor. Hansson EC, Rexius H, Dellborg M, et al. Eur J Cardiothorac Surg Jan 30. [Epub ahead of print] ABSTRACT Objectives Ticagrelor reduces thrombotic events compared with clopidogrel in patients with acute coronary syndrome, but may also increase bleeding complications. Coronary artery bypass grafting (CABG)-related bleeding complications have not previously been compared in clopidogrel and ticagrelor-treated patients outside the controlled environment of clinical trials. Methods Four hundred and five consecutive CABG patients with acute coronary syndrome were included in a prospective observational study. The patients were treated with aspirin and ticagrelor (n = 173) or aspirin and clopidogrel (n = 232). Ticagrelor/clopidogrel was discontinued 5 days before surgery whenever deemed possible. Major bleeding complications according to modified blood conservation using antifibrinolytics in a randomized trial criteria (postoperative blood loss >1500 ml/12 h, re-exploration, red blood cell transfusion >10 units or death because of bleeding) were compared in all patients and when ticagrelor/clopidogrel was discontinued 5 days (n = 280), 2 4 days (n = 40) or 0 1 day before surgery (n = 85). Results Major bleeding complications did not differ significantly between ticagrelor- and clopidogrel-treated patients when all patients were compared (14.5 vs 13.8%, P = 0.89). Likewise, there were no significant differences between ticagrelor and clopidogrel when either drug was discontinued 5 days before surgery (6.8 vs 9.9%, P = 0.40) or 2 4 days before surgery (6.3 vs 25.0%, P = 0.21). When ticagrelor/clopidogrel was discontinued 0 1 day before surgery, there was a strong trend towards higher incidence of major bleeding in ticagrelor-treated patients (41.0 vs 21.7%, P = 0.063). Conclusions There was no difference in major bleeding complications overall or when ticagrelor or clopidogrel was used in accordance with guidelines. In patients on dual antiplatelet medication up to 1 day before surgery, there tended to be more bleeding complications in ticagrelor-treated patients. SYNOPSIS Dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 receptor inhibitor is routinely used in the treatment of patients with acute coronary syndrome (ACS). More potent alternatives to clopidogrel prasugrel and ticagrelor have been developed as a component of DAPT for patients with acute coronary syndromes. Although DAPT reduces the risk for thrombotic events in ACS patients, the risk for excessive bleeding is increased, particularly with the use of prasugrel or ticagrelor. Current guidelines, therefore, indicate that P2Y 12 inhibitors should be discontinued prior to elective surgical procedures while aspirin therapy is continued. Rates of coronary artery bypass grafting (CABG)-related bleeding complications in ACS patients receiving ticagrelor and clopidogrel have been assessed in clinical trials but not in a clinical practice setting. Hansson et al. conducted a prospective observational study in which consecutive patients presenting for acute or urgent CABG were treated with aspirin and clopidogrel (n = 232) or aspirin and ticagrelor (n = 173) prior to surgery. Analysis groups were based on which P2Y 12 receptor inhibitor was administered prior to surgery and on the time between discontinuation of the P2Y 12 receptor inhibitor and the time of surgery. Aspirin therapy was maintained prior to surgery.

7 7 Intervention & Prevention: Keeping Current with Acute Coronary Syndrome The primary end point was major bleeding complications according to a modified definition from the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study that included one or more of the following: postoperative blood loss >1500 ml/12 h; re-exploration due to bleeding; red blood cell transfusion >10 units; or death due to bleeding. There was no significant difference in the overall rate of major bleeding complications between the clopidogrel and ticagrelor groups (13.8% vs. 14.5%, P=.89). Similarly, the occurrence of the individual components of the BART criteria did not differ significantly between the two groups. Neither were significant differences observed between the groups when either clopidgrel (n = 162) or ticagrelor (n = 118) was discontinued >5 days before CABG (9.9% vs. 6.8%, P=.40), and again, prevalences of bleeding >1500 ml/12 h, re-exploration, or transfusions were comparable between the groups. However, there was a difference in major bleeding rates when clopidogrel (n = 24) or ticagrelor (n = 16) was discontinued 2 to 4 days before surgery (25% vs. 6.3%, P=.21) This discontinuation interval was associated with an increase in transfusions in the clopidogrel group compared with the ticagrelor group. Delaying discontinuation of the P2Y 12 receptor inhibitors until the day before or the day of CABG resulted in a strong trend for an increase in major bleeding complications in ticagrelor-treated patients (n = 39) compared with clopidogrel-treated patients (n = 46) (41% vs. 22%, P=.063). In addition, more transfusions and re-explorations were required in the ticagrelor group, although the differences did not reach statistical significance. This observational study showed that when DAPT was used according to current guidelines in ACS patients undergoing CABG in actual clinical practice, the overall incidence of major bleeding complications did not differ between clopidogrel- or ticagrelor-treated patients. Delay of discontinuation of the platelet inhibitor, however, was associated with an increased risk for major bleeding complications. COMMENTARY: HOW LONG MUST I WAIT? TICAGRELOR VS CLOPIDOGREL DISCONTINUATION PRIOR TO CABG In PLATO, ACS patients treated with the ticagrelor had lower all-cause and cardiovascular (CV) mortality versus those treated with clopidogrel, 1 possibly due to an adenosine-mediated mechanism that also contributes to ticagrelor s side effect profile. Since that time, and despite some very vocal detractors, ticagrelor has received the strongest guideline recommendations in both the US and Europe as first-line therapy for acute coronary syndrome. Ticagrelor has faster onset and offset of action and more potent platelet inhibition compared with clopidogrel. With antiplatelet agents, this tends to result in higher bleeding but lower incidence of myocardial infarction (MI), which was seen in the PLATO trial. Note that the original PLATO trial used a very liberal coronary artery bypass graft (CABG)-related bleeding definition, so it s more useful to look at non-cabgrelated bleeding in PLATO, which was higher with ticagrelor versus clopidogrel and offset by an expected modest decrease in MI. 2,3 The present study offers some observational real world experience on ticagrelor vs clopidogrel in clinical practice. 4 It is important to recognize potential shortcomings of the study design. This single-center study reflects care at one Swedish hospital, so data may be less generalizable to other settings. Although with multivariable adjustment there is some ability to account for differences between patients treated with ticagrelor and those treated with clopidogrel, it is impossible to adjust for unmeasured confounding. In addition, knowledge of open-label treatment may have affected subsequent care decisions. With those caveats in mind, we can still get useful information from most well-done studies, including this one. Bleeding and death were similar among patients for whom dual antiplatelet therapy (DAPT) was held for at least 5 days prior to surgery. However, for those patients taken to CABG within 0-1 days of their last ticagrelor dose, there appears to be a signal for increased bleeding (Figure). Although this study was not sufficiently powered to demonstrate this difference as statistically significant, the crude bleeding rates of 41% vs 22% for ticagrelor vs clopidogrel are striking and suggest that taking patients to CABG within 1 day of their last ticagrelor dose may carry a clinically relevant increased risk. The middle category those who stopped DAPT 2 to 4 days pre-cabg is difficult to interpret given the very small number of bleeding events (6 vs 1 for clopidogrel vs ticagrelor). Keeping in mind the earlier caveats, the specific numbers here may not be exact but the principle is probably correct. Holding DAPT for >5 days pre- CABG, continuing lower-dose (75 mg to 100 mg daily) aspirin seems safest from a bleeding risk standpoint for either drug. For ticagrelor, there seems to be a clinically relevant drop-off in bleeding risk after 48 hours, which fits with the shorter half-life and higher antiplatelet potency of the drug. If CABG cannot be delayed >5 days, it would seem prudent to strongly consider a delay of 48 hours unless the patient is truly emergent. Sandeep R. Das, MD, MPH REFERENCES 1. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361: Becker RC, et al. Bleeding complications with the P2Y 12 receptor antagonists clopidogrel and ticagrelor in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Eur Heart J. 2011;32: de Lemos JA, Brilakis ES. No free lunches: balancing bleeding and efficacy with ticagrelor. Eur Heart J. 2011;32: Hansson EC, Rexius H, Dellborg M, et al. Coronary artery bypass grafting-related bleeding complications in reallife acute coronary syndrome patients treated with clopidogrel or ticagrelor. Eur J Cardiothorac Surg Jan 30. [Epub ahead of print]

8 September Optimizing P2Y 12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing. Impact of prasugrel and highdose clopidogrel. Aradi D, Tornyos A, Pintér T, et al. J Am Coll Cardiol. 2014;63: ABSTRACT Objectives This study sought to evaluate the impact of treatment with prasugrel and highdose clopidogrel on the basis of platelet function testing in patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention (PCI). Background The clinical impact of treatment with prasugrel in patients with ACS who have high platelet reactivity (HPR) is unknown. Methods Patients with ACS who were pre-treated with clopidogrel and undergoing successful PCI were enrolled in a single-center, prospective registry. Platelet function was measured 12 to 36 h after PCI with the Multiplate device (Roche Diagnostics GmbH, Mannheim, Germany). Patients with HPR (>46 U) were switched to prasugrel or treated with high-dose clopidogrel, and those without HPR continued treatment with 75 mg of clopidogrel. Results A total of 741 consecutive patients were enrolled in the study between September 2011 and August 2012, and 219 of these patients (29.5%) had HPR. Although platelet reactivity decreased after treatment adjustments in those with HPR, prasugrel provided significantly more potent platelet inhibition compared with high-dose clopidogrel (p < ). Compared with patients without HPR, the risk of all-cause death, myocardial infarction, stent thrombosis, or stroke at 1 year was significantly higher in the high-dose clopidogrel group (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.45 to 3.55; p < ), and patients who were switched to prasugrel had similar outcomes (HR: 0.90; 95% CI: 0.44 to 1.81; p = 0.76). Bleeding Academic Research Consortium (BARC) type 3/5 bleeding was also more frequent in patients treated with high-dose clopidogrel (HR: 2.09; 95% CI: 1.05 to 4.17; p = 0.04) than in patients switched to prasugrel (HR: 0.45; 95% CI: 0.11 to 1.91; p = 0.28). In a multivariate model, HPR with high-dose clopidogrel, but not with prasugrel, was an independent predictor of the composite ischemic endpoint (HR: 1.90; 95% CI: 1.17 to 3.08; p = 0.01). Conclusions Switching patients with ACS who have HPR to treatment with prasugrel reduces thrombotic and bleeding events to a level similar to that of those without HPR; however, there is a higher risk of both thrombotic and bleeding complications with high-dose clopidogrel. SYNOPSIS Treatment with a P2Y 12 inhibitor clopidogrel, prasugrel, or ticagrelor with aspirin is recommended therapy for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Compared with clopidogrel, prasugrel and ticagrelor reduce the occurrence of death, myocardial infarction (MI), or stroke in patients with ACS but are associated with a higher risk for bleeding. Until recently, there was little evidence of potential clinical benefits of switching ACS patients with high ontreatment platelet reactivity (HPR) to treatment with prasugrel. A study by Aradi et al. determined HPR in patients undergoing PCI with stent implantation and pretreated with clopidogrel as either a 600-mg loading dose (LD) before admission or 75 mg/d for >5 days) with an adenosine diphosphate test cutoff of 46 U. Patients with HPR after were treated with high-dose clopidogrel (150 mg/d; n = 128) or switched to prasugrel (60-mg LD and 10-mg/d maintenance dose; n = 91) for 1 year at the individual investigator s discretion. Those without HPR (ADP test <46 U; n = 522) were treated with clopidogrel at 75 mg/d as a control cohort. Overall rates of mortality, definite/ probable stent thrombosis, and major bleeding (according to Bleeding Academic Research Consortium [BARC] type 3 or 5 criteria) were 8.1%, 2.8%, and 5.3%, respectively. Analysis for the combined outcome of all-cause mortality or stent thrombosis found a significantly higher risk for the pooled HPR groups compared with the no HPR group (hazard ratio [HR] 2.15, P=.002). However, there was no significant difference between the HPR and no HPR groups in the occurrence of major bleeding events, the primary safety outcome (HR 1.38, P=.33). However, a comparison of the individual HPR groups with the no HPR group showed patients in the high-dose clopidogrel group were significantly more likely to experience the combined primary clinical outcome all-cause mortality, stent thrombosis, nonfatal MI, or stroke at 1 year compared with patients without HPR (HR 2.27, P<.0001), as well as the components of all-cause death (HR 2.77) and all-cause death or stent thrombosis (HR 2.94; P<.0001 for both). The risk for major bleeding was also significantly higher in the high-dose clopidogrel group compared with the no HPR group (HR 2.09, P=.04). In contrast, patients with HPR who were switched to prasugrel after PCI had rates of thrombotic complications similar to those in the no HPR group for the primary clinical outcome (HR 0.90), all-cause death (HR 1.04), or all-cause death or stent thrombosis (HR 1.12). Furthermore, there was no excess of major bleeding in the prasugrel group (HR 0.45). Even when the analysis was adjusted for age and baseline clinical characteristics of the patients with HPR, there was still a 2.5 higher risk for the primary composite outcome in the high-dose clopidogrel group compared with the prasugrel group. Furthermore, a multivariate model found that HPR with high-dose clopidogrel was a significant and independent predictor for thrombotic events at 1 year, while patients with HPR switched to treatment with prasugrel had no increase in these events. In summary, ACS patients with HPR treated with high-dose clopidogrel had a higher risk for both thrombotic events

9 9 Intervention & Prevention: Keeping Current with Acute Coronary Syndrome and major bleeding after PCI, whereas the risk for patients switched to prasugrel treatment had a risk comparable to that of ACS patients without HPR after PCI. Use of high-dose clopidogrel in patients with HPR independently predicted allcause mortality and thrombotic outcomes at 1 year, but use of prasugrel did not. COMMENTARY: SCORE ONE FOR PRASUGREL INSTEAD OF HIGH-DOSE CLOPIDOGREL IN HYPORESPONSIVE PATIENTS Controversy continues to swirl regarding whether and how clinicians should evaluate for and manage patients who have a less-than-expected response (hyporesponse) to standard-dose clopidogrel. In this manuscript, Aradi et al. studied 741 patients with acute coronary syndromes (ACS) who underwent successful percutaneous coronary intervention (PCI). The investigators measured platelet reactivity after standard-dose clopidogrel (load of 600 mg and/or 75 mg daily for >5 days). They identified 219 patients with highplatelet reactivity after standard-dose clopidogrel, and these patients were then switched to either prasugrel (60-mg load, 10 mg daily thereafter) or high-dose clopidogrel as guided by platelet reactivity testing (up to 600-mg loading doses x 4, daily dose 75 or 150 mg). The selection of prasugrel or high-dose clopidogrel was left to the investigator. The authors confirmed prior reports that hyporesponse to standard clopidogrel dosing is common (30% of patient in this study); that such patients have more subsequent thrombotic events; and that more intensive antiplatelet therapy reduces the rate of high platelet reactivity. Novel findings in this study include: 1. Prasugrel was more effective than high-dose clopidogrel in achieving the desired level of antiplatelet effect. 2. Patients who were hyporesponsive to clopidogrel and then switched to prasugrel had fewer thrombotic events and less bleeding than those who were switched to high-dose clopidogrel. 3. Hyporesponders who switched to prasugrel had clinical outcomes similar to those of patients on standard-dose clopidogrel who did not have high platelet reactivity after multivariate adjustment for potential confounders. The limitations of this study include the lack of randomization to prasugrel vs high-dose clopidogrel, increasing the potential for bias and confounding, and the lack of power due to a modest sample size with low clinical event rates. Also the study did not include patients older than 80 years or those on ticagrelor, which is another potential choice in patients with high platelet reactivity on standard-dose clopidogrel. Nevertheless, these data provide support for using prasugrel instead of high-dose clopidogrel in patients who are hyporesponsive to standard clopidogrel dosing. Robert P. Giugliano, MD, SM, FACC, FAHA

10 September ST-segment elevation myocardial infarction treated by radial or femoral approach in a multicenter randomized clinical trial. The STEMI-RADIAL Trial. Bernat I, Horak D, Stasek J, et al. J Am Coll Cardiol. 2014;63: ABSTRACT Objectives This study sought to compare radial and femoral approaches in patients presenting with ST-segment elevation myocardial infarction (STEMI) and undergoing primary percutaneous coronary intervention (PCI) by high-volume operators experienced in both access sites. Background The exact clinical benefit of the radial compared to the femoral approach remains controversial. Methods STEMI-RADIAL (ST Elevation Myocardial Infarction treated by RADIAL or femoral approach) was a randomized, multicenter trial. A total of 707 patients referred for STEMI <12 h of symptom onset were randomized in 4 high-volume radial centers. The primary endpoint was the cumulative incidence of major bleeding and vascular access site complications at 30 days. The rate of net adverse clinical events (NACE) was defined as a composite of death, myocardial infarction, stroke, and major bleeding/vascular complications. Access site crossover, contrast volume, duration of intensive care stay, and death at 6 months were secondary endpoints. Results The primary endpoint occurred in 1.4% of the radial group (n = 348) and 7.2% of the femoral group (n = 359; p = ). The NACE rate was 4.6% versus 11.0% (p = ), respectively. Crossover from radial to femoral approach was 3.7%. Intensive care stay (2.5 ± 1.7 days vs. 3.0 ± 2.9 days, p = ) as well as contrast utilization (170 ±71 ml vs. 182 ± 60 ml, p = 0.01) were significantly reduced in the radial group. Mortality in the radial and femoral groups was 2.3% versus 3.1% (p = 0.64) at 30 days and 2.3% versus 3.6% (p = 0.31) at 6 months, respectively. Conclusions In patients with STEMI undergoing primary PCI by operators experienced in both access sites, the radial approach was associated with significantly lower incidence of major bleeding and access site complications and superior net clinical benefit. These findings support the use of the radial approach in primary PCI as first choice after proper training. SYNOPSIS Primary percutaneous coronary intervention (PCI) is the recommended strategy for the treatment of patients with acute ST-elevation myocardial infarction (STEMI) in North America and Europe and is preferred to thrombolysis for patients who can undergo the procedure in <120 min of the first medical encounter. However, PCI remains associated with a higher risk for major bleeding compared with thrombolysis, and periprocedural major bleeding is an independent predictor of early and late mortality and major adverse cardiovascular events (MACE). Although the use of smaller vascular sheaths and catheters and less intensive antithrombotic regimens have reduced the incidence of periprocedural bleeding, major bleeding remains a significant risk. Several clinical trials have reported a reduction in periprocedural bleeding and access-site complications with the radial approach to PCI compared with the femoral approach. However, these studies had a number of limitations involving patient inclusion and comorbidities, as well as operator experience. The STEMI-RADIAL study was designed to overcome these limitations by comparing the clinical outcomes after a radial or femoral approach in patients presenting with acute STEMI within 12 hours of symptom onset to one of four high-volume centers with operators highly experienced in both access sites. Bernat and colleagues enrolled 707 STEMI patients who were pretreated with acetylsalicylic acid, a 600-mg loading dose of clopidogrel, and a bolus of unfractionated heparin 70 IU/kg or 5,000 IU. Patients were randomized to the radial approach (n=349) or 359 to the femoral approach (n=359. Anticoagulants were discontinued at the end of the procedure, but dual antiplatelet therapy was recommended for the next 12 months. The primary end point was cumulative incidence of major bleeding (defined by Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial [HORIZONS AMI] criteria) and vascular complications at 30 days. Secondary end points included access site crossover, contrast volume, duration of stay in the intensive care unit (ICU), and mortality at 6 months. At 30 days, rates of major bleeding and vascular complications were significantly lower with the radial approach than the femoral approach (1.4% vs. 7.2%, P=.0001), primarily due to a significantly lower rate of hematoma >15 cm (0.6% vs. 5.3%, P=.0002). Gastrointestinal bleeding, a drop in hemoglobin >3 g/dl with overt bleeding, transfusion, and vascular complications occurred at lower rates in the radial group, but the differences did not reach statistical significance. No intracranial, intraocular, or retroperitoneal bleeding occurred in either group. The rate of net adverse clinical outcomes (NACE; bleeding and MACE) also was significantly lower in the radial group at 30 days (4.6% vs. 11%, P=0.0028), although the rates of MACE alone (the composite of death, MI, and stroke) were not significantly different between the groups (3.5% vs. 4.2%, P=0.70). The mortality rate at 30 days was 2.3% in the radial group and 3.1% in the femoral group (P=.64) and remained comparable at 1 year (2.3% vs 3.6%, P=0.31). For the secondary end points, 13 patients randomized to the radial approach crossed over to femoral access, and 2 patients randomized to the femoral approach crossed over to radial access. In addition, the duration of ICU stay was shorter (P=.0016) and contrast volume utilization was lower (P=.01) in the radial group. In STEMI-RADIAL, the radial approach for PCI performed in highvolume centers by experienced operators provided a superior net clinical benefit for