Intravenous Platelet Blockade with Cangrelor During PCI

The new england journal of medicine

original article

Intravenous Platelet Blockade with Cangrelor during PCI

Deepak L. Bhatt, M.D., M.P.H., A. Michael Lincoff, M.D., C. Michael Gibson, M.D., Gregg W. Stone, M.D., Steven McNulty, M.S., Gilles Montalescot, M.D., Ph.D., Neal S. Kleiman, M.D., Shaun G. Goodman, M.D., Harvey D. White, D.Sc., Kenneth W. Mahaffey, M.D., Charles V. Pollack, Jr., M.D., Steven V. Manoukian, M.D., Petr Widimsky, M.D., Dr.Sc., Derek P. Chew, M.B., B.S., M.P.H., Fernando Cura, M.D., Ivan Manukov, M.D., Frantisek Tousek, M.D., M. Zubair Jafar, M.D., Jaspal Arneja, M.D., Simona Skerjanec, Pharm.D., and Robert A. Harrington, M.D., for the CHAMPION PLATFORM Investigators*

Abstract

Background Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) recep- The authors’ affiliations are listed in the tor antagonist, might reduce ischemic events during percutaneous coronary interven- Appendix. Address reprint requests to Dr. Bhatt at VA Boston Healthcare System, tion (PCI). 1400 VFW Pkwy., Boston, MA 02132, or at [email protected]. Methods In this double-blind, placebo-controlled study, we randomly assigned 5362 patients *Investigators in the Cangrelor versus Standard Therapy to Achieve Optimal who had not been treated with clopidogrel to receive either cangrelor or placebo at Management of Platelet Inhibition the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a (CHAMPION) PLATFORM trial are listed composite of death, myocardial infarction, or ischemia-driven revascularization at in the Supplementary Appendix, available with the full text of this article at 48 hours. Enrollment was stopped when an interim analysis concluded that the NEJM.org. trial would be unlikely to show superiority for the primary end point. This article (10.1056/NEJMoa0908629) Results was published on November 15, 2009, at NEJM.org. The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor N Engl J Med 2009;361. group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P = 0.17) (modified intention- Copyright © 2009 Massachusetts Medical Society. to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P = 0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P = 0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P = 0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas.

Conclusions The use of periprocedural cangrelor during PCI was not superior to placebo in re- ducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)

10.1056/nejmoa0908629 nejm.org 1

lockade of the platelet adenosine PCI trial,16 which compared the use of cangrelor diphosphate (ADP) receptor has been dem- with the use of 600 mg of clopidogrel given at the Bonstrated to improve cardiovascular out- start of the PCI procedure, are also reported in comes in patients undergoing percutaneous cor- this issue of the Journal. o n a r y i n t e r v e n t i o n ( P C I ) . 1-5 I n p a t i e n t s u n d e r g o i n g coronary stenting, ticlopidine given with aspirin Methods was found to decrease the risk of stent thrombosis and other important ischemic complications, Patients as compared with aspirin alone or aspirin plus A total of 5362 patients who provided consent warfarin.6 Ticlopidine was ultimately replaced by were enrolled at 218 sites in 18 countries from clopidogrel as the ADP-receptor blocker of choice October 2006 through May 2009. Patients under- because of the drug’s improved profile for side went randomization according to a double-blind, effects and adverse events.7 placebo-controlled, double-dummy design to re- Despite its efficacy, clopidogrel has a delayed ceive either cangrelor (in a bolus of 30 μg per onset of action, even when given with a loading kilogram of body weight and an infusion of 4 μg dose; it also does not provide complete ADP-recep- per kilogram per minute) or a placebo bolus and tor inhibition and has substantial variability among infusion for the duration of the PCI procedure, patients.8 Even in the contemporary era, the vex- with a minimum infusion duration of 2 hours ing problem of acute stent thrombosis has not and a maximum of 4 hours. Patients in the can- been eliminated.9,10 Moreover, many physicians grelor group received 600 mg of clopidogrel after refrain from administering clopidogrel before ob- the end of the cangrelor infusion, and those in taining angiographic definition of the coronary the placebo group received 600 mg of clopidogrel anatomy, since this irreversible platelet inhibitor at the end of the procedure (Fig. 1). has been associated with an increased risk of Inclusion criteria for the trial were an age of perioperative bleeding if coronary-artery bypass at least 18 years, diagnostic coronary angiogra- grafting (CABG) is required rather than PCI. In phy revealing at least one atherosclerotic lesion addition, more potent oral ADP-receptor blockers amenable to PCI with or without stent implanta- have been tested and found to reduce ischemic tion, and evidence of either myocardial infarction outcomes even further but also increase the rate without ST-segment elevation or unstable angina. of bleeding.11-15 Therefore, an even more potent Patients with stable angina were initially eligible intravenous agent with fast onset and fast offset at the beginning of the trial before a protocol of action might provide a desirable combination amendment. The diagnosis of non–ST-segment of protection from ischemia without an excessive elevation myocardial infarction required a level risk of bleeding. of troponin I or troponin T that was higher than Cangrelor (the Medicines Company) is an ade- the upper limit of the normal range within 24 nosine triphosphate analogue that reversibly binds hours before randomization (or if troponin re- to and inhibits the P2Y12 ADP receptor. It has a sults were unavailable at that time, a level of half-life of 3 to 6 minutes and, when given as a creatine kinase–myocardial band [CK-MB] isoen- bolus plus infusion, quickly and consistently in- zyme that was higher than the upper limit of the hibits platelets to a high degree, with normaliza- normal range). The diagnosis of unstable angina tion of platelet function within 60 minutes after required ischemic chest discomfort occurring at discontinuation. In the Cangrelor versus Standard rest and lasting for at least 10 minutes within 24 Therapy to Achieve Optimal Management of hours before randomization and dynamic electro- Platelet Inhibition (CHAMPION) PLATFORM trial, cardiographic changes; an age of 65 years or older which we report here, we examined the efficacy or the presence of diabetes mellitus (or both) was of cangrelor versus placebo administered to pa- also required. All patients provided written in- tients during PCI, with patients in the placebo formed consent. group subsequently receiving a loading dose of Exclusion criteria included the use of any 600 mg of clopidogrel at the end of the revascu- thienopyridine in the previous 7 days, a planned larization procedure and patients in the cangrelor staged PCI procedure in which the second stage group receiving 600 mg of clopidogrel at the end would occur within 30 days after the first proce- of the infusion. The results of the CHAMPION dure, admission planned within 12 hours after

2 10.1056/nejmoa0908629 nejm.org

PCI, the occurrence of myocardial infarction with

ST-segment elevation within 48 hours before ran- 5301 Patients requiring PCI (with or domization, known or suspected pregnancy, lac- without stent, excluding STEMI) tation, increased bleeding risk (the occurrence of underwent randomization ischemic stroke within the previous year or any previous hemorrhagic stroke), intracranial tumor, cerebral arteriovenous malformation, intracranial aneurysm, trauma or major surgery (including 2656 Received cangrelor, 30 µg/kg 2645 Received placebo, 30 µg/kg CABG) within the previous month, current war- bolus and 2654 received 4 µg/kg/min bolus and 4 µg/kg/min infusion infusion for ≥2 hr or the duration of for ≥2 hr or the duration of the farin use, active bleeding, a known international the procedure, whichever was longer procedure, whichever was longer normalized ratio of more than 1.5, a past or present bleeding disorder, a platelet count of less than 100,000 per cubic millimeter, severe hyper- 2627 Received 600-mg placebo 2620 Received 600-mg clopidogrel tension (systolic blood pressure, >180 mm Hg; or capsules immediately after capsules immediately after diastolic blood pressure, >110 mm Hg), or the procedure procedure use of fibrinolytic therapy or a glycoprotein IIb/ IIIa inhibitor in the 12 hours preceding randomization. 2620 Received 600-mg clopidogrel 2607 Received 600-mg placebo capsules immediately after infusion capsules immediately after infusion Primary and Secondary End Points The primary eff icacy end point was a composite of death, myocardial infarction, or ischemia-driven revascularization 48 hours after PCI. The prima- 48 hr after randomization 48 hr after randomization 2654 Included in modified 2641 Included in modified ry analysis was performed on a modified inten- intention-to-treat analysis intention-to-treat analysis tion-to-treat population. Confirmatory analyses 2662 Included in safety analysis 2650 Included in safety analysis 2691 Included in intention-to- 2664 Included in intention-to- were performed on an intention-to-treat popula- treat analysis treat analysis tion. Secondary end points included the individ- ual rates of death, myocardial infarction, new Q-wave myocardial infarction, ischemia-driven revascularization, abrupt vessel closure, or stroke at 48 hours. Rates of death at 30 days and 1 year Follow-up analysis were also recorded. The clinical events commit- Primary and secondary end points at 30 days Death at 6 mo and 1 yr tee adjudicated the rates of myocardial infarction, Q-wave myocardial infarction, ischemia-driven revascularization, stent thromboses, and stroke Figure 1. Enrollment and Outcomes in the Modified Intention-to-Treat (ischemic or hemorrhagic). The definition of Population.AUTHOR: Bhatt RETAKE: 1st All patients who underwent randomization, received at least one2nd dose of a stent thrombosis was based on the Academic Re- FIGURE: 1 of 2 3rd study drug, and underwent the index percutaneous coronaryRevised intervention search Consortium’s definition of definite stent ARTIST: MRL (PCI) were included in the modified intention-to-treat population.SIZE All effi- thrombosis. cacy analyses of the primary and secondary end points were performed in TYPE: Line Combo 4-C H/T After review of the prespecified analyses, we this population. The safety population included all patients who received AUTHOR, PLEASE NOTE: 4 col examined two exploratory end points that were at least one dose of a study drug. Intention-to-treat analyses22p3 were also reported. STEMI denotesFigure has ST-segment been redrawn elevation and type hasmyocardial been reset. infarction. less reliant on the measurement of periprocedural Please check carefully. biomarkers. The exploratory end points, which JOB: 36124 ISSUE: 12-10-09 were composed of prespecified and adjudicated end points, were a composite of death, Q-wave to discern a bleeding effect if present and pro- myocardial infarction, or ischemia-driven revas- vide full disclosure of such bleeding. The defini- cularization and a composite of death, Q-wave tions of all these end points were consistent with myocardial infarction, or stent thrombosis. We those used in the CHAMPION PCI trial.16 compared the rates of bleeding and adverse events The statistical group at the Duke Clinical at 48 hours and examined several bleeding end Research Institute (DCRI) received regular trans- points. None of these events were prespecified as fers of data from the sponsor. The DCRI was re- a primary bleeding end point, since we wanted sponsible for coordinating activities and analyses

10.1056/nejmoa0908629 nejm.org 3

5 (0.2) 5 5 (0.2) 5 84 (3.2) 84 73 (2.8) 73 911 (34.4) 911 141 (5.3) 141 474 (17.9) 474 784 (29.6) 784 1598 (60.3) 1598 2009 (75.8) 2009 1866 (70.4) 1866 191/2646 (7.2) 191/2646 (5.5) 142/2603 221/2649 (8.3) 221/2649 409/2642 (15.5) 409/2642 891/2484 (35.9) 891/2484 (25.7) 680/2641 158/2644 (6.0) 158/2644 799/2633 (30.3) 799/2633 862/2647 (32.6) 862/2647 80.0 (70.0– 92.0) (70.0– 80.0 1335/2477 (53.9) 1335/2477 1966/2638 (74.5) 1966/2638 63.0 (54.0– 71.0) (54.0– 63.0 170.0 (163.0–176.0) 170.0 Placebo (N Placebo 2662)

Safety Population =

9 (0.3) 9 8 (0.3) 8 75 (2.8) 75 76 (2.9) 76 138 (5.2) 138 940 (35.3) 940 477 (17.9) 477 747 (28.1) 747 1584 (59.5) 1584 2017 (75.8) 2017 1915 (71.9) 1915 124/2610 (4.8) 124/2610 208/2650 (7.8) 208/2650 200/2661 (7.5) 200/2661 641/2648 (24.2) 641/2648 377/2651 (14.2) 377/2651 160/2650 (6.0) 160/2650 (36.4) 907/2495 815/2661 (30.6) 815/2661 (31.9) 845/2645 80.0 (70.0– 92.0) (70.0– 80.0 1325/2477 (53.5) 1325/2477 1974/2653 (74.4) 1974/2653 63.0 (54.0– 71.0) (54.0– 63.0 170.0 (163.0–176.0) 170.0 Cangrelor (N Cangrelor 2669)

6 (0.2) 6 5 (0.2) 5 85 (3.2) 85 73 (2.7) 73 918 (34.4) 918 142 (5.3) 142 476 (17.8) 476 792 (29.7) 792 1609 (60.3) 1609 2024 (75.8) 2024 1877 (70.3) 1877 143/2619 (5.5) 143/2619 192/2664 (7.2) 192/2664 411/2659 (15.5) 411/2659 223/2667 (8.4) 223/2667 901/2502 (36.0) 901/2502 (25.7) 683/2659 160/2662 (6.0) 160/2662 806/2651 (30.4) 806/2651 868/2666 (32.6) 868/2666 80.0 (70.0– 92.0) (70.0– 80.0 1347/2494 (54.0) 1347/2494 1979/2656 (74.5) 1979/2656 63.0 (54.0–71.0) 63.0 Placebo (N Placebo 170.0 (163.0–176.0) 170.0 2693)

Intention-to-Treat Population 9 (0.3) 9 8 (0.3) 8 75 (2.8) 75 80 (3.0) 80 145 (5.4) 145 949 (35.2) 949 482 (17.9) 482 755 (28.0) 755 1599 (59.4) 1599 2039 (75.7) 2039 1938 (72.0) 1938 126/2641 (4.8) 126/2641 210/2681 (7.8) 210/2681 381/2682 (14.2) 381/2682 (7.5) 203/2692 918/2525 (36.4) 918/2525 (24.1) 645/2678 162/2681 (6.0) 162/2681 850/2675 (31.8) 850/2675 828/2692 (30.8) 828/2692 80.0 (70.0– 92.0) (70.0– 80.0 1342/2508 (53.5) 1342/2508 1994/2684 (74.3) 1994/2684 63.0 (54.0–71.0) 63.0 170.0 (163.0–176.0) 170.0 Cangrelor (N Cangrelor 2645)

5 (0.2) 5 5 (0.2) 5 84 (3.2) 84 72 (2.7) 72 140 (5.3) 140 909 (34.4) 909 473 (17.9) 473 782 (29.6) 782 1596 (60.3) 1596 2006 (75.8) 2006 1863 (70.4) 1863 191/2641 (7.2) 191/2641 142/2598 (5.5) 142/2598 221/2644 (8.4) 221/2644 409/2637 (15.5) 409/2637 679/2636 (25.8) 679/2636 890/2479 (35.9) 890/2479 158/2639 (6.0) 158/2639 799/2628 (30.4) 799/2628 862/2642 (32.6) 862/2642 80.0 (70.0– 92.0) (70.0– 80.0 1332/2472 (53.9) 1332/2472 1962/2633 (74.5) 1962/2633 63.0 (54.0– 71.0) (54.0– 63.0 Placebo (N Placebo 170.0 (163.0–176.0) 170.0 2656)

9 (0.3) 9 8 (0.3) 8 74 (2.8) 74 75 (2.8) 75 139 (5.2) 139 939 (35.4) 939 475 (17.9) 475 747 (28.1) 747 1578 (59.4) 1578 2015 (75.9) 2015 1909 (71.9) 1909 122/2604 (4.7) 122/2604 206/2644 (7.8) 206/2644 199/2655 (7.5) 199/2655 374/2645 (14.1) 374/2645 640/2642 (24.2) 640/2642 902/2489 (36.2) 902/2489 159/2644 (6.0) 159/2644 812/2655 (30.6) 812/2655 842/2639 (31.9) 842/2639 Modified Intention-to-Treat Population 80.0 (70.0– 92.0) (70.0– 80.0 1324/2472 (53.6) 1324/2472 1972/2647 (74.5) 1972/2647 63.0 (54.0– 71.0) (54.0– 63.0 170.0 (163.0–176.0) 170.0 Cangrelor (N Cangrelor

Baseline Characteristics of the Patients, According to Study Population.* Study to According Patients, the of Characteristics Baseline elevation — no. (%) no. — elevation Peripheral artery disease artery Peripheral Congestive heart failure heart Congestive CABG PTCA or PCI or PTCA Myocardial infarction Myocardial Family history of coronary artery disease artery coronary of history Family Stroke or transient ischemic attack ischemic transient or Stroke Hyperlipidemia Hypertension Current smoker Current Diabetes mellitus Diabetes Missing data Missing Other Hispanic Black Asian White Female Male Medical history — no./total no. (%) no. no./total — history Medical Myocardial infarction without ST-segment without infarction Myocardial Unstable angina — no. (%) no. — angina Unstable Stable angina — no. (%) no. — angina Stable Median height (interquartile range) — cm — range) (interquartile height Median Median weight (interquartile range) — kg — range) (interquartile weight Median Table 1. Table Characteristic Race or ethnic group — no. (%)† no. — group ethnic or Race Sex — no. (%) no. — Sex Median age (interquartile range) — yr — range) (interquartile age Median

4 10.1056/nejmoa0908629 nejm.org

3 (0.1) 3 5 (0.2) 5 9 (0.3) 9 15 (0.6) 15 16 (0.6) 16 95 (3.6) 95 1/2644 (<0.1) 1/2644 2.1 (2.0–2.3) 2.1 29/2644 (1.1) 29/2644 2627 (99.1) 2627 2650 (100.0) 2650 2650 (100.0) 2650 2650 (100.0) 2650 111/2644 (4.2) 111/2644 244/2647 (9.2) 244/2647 497/2650 (18.8) 497/2650 412/2644 (15.6) 412/2644 556/2649 (21.0) 556/2649 1510/2644 (57.1) 1510/2644 2202/2644 1022/2644 (38.7) 1022/2644 1699/2649 (64.1) 1699/2649 1 (<0.1) 1 (0.2) 5 14 (0.5) 14 13 (0.5) 13 81 (3.1) 81 10 (0.4) 10 3/2653 (0.1) 3/2653 2.1 (2.0–2.3) 2.1 19/2653 (0.7) 19/2653 2629 (98.8) 2629 2658 (99.8) 2658 2662 (100.0) 2662 2662 (100.0) 2662 112/2653 (4.2) 112/2653 242/2659 (9.1) 242/2659 484/2660 (18.2) 484/2660 561/2662 (21.1) 561/2662 414/2653 (15.6) 414/2653 2217/2653 (83.6) 2217/2653 1509/2653 (56.9) 1509/2653 1032/2653 (38.9) 1032/2653 1701/2662 (63.9) 1701/2662 4 (0.2) 4 5 (0.2) 5 9 (0.3) 9 15 (0.6) 15 16 (0.6) 16 97 (3.7) 97 1/2653 (<0.1) 1/2653 2.1 (2.0–2.3) 2.1 29/2653 (1.1) 29/2653 2626 (98.4) 2626 2649 (99.3) 2649 2649 (99.3) 2649 2649 (99.3) 2649 115/2667 (4.3) 115/2667 501/2667 (18.8) 501/2667 (9.3) 247/2664 561/2666 (21.0) 561/2666 412/2653 (15.5) 412/2653 2211/2653 (83.3) 2211/2653 1515/2653 (57.1) 1515/2653 1023/2653 (38.6) 1023/2653 1709/2666 (64.1) 1709/2666 1 (<0.1) 1 (0.2) 5 14 (0.5) 14 13 (0.5) 13 10 (0.4) 10 (3.1) 84 3/2667 (0.1) 3/2667 2.1 (2.0–2.3) 2.1 19/2667 (0.7) 19/2667 2630 (97.7) 2630 2659 (98.7) 2659 2663 (98.9) 2663 2663 (98.9) 2663 116/2667 (4.3) 116/2667 245/2689 (9.1) 245/2689 487/2690 (18.1) 487/2690 414/2667 (15.5) 414/2667 565/2692 (21.0) 565/2692 1514/2667 (56.8) 1514/2667 2231/2667 (83.7) 2231/2667 1037/2667 (38.9) 1037/2667 1714/2692 (63.7) 1714/2692 3 (0.1) 3 5 (0.2) 5 9 (0.3) 9 15 (0.6) 15 16 (0.6) 16 95 (3.6) 95 2.1 (2.0–2.3) 2.1 1/2643 (<0.1) 1/2643 29/2643 (1.1) 29/2643 2625 (99.2) 2625 2645 (100.0) 2645 2645 (100.0) 2645 2645 (100.0) 2645 112/2643 (4.2) 112/2643 244/2642 (9.2) 244/2642 497/2645 (18.8) 497/2645 412/2643 (15.6) 412/2643 555/2644 (21.0) 555/2644 1510/2643 (57.1) 1510/2643 2201/2643 (83.3) 2201/2643 1021/2643 (38.6) 1021/2643 1695/2644 (64.1) 1695/2644 1 (<0.1) 1 5 (0.2) 5 14 (0.5) 14 13 (0.5) 13 81 (3.1) 81 10 (0.4) 10 3/2654 (0.1) 3/2654 2.1 (2.0–2.3) 2.1 19/2654 (0.7) 19/2654 2629 (99.0) 2629 2654 (99.9) 2654 2656 (100.0) 2656 2656 (100.0) 2656 112/2654 (4.2) 112/2654 241/2653 (9.1) 241/2653 481/2654 (18.1) 481/2654 414/2654 (15.6) 414/2654 559/2656 (21.0) 559/2656 2218/2654 (83.6) 2218/2654 1509/2654 (56.9) 1509/2654 1033/2654 (38.9) 1033/2654 1699/2656 (64.0) 1699/2656

range) — hr — range) no. (%) no. no. (%) no. (%) Need for urgent CABG urgent for Need Acute stent thrombosis stent Acute New thrombus or suspected thrombus suspected or thrombus New Abrupt vessel closure vessel Abrupt Unsuccessful procedure‡ Unsuccessful Threatened abrupt closure abrupt Threatened No stent or other or stent No 1 Non–drug-eluting Glycoprotein IIb/IIIa Glycoprotein Drug-eluting Low-molecular-weight heparin Low-molecular-weight Missing data Missing Unfractionated heparin Unfractionated 3 Bivalirudin 2 Oral study drug administered — no. (%) no. — administered drug study Oral Median duration of infusion (interquartile infusion of duration Median Infusion administered — no. (%) no. — administered Infusion Bolus administered — no. (%) no. — administered Bolus Intravenous study drug administered — administered drug study Intravenous Angiographic complication (site reported) — reported) (site complication Angiographic No. of target vessels — no./total no. (%) no. no./total — vessels target of No. Type of stent — no./total no. (%) no. no./total — stent of Type Periprocedural medications — no./total no. no./total — medications Periprocedural Percentages may not total 100 because of rounding. CABG denotes coronary-artery bypass grafting, PCI percutaneous coronary intervention, and PTCA percutaneous transluminal coronary angioplasty. Race or ethnic group was self-reported. Data on unsuccessful procedures were available for 2653 patients in the placebo group in the intention-to-treat population, for 2654 patients in the cangrelor group in the modified intention-to-treat population, and for 2653 patients in the cangrelor group in the safety population.

* † ‡

10.1056/nejmoa0908629 nejm.org 5

for the independent data and safety monitoring Results committee and an interim analysis review committee. At the conclusion of the trial, the full data- Patients base was transferred to the DCRI for the primary A total of 5362 patients were included in the in- and secondary analyses. These analyses were per- tention-to-treat population; 61 of these patients formed independently but in collaboration with did not receive a study drug or undergo PCI, the sponsor. One of the trial’s principal academic which left 5301 patients in the primary modified investigators prepared the first draft of the manu- intention-to-treat population (Fig. 1 in the Sup- script, which was then reviewed and edited by plementary Appendix, available with the full text the executive committee and selected members of this article at NEJM.org). Baseline characteris- of the steering committee and site investigators. tics were well matched in the two study groups The sponsor had the right to review but not ap- (Table 1). The majority of patients (59.8%) had prove the final manuscript. The trial’s principal received the diagnosis of myocardial infarction investigators accept full responsibility for the ac- without ST-segment elevation. During PCI, unfrac- curacy and completeness of the reported analyses tionated heparin was the most frequently used and interpretations of the data. antithrombin agent (in 63.9% of patients), and glycoprotein IIb/IIIa inhibitors were used spar- Statistical Analysis ingly (in 9.2% of patients). Drug-eluting stents All efficacy analyses were performed in the mod- were used less often than bare-metal stents (in ified intention-to-treat population, which consist- 38.7% of patients vs. 56.9% of patients). The time ed of all patients who underwent randomization, from hospital admission to PCI was short (me- received at least one dose of a study drug, and dian, 7.9 hours; interquartile range, 3.3 to 24.1). underwent the index PCI. All safety-related analyses were performed on the safety population, Primary End Point which included all patients who received at least The primary end point occurred in 185 of 2654 one dose of a study drug. Patients in the safety patients receiving cangrelor (7.0%) and in 210 of analyses were assigned to a study group on the 2641 patients receiving placebo (8.0%) (odds ra- basis of the treatment they actually received, not tio in the cangrelor group, 0.87; 95% confidence as randomized. Intention-to-treat analyses are also interval [CI], 0.71 to 1.07; P = 0.17) (Table 2 and presented for full disclosure of results. The be- Fig. 2A). (Data were missing for two patients in the tween-group comparison of the primary end point cangrelor group and four in the placebo group.) was performed by calculating an odds ratio with There was no significant between-group differ- accompanying 95% confidence intervals with the ence in the overall rate of myocardial infarction, use of logistic regression. Logistic regression was Q-wave myocardial infarction, or ischemia-driven also used to analyze the majority of the remain- revascularization. ing secondary end points. All reported P values The rate of stent thrombosis at 48 hours was are two-sided, with a P value of less than 0.05 significantly lower in the cangrelor group (0.2%) considered to indicate statistical significance. than in the placebo group (0.6%) (5 vs. 16 pa- The trial had a power of 85% to detect a 25% tients) (odds ratio, 0.31; 95% CI, 0.11 to 0.85; relative reduction in the primary end point, on the P = 0.02), and the difference was still significant assumption that the event would occur in 7.7% at 30 days (Fig. 2B). The rate of death at 48 hours of patients in the placebo group, with a projected was significantly lower in the cangrelor group sample size of 6400 patients. While the trial was (0.2%) than in the placebo group (0.7%) (6 vs. 18 under way and the results were still blinded, an patients) (odds ratio, 0.33; 95% CI, 0.13 to 0.83; adaptive design was prospectively implemented.17 P = 0.02), though at 30 days, this difference was This design allowed for early termination for ei- no longer significant (Fig. 2C, and Table 1 in the ther lack of efficacy or superiority of the primary Supplementary Appendix). end point, for a sample-size increase in the entire Somewhat counterintuitively, in the subgroup trial population, or for a sample-size increase in of 1659 patients who did not have an elevation specified subgroups.17 After a second interim in the troponin level at baseline, the primary end analysis, trial enrollment was terminated because point was reduced in the cangrelor group (4.6%), the review committee decided that the trial was as compared with the placebo group (7.2%) unlikely to show the superiority of cangrelor. (odds ratio, 0.62; 95% CI, 0.41 to 0.95; P = 0.03).

6 10.1056/nejmoa0908629 nejm.org

Table 2. Major End Points at 48 Hours, According to Study Population.*

Odds Ratio Population and End Point Cangrelor Placebo (95% CI) P Value no. (%) Modified intention-to-treat population No. of patients evaluated 2654 2641 Adjudicated end points Death, myocardial infarction, or ischemia-driven revascularization 185 (7.0) 210 (8.0) 0.87 (0.71–1.07) 0.17 (primary end point) Myocardial infarction 177 (6.7) 191 (7.2) 0.92 (0.74–1.13) 0.42 Ischemia-driven revascularization 19 (0.7) 24 (0.9) 0.79 (0.43–1.44) 0.44 Death from any cause 6 (0.2) 18 (0.7) 0.33 (0.13–0.83) 0.02 Stroke 7 (0.3) 5 (0.2) 1.39 (0.44–4.40) 0.57 Stent thrombosis 5 (0.2) 16 (0.6) 0.31 (0.11–0.85) 0.02 Q-wave myocardial infarction 4 (0.2) 8 (0.3) 0.50 (0.15–1.65) 0.25 Exploratory end points Death, Q-wave myocardial infarction, or ischemia-driven revascular- 23 (0.9) 41 (1.6) 0.55 (0.33–0.93) 0.02 ization Death, Q-wave myocardial infarction, or stent thrombosis 13 (0.5) 34 (1.3) 0.38 (0.20–0.72) 0.003 Intention-to-treat population No. of patients evaluated 2691 2664 Adjudicated end points Death, myocardial infarction, or ischemia-driven revascularization 187 (6.9) 213 (8.0) 0.86 (0.70–1.05) 0.15 Myocardial infarction 177 (6.6) 192 (7.2) 0.91 (0.73–1.12) 0.36 Ischemia-driven revascularization 19 (0.7) 26 (1.0) 0.72 (0.40–1.31) 0.28 Death from any cause 8 (0.3) 19 (0.7) 0.42 (0.18–0.95) 0.04 Stroke 7 (0.3) 6 (0.2) 1.16 (0.39–3.44) 0.80 Stent thrombosis 5 (0.2) 16 (0.6) 0.31 (0.11–0.84) 0.02 Q-wave myocardial infarction 4 (0.1) 9 (0.3) 0.44 (0.14–1.43) 0.17 Exploratory end points Death, Q-wave myocardial infarction, or ischemia-driven revascular- 25 (0.9) 44 (1.7) 0.56 (0.34–0.92) 0.02 ization Death, Q-wave myocardial infarction, or stent thrombosis 15 (0.6) 36 (1.4) 0.41 (0.22–0.75) 0.004 Safety population No. of patients evaluated 2660 2646 Adjudicated end points Death, myocardial infarction, or ischemia-driven revascularization 185 (7.0) 212 (8.0) 0.86 (0.70–1.05) 0.14 Myocardial infarction 176 (6.6) 193 (7.3) 0.90 (0.73–1.11) 0.33 Ischemia-driven revascularization 19 (0.7) 25 (0.9) 0.75 (0.41–1.37) 0.36 Death from any cause 7 (0.3) 18 (0.7) 0.39 (0.16–0.92) 0.03 Stroke 7 (0.3) 5 (0.2) 1.39 (0.44–4.40) 0.57 Stent thrombosis 5 (0.2) 16 (0.6) 0.31 (0.11–0.85) 0.02 Q-wave myocardial infarction 4 (0.2) 9 (0.3) 0.44 (0.14–1.44) 0.17 Exploratory end points Death, Q-wave myocardial infarction, or ischemia-driven revascular- 24 (0.9) 42 (1.6) 0.56 (0.34–0.94) 0.03 ization Death, Q-wave myocardial infarction, or stent thrombosis 14 (0.5) 35 (1.3) 0.40 (0.21–0.74) 0.003

* Data were missing for two patients in the cangrelor group and three in the placebo group in the modified intention-to-treat population, for two patients in the cangrelor group and five in the placebo group in the intention-to-treat population, and for two patients in the cangrelor group and four in the placebo group in the safety population.

10.1056/nejmoa0908629 nejm.org 7

Therefore, exploratory analyses were performed Figure 2 (facing page). Kaplan–Meier Curves for the in the overall study population to evaluate the fol- Rate of the Primary End Point, Stent Thrombosis, lowing two composite clinical end points: death, and Death. Q-wave myocardial infarction, or stent thrombo- Panel A shows the rate of the primary efficacy end sis; and death, Q-wave myocardial infarction, or point — a composite of death, myocardial infarction, ischemia-driven revascularization. These end or ischemia-driven revascularization at 48 hours after points were significantly reduced in the cangre- percutaneous coronary intervention (PCI) — in the cangrelor group and the placebo group. Panel B shows lor group (Table 2). the rate of stent thrombosis at 48 hours (at left) and at 35 days (at right) after PCI. Panel C shows the rate Bleeding of death at 48 hours (left) and 35 days (right). In Pan- According to the criteria for major or minor els B and C, which both show landmark analyses of bleeding in the Thrombolysis in Myocardial In- the Kaplan–Meier curves, the value at day 2 has been reset to zero in the right-hand panels. In all three pan- farction (TIMI) study or of severe or moderate els, data are shown for the end points at 30±5 days, bleeding in the Global Utilization of Streptoki- as specified in the protocol. nase and Tissue Plasminogen Activator for Oc- cluded Coronary Arteries (GUSTO) study, the rates of bleeding did not differ significantly between including rates of stent thrombosis and death from the two groups. However, according to criteria of any cause, were significantly reduced in the can- the Acute Catheterization and Urgent Interven- grelor group at 48 hours. Given the mechanism tion Triage Strategy (ACUITY) trial and the crite- of action of cangrelor, these reductions in impor- ria for minor bleeding in the GUSTO trial, the tant clinical outcomes are plausible. rates of major and minor bleeding were signifi- In light of a recent trial of another reversible cantly higher in the cangrelor group (Table 3). ADP-receptor antagonist (the oral agent ticagrelor), The difference in major bleeding according to the potential mechanistic benefits of cangrelor the ACUITY criteria was due to an excess of groin seem even more likely to affect important ische hematomas but not in more serious forms of mic outcomes.14 The Study of Platelet Inhibition bleeding in the cangrelor group. The rates of red- and Patient Outcomes (PLATO) (ClinicalTrials.gov cell transfusion were not significantly different number, NCT00391872) showed a significant (0.9% in the cangrelor group vs. 0.6% in the pla- reduction in mortality among patients receiving cebo group, P = 0.12). Notably, among patients ticagrelor, as compared with those receiving clopi- who were at increased risk for bleeding, such as dogrel, with 6 to 12 months of therapy.14 Al- the elderly and those who had a history of stroke though a periprocedural infusion of cangrelor or transient ischemic attack, the rate of transfu- would not be expected to have as profound a re- sion was not signif icantly higher in the cangrelor duction in mortality against an active control group than in the placebo group (Fig. 2 in the (600 mg of clopidogrel, as was administered in Supplementary Appendix). There was no signifi- the CHAMPION PCI trial), it is conceivable that cant difference in the rate of arrhythmia in the such benefits might be apparent as compared with cangrelor group, as compared with the placebo administering placebo, as was done in our study. group (2.3% vs. 2.4%, P = 0.77). There was a high- Our study raises questions about the appro- er incidence of dyspnea in the cangrelor group priate def inition for and prognostic use of peripro- (1.4%) than in the placebo group (0.5%), with 37 cedural myocardial infarction in patients enter- patients and 14 patients, respectively (P = 0.002) ing a study with raised biomarkers at baseline. (for details on adverse events, see Table 2 in the In such patients short times from admission to Supplementary Appendix). PCI prevent a clear delineation between myocardial infarction that occurred before randomiza- Discussion tion and myocardial infarction that occurred after randomization. In addition, although the inclu- Cangrelor was not superior to placebo in reduc- sion of periprocedural myocardial infarction as ing the composite of death, myocardial infarc- an end point is useful to increase the number of tion, or ischemia-driven revascularization at 48 events in clinical trials, its clinical relevance con- hours after PCI, the primary end point of this tinues to be widely debated.18-21 Our results do study. However, important prespecified second- not show an effect of cangrelor on periproce- ary end points, which are considered exploratory, dural myocardial infarction (as defined in this

8 10.1056/nejmoa0908629 nejm.org

A Primary End Point 10 9.6% Placebo 9 8 8.9% Cangrelor 7 6 5 4

Event Rate (%) 3 2 1 P=0.25 0 0 1 5 10 15 20 25 30 35 Days No. at Risk Cangrelor 2656 2642 2636 2631 2630 2628 2594 569 Placebo 2645 2617 2608 2603 2601 2599 2574 566

B Stent Thrombosis 0.7 0.7 0.61% 0.6 Placebo 0.6

0.5 0.5 0.46% Placebo 0.4 0.4 0.38%

0.3 0.3 Cangrelor

Event Rate (%) 0.19% 0.2 Cangrelor 0.2 0.1 0.1 P=0.02 P=0.65 0.0 0.0 0 12 24 36 48 2 5 10 15 20 25 30 35 Hours Days No. at Risk Cangrelor 2656 2648 2646 2645 2644 2644 2634 2624 2619 2617 2616 2582 569 Placebo 2645 2624 2618 2617 2614 2614 2603 2589 2581 2579 2577 2551 559

C Death 1.2 1.2 1.10% 1.0 P=0.02 1.0 P=0.97

1.10% 0.8 0.8 Placebo 0.68% 0.6 0.6 Cangrelor Placebo 0.4 0.4 Event Rate (%) 0.23% 0.2 Cangrelor 0.2

0.0 0.0 0 12 24 36 48 2 5 10 15 20 25 30 35 Hours Days No. at Risk Cangrelor 2656 2652 2651 2649 2648 2648 2642 2634 2629 2627 2626 2614 1685 Placebo 2645 2635 2629 2627 2623 2623 2617 2604 2599 2596 2595 2586 1667

trial) except in the subgroupAUTHOR: of patientsBhatt with a (e.g., stentRETAKE: thrombosis1st and death). These find- negative troponin test at baseline but do show an ings should lead to 2ndfurther research on the most FIGURE: 2 of 2 3rd effect of cangrelor on more important outcomes appropriate Revisedend points for clinical trials involv- ARTIST: MRL SIZE 6 col TYPE: 10.1056/nejmLine Combooa09086294-C H/Tnejm.org 33p9 9 AUTHOR, PLEASE NOTE: Downloaded from www.nejm.orgFigure on November has been redrawn 15, 2009 and type . For has personal been reset. use only. No other uses without permission. Copyright © 2009 MassachusettsPlease check carefully. Medical Society. All rights reserved.

JOB: 36124 ISSUE: 12-10-09 The new england journal of medicine

Table 3. Bleeding Events at 48 Hours (Safety Population).

Cangrelor Placebo Odds Ratio Event (N = 2662) (N = 2650) (95% CI) P Value no. (%) Access-site bleeding requiring radiologic 8 (0.3) 10 (0.4) 0.80 (0.31–2.02) 0.63 or surgical intervention Hematoma at puncture site ≥5 cm 115 (4.3) 71 (2.7) 1.64 (1.21–2.22) 0.001 <5 cm 150 (5.6) 119 (4.5) 1.27 (0.99–1.63) 0.06 Intracranial hemorrhage 2 (0.1) 1 (<0.1) 1.99 (0.18–21.98) 0.57 Intraocular hemorrhage 0 0 Bleeding requiring surgery 1 (<0.1) 1 (<0.1) 1.00 (0.06–15.92) 1.00 Retroperitoneal hemorrhage 2 (0.1) 1 (<0.1) 1.99 (0.18–21.98) 0.57 Ecchymosis 95 (3.6) 57 (2.2) 1.68 (1.21–2.35) 0.002 Epistaxis 6 (0.2) 12 (0.5) 0.50 (0.19–1.33) 0.16 Oozing at puncture site 125 (4.7) 91 (3.4) 1.39 (1.05–1.83) 0.02 Thrombocytopenia 2 (0.1) 3 (0.1) 0.66 (0.11–3.97) 0.65 Hemodynamic compromise 7 (0.3) 5 (0.2) 1.40 (0.44–4.40) 0.57 Transfusion Any blood 26 (1.0) 16 (0.6) 1.62 (0.87–3.03) 0.13 Platelet 4 (0.2) 2 (0.1) 1.99 (0.37–10.89) 0.43 Red-cell 25 (0.9) 15 (0.6) 1.67 (0.88–3.17) 0.12 Drop in hemoglobin or hematocrit* 33 (1.2) 35 (1.3) 0.94 (0.58–1.51) 0.79 Category of bleeding† ACUITY criteria Minor bleeding 320 (12.0) 246 (9.3) 1.34 (1.12–1.59) 0.001 Major bleeding 147 (5.5) 93 (3.5) 1.61 (1.23–2.10) <0.001 GUSTO criteria Mild bleeding 427 (16.0) 310 (11.7) 1.44 (1.23–1.69) <0.001 Moderate bleeding 20 (0.8) 13 (0.5) 1.54 (0.76–3.09) 0.23 Severe or life-threatening bleeding 9 (0.3) 6 (0.2) 1.50 (0.53–4.21) 0.45 TIMI criteria Minor bleeding 22 (0.8) 16 (0.6) 1.37 (0.72–2.62) 0.34 Major bleeding 4 (0.2) 9 (0.3) 0.44 (0.14–1.44) 0.17

* A drop in hemoglobin or hematocrit was defined as a decrease of at least 3 g per deciliter in hemoglobin or a 9% decrease in hematocrit after treatment, as compared with baseline, as reported by investigators. † The bleeding options under each criterion are not mutually exclusive. For example, a patient may have had both major and minor bleeding on the basis of criteria from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial if more than one bleeding episode occurred. Each patient was counted only once for each criterion level, regardless of the number of bleeding events that were identified under each criterion. Listed bleeding events include bleeding associated with coronary-artery bypass grafting. GUSTO denotes Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries, and TIMI Thrombolysis in Myocardial Infarction.

ing patients with acute coronary syndromes and periprocedural antiplatelet blockade with clopid positive biomarkers at baseline who undergo PCI. ogrel. In the examination of secondary compos- Taken together, the two CHAMPION trials ite end points, there was a more robust effect in may provide insight into the optimal timing of the CHAMPION PLATFORM trial (600 mg of

10 10.1056/nejmoa0908629 nejm.org

Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Intravenous Platelet Blockade with Cangrelor during PCI clopidogrel at the end of the procedure) than in are both reversible platelet ADP-receptor antago- the CHAMPION PCI trial (600 mg of clopidogrel nists that may act through other adenosine-depen- at the beginning of the procedure). Therefore, if dent pathways as well. one contrasts the results of the two CHAMPION The early termination of this study does de- trials, it appears that the 600 mg loading dose crease its statistical power. The primary end of clopidogrel may provide incremental benefit point of this trial was negative; therefore, any when given at the start of the procedure versus additional end points, even prespecified ones, only at the end, though this conclusion remains should be interpreted with caution but may serve speculative. However, even when clopidogrel is to generate hypotheses for future investigations. given at the start of the procedure, the additional The definition of periprocedural myocardial in- antiplatelet blockade conferred by cangrelor may farction that was used in this trial may not have provide clinical benefit, as suggested by the reduc- been a good end point to detect an effect of can- tion in secondary end points in the CHAMPION grelor for patients who had an elevated troponin PCI trial and by the results of the platelet sub- level at baseline and had rapid times to PCI. study in the two CHAMPION trials.16 In conclusion, although the use of cangrelor Cangrelor did not cause more major or minor in our study did not result in a significant reduc- bleeding on the basis of GUSTO and TIMI crite- tion in the primary end point of death, myocar- ria.22,23 However, it did cause more bleeding on dial infarction, or ischemia-driven revasculariza- the basis of the more sensitive ACUITY criteria tion in patients undergoing PCI, in exploratory for major bleeding and GUSTO criteria for mild analyses the rates of important prespecified sec- bleeding, as one might expect for a potent anti- ondary end points of stent thrombosis and death platelet agent, as compared with placebo.24 Re- were reduced. Given the rapid effect on platelet assuringly, there was no significant increase in inhibition seen in the CHAMPION platelet sub- the rate of blood transfusion in the cangrelor study, the reductions in these secondary end points group, as compared with the placebo group, and are biologically plausible. the excess in major bleeding on the basis of Supported by the Medicines Company. ACUITY criteria was because of an increased num- Financial and other disclosures provided by the authors are ber of groin hematomas in the cangrelor group. available with the full text of this article at NEJM.org. We thank Penny Hodgson and Elizabeth Cook of the Duke The occurrence of transient dyspnea is intriguing, Clinical Research Institute for their editorial support; and Med- given a similar observation in the PLATO trial.14 icines Company employees Jayne Prats and Meredith Todd for Perhaps this effect reflects the similar mecha- their assistance in constructing figures and appendices and Bo Gao for his collaboration on statistical analyses. nisms of action of cangrelor and ticagrelor, which

Appendix The affiliations of the authors are as follows: the VA (Veterans Affairs) Boston Healthcare System and Brigham and Women’s Hospital (D.L.B.) and Beth Israel Deaconess Medical Center (C.M.G.) — all in Boston; Cleveland Clinic, Cleveland (A.M.L.); Columbia Univer- sity Medical Center and the Cardiovascular Research Foundation, New York (G.W.S.); Interventional Cardiology and Cardiac Research, Hudson Valley Heart Center, Poughkeepsie, NY (M.Z.J.); Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (S.M., K.W.M., R.A.H.); Institut de Cardiologie, Pitié–Salpêtrière Hospital, Paris (G.M.); Methodist DeBakey Heart Center, Methodist Hospital, Houston (N.S.K.); Terrence Donnelly Heart Centre, Division of Cardiology, St. Michael’s Hospital and the Canadian Heart Research Centre, Toronto (S.G.G.); Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand (H.D.W.); Pennsylvania Hospital, University of Pennsylvania, Philadelphia (C.V.P.); Sarah Cannon Research Institute and Hospital Corporation of America, Nashville (S.V.M.); Third Faculty of Medicine, Charles University, Prague, Czech Republic (P.W.); Flinders University/Flinders Medical Centre, Adelaide, SA, Australia (D.P.C.); the Department of Interventional Cardiology, Instituto Cardiovascular de Buenos Aires, Buenos Aires (F.C.); Clinic of Invasive Cardiology, St. George’s University Hospital, Plovdiv, Bulgaria (I.M.); Regional Hospital, České Budějovice, Czech Republic (F.T.); Arneja Heart Institute, Nagpur, Maharashtra, India (J.A.); and the Medicines Company, Parsippany, NJ (S.S.).

References 1. Yusuf S, Zhao F, Mehta SR, Chrolav- Effects of pretreatment with clopidogrel and fibrinolytic therapy for myocardial in- icius S, Tognoni G, Fox KK. Effects of and aspirin followed by long-term therapy farction with ST-segment elevation. N Engl clopidogrel in addition to aspirin in pa- in patients undergoing percutaneous cor- J Med 2005;352:1179-89. tients with acute coronary syndromes onary intervention: the PCI-CURE study. 4. Sabatine MS, Cannon CP, Gibson CM, without ST-segment elevation. N Engl J Lancet 2001;358:527-33. et al. Effect of clopidogrel pretreatment Med 2001;345:494-502. 3. Sabatine MS, Cannon CP, Gibson CM, before percutaneous coronary intervention 2. Mehta SR, Yusuf S, Peters RJ, et al. et al. Addition of clopidogrel to aspirin in patients with ST-elevation myocardial

10.1056/nejmoa0908629 nejm.org 11

infarction treated with fibrinolytics: the tion — navigating between Scylla and al. Prognostic significance of periproce- PCI-CLARITY study. JAMA 2005;294: Charybdis. N Engl J Med 2007;357:2078- dural versus spontaneously occurring 1224-32. 81. myocardial infarction after percutaneous 5. Steinhubl SR, Berger PB, Mann JT III, 13. Idem. Prasugrel in clinical practice. coronary intervention in patients with et al. Early and sustained dual oral anti- N Engl J Med 2009;361:940-2. acute coronary syndromes: an analysis platelet therapy following percutaneous 14. Wallentin L, Becker RC, Budaj A, et al. from the ACUITY (Acute Catheterization coronary intervention: a randomized con- Ticagrelor versus clopidogrel in patients and Urgent Intervention Triage Strategy) trolled trial. JAMA 2002;288:2411-20. [Er- with acute coronary syndromes. N Engl J trial. J Am Coll Cardiol 2009;54:477-86. ratum, JAMA 2003;289:987.] Med 2009;361:1045-57. 21. Prasad A, Rihal CS, Lennon RJ, Singh 6. Leon MB, Baim DS, Popma JJ, et al. 15. Schömig A. Ticagrelor — is there M, Jaffe AS, Holmes DR. Significance of A clinical trial comparing three anti- need for a new player in the antiplatelet- periprocedural myonecrosis on outcomes thrombotic-drug regimens after coronary- therapy field? N Engl J Med 2009;361: after percutaneous coronary intervention: artery stenting. N Engl J Med 1998;339: 1108-11. an analysis of preintervention and post 1665-71. 16. Harrington RA, Stone GW, McNulty intervention troponin T levels in 5487 pa- 7. Bhatt DL, Bertrand ME, Berger PB, et S, et al. Platelet inhibition with cangrelor tients. Circ Cardiovasc Intervent 2008;1: al. Meta-analysis of randomized and reg- in patients undergoing PCI. N Engl J Med 10-9. istry comparisons of ticlopidine with clo 2009;361. DOI: 10.1056/NEJMoa0908628. 22. Medina HM, Bhatt DL. Evolution of pidogrel after stenting. J Am Coll Cardiol 17. Mehta C, Gao P, Bhatt DL, Harrington anticoagulant and antiplatelet therapy: 2002;39:9-14. RA, Skerjanec S, Ware JH. Optimizing benefits and risks of contemporary phar- 8. Meadows TA, Bhatt DL. Clinical as- trial design: sequential, adaptive, and en- macologic agents and their implications pects of platelet inhibitors and thrombus richment strategies. Circulation 2009; for myonecrosis and bleeding in percuta- formation. Circ Res 2007;100:1261-75. 119:597-605. neous coronary intervention. Clin Cardiol 9. Stone GW, Lansky AJ, Pocock SJ, et al. 18. Harrington RA, Lincoff AM, Califf 2007;30:Suppl 2:II-4–II-15. Paclitaxel-eluting stent versus bare-metal RM, et al. Characteristics and consequenc- 23. Rao AK, Pratt C, Berke A, et al. stents in acute myocardial infarction. es of myocardial infarction after percuta- Thrombolysis in Myocardial Infarction N Engl J Med 2009;360:1946-59. neous coronary intervention: insights from (TIMI) Trial — phase I: hemorrhagic 10. Bavry AA, Bhatt DL. Appropriate use the Coronary Angioplasty Versus Excision- manifestations and changes in plasma of drug-eluting stents: balancing the re- al Atherectomy Trial (CAVEAT). J Am Coll fibrinogen and the fibrinolytic system in duction in restenosis with the concern of Cardiol 1995;25:1693-9. patients treated with recombinant tissue late thrombosis. Lancet 2008;371:2134- 19. Bhatt DL, Topol EJ. Does creatinine plasminogen activator and streptokinase. 43. kinase-MB elevation after percutaneous J Am Coll Cardiol 1988;11:1-11. 11. Wiviott SD, Braunwald E, McCabe CH, coronary intervention predict outcomes 24. Stone GW, McLaurin BT, Cox DA, et et al. Prasugrel versus clopidogrel in pa- in 2005? Periprocedural cardiac enzyme al. Bivalirudin for patients with acute tients with acute coronary syndromes. elevation predicts adverse outcomes. Cir- coronary syndromes. N Engl J Med 2006; N Engl J Med 2007;357:2001-15. culation 2005;112:906-15. 355:2203-16. 12. Bhatt DL. Intensifying platelet inhibi- 20. Prasad A, Gersh BJ, Bertrand ME, et Copyright © 2009 Massachusetts Medical Society.

12 10.1056/nejmoa0908629 nejm.org