new england

The
journal of medicine
established in 1812 september 10, 2009 vol. 361  no. 11

Ticagrelor versus Clopidogrel in Patients with Acute
Coronary Syndromes
Lars Wallentin, M.D., Ph.D., Richard C. Becker, M.D., Andrzej Budaj, M.D., Ph.D., Christopher P. Cannon, M.D.,
Håkan Emanuelsson, M.D., Ph.D., Claes Held, M.D., Ph.D., Jay Horrow, M.D., Steen Husted, M.D., D.Sc.,
Stefan James, M.D., Ph.D., Hugo Katus, M.D., Kenneth W. Mahaffey, M.D., Benjamin M. Scirica, M.D., M.P.H.,
Allan Skene, Ph.D., Philippe Gabriel Steg, M.D., Robert F. Storey, M.D., D.M., and Robert A. Harrington, M.D.,
for the PLATO Investigators*

A bs t r ac t

Background
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphos- From the Uppsala Clinical Research Cen-
phate receptor P2Y12 that has a more rapid onset and more pronounced platelet ter, Uppsala, Sweden (L.W., C.H., S.J.);
Duke Clinical Research Institute, Durham,
inhibition than clopidogrel. NC (R.C.B., K.W.M., R.A.H.); Grochowski
Hospital, Warsaw, Poland (A.B.); Throm-
Methods bolysis in Myocardial Infarction Study
In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg Group, Brigham and Women’s Hospital,
loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading Boston (C.P.C., B.M.S.); AstraZeneca Re-
search and Development, Mölndal, Swe-
dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 den (H.E.), and Wilmington, DE (J.H.);
patients admitted to the hospital with an acute coronary syndrome, with or without Århus University Hospital, Århus, Den-
ST-segment elevation. mark (S.H.); Universitätsklinikum Heidel-
berg, Heidelberg, Germany (H.K.); World-
Results wide Clinical Trials U.K., Nottingham,
United Kingdom (A.S.); INSERM Unité
At 12 months, the primary end point — a composite of death from vascular causes, 698, Assistance Publique–Hôpitaux de
myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ti- Paris and Université Paris 7, Paris (P.G.S.);
cagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; and the University of Sheffield, Sheffield,
United Kingdom (R.F.S.). Address reprint
95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing requests to Dr. Wallentin at Uppsala
of secondary end points showed significant differences in the rates of other com- ­Clinical Research Center, University Hos-
posite end points, as well as myocardial infarction alone (5.8% in the ticagrelor pital, 75185 Uppsala, Sweden, or at lars.
wallentin@ucr.uu.se.
group vs. 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes
(4.0% vs. 5.1%, P = 0.001) but not stroke alone (1.5% vs. 1.3%, P = 0.22). The rate of *The Study of Platelet Inhibition and Pa-
death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopid­ tient Outcomes (PLATO) investigators
are listed in the Appendix and the Sup-
ogrel; P<0.001). No significant difference in the rates of major bleeding was found plementary Appendix, available with the
between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; full text of this article at NEJM.org.
P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not re-
This article (10.1056/NEJMoa0904327) was
lated to coronary-artery bypass grafting (4.5% vs. 3.8%, P = 0.03), including more published on August 30, 2009, at NEJM.
instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. org.
Conclusions N Engl J Med 2009;361:1045-57.
In patients who have an acute coronary syndrome with or without ST-segment eleva- Copyright © 2009 Massachusetts Medical Society.

tion, treatment with ticagrelor as compared with clopidogrel significantly reduced
the rate of death from vascular causes, myocardial infarction, or stroke without an
increase in the rate of overall major bleeding but with an increase in the rate of non–
procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)
n engl j med 361;11  nejm.org  september 10, 2009 1045
The New England Journal of Medicine
Downloaded from nejm.org on February 12, 2017. For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.

No other uses without permission.73 m2 of body- the Study of Platelet Inhibition and Patient Out. a need for oral anticoagulation PLATO was a multicenter. Ticagrelor was unblinded data.6 resulting in a Patients were eligible for enrollment if they were lower risk of myocardial infarction and stent hospitalized for an acute coronary syndrome.org on February 12. Patients in the clopid­ by Worldwide Clinical Trials. at the academic centers and the sponsor. The details of the design have been concomitant therapy with a strong cytochrome published previously.5. an increased risk of bradycardia.12 In ing myocardial necrosis. tions committee. but is associated with a higher risk or without ST-segment elevation. designed and oversaw the conduct of the Patients were randomly assigned to receive tica­ trial. peripheral arterial disease. The sponsor coordinated the data given in a loading dose of 180 mg followed by a management.P-450 3A inhibitor or inducer. patients who had an acute coronary syndrome ous coronary intervention (PCI). The efficacy of clopidogrel is ecutive and operations committee. in collaboration with investigators syndromes with or without ST-segment eleva. bundle-branch block. ticagrelor at a dose of 90 mg or 180 mg twice coronary artery disease with stenosis of ≥50% in daily and the rate with the use of clopidogrel at at least two vessels. with an onset of major bleeding in patients with an acute coro. all of tion. or cerebral revascularization. at least two of the Ticagrelor. a positive test of a biomarker. is superior to clopidogrel for the prevention of the following two inclusion criteria had to be met: vascular events and death in a broad population persistent ST-segment elevation of at least 0. consisting of both academic members and representatives of the sponsor. and all participants provided writ- patients with a poor response. For patients who had an acute comes (PLATO) to determine whether ticagrelor coronary syndrome with ST-segment elevation. has a more consistent and pronounced Study Patients inhibitory effect on platelets. previous ischemic stroke.11  nejm. greater. 2009 The New England Journal of Medicine Downloaded from nejm. of symptoms during the previous 24 hours. However.6 an in. surface area). and blind trial. manuscript was drafted by the chairs of the ex- rin and clopidogrel. dose-related epi. For personal use only. design was approved by the appropriate national creased risk of bleeding. The study modest and variable platelet inhibition. All rights reserved.10 without ST-segment elevation. double. fibrinolytic therapy within 24 hours before Study Design randomization.14 The executive and opera. with thrombosis. demic authors and who vouch for the accuracy tion of the prodrug to the active metabolite.ischemia. clopidogrel. or chronic ticagrelor. prasugrel.8 and an increased risk and institutional regulatory authorities and ethics of stent thrombosis and myocardial infarction in committees.13 We conducted ance of <60 ml per minute per 1. indicat- sistent P2Y12 inhibition than clopidogrel. indicating tor P2Y12.7.1 mV of patients presenting with an acute coronary in at least two contiguous leads or a new left syndrome. another thienopyridine prodrug. carotid stenosis of at sodes of dyspnea and ventricular pauses on Holter least 50%. and completeness of the reported data. or one of several risk a dose-guiding trial.11.5. Statistical analysis was performed dose of 90 mg twice daily. there was no significant factors (age ≥60 years.org  september 10. diabetes monitoring. transient ischemic attack. . who were aca- hampered by the slow and variable transforma. ment changes on electrocardiography. which occurred more frequently with mellitus. a contract research ogrel group who had not received an open-label 1046 n engl j med 361. provides faster. led to the selection of the dose of 90 mg renal dysfunction. previous myocardial infarc- difference in the rate of bleeding with the use of tion or coronary-artery bypass grafting [CABG].9 As compared with ten informed consent. Copyright © 2009 Massachusetts Medical Society. 2017. and the intention to per- form primary PCI. The recommend dual antiplatelet treatment with aspi.therapy. defined as a creatinine clear- twice daily for further studies. The n e w e ng l a n d j o u r na l of m e dic i n e I n patients who have acute coronary organization. Major exclusion criteria were Me thods any contraindication against the use of clopido­ grel. For nary syndrome who are undergoing percutane. current clinical practice guidelines1-4 whom had full access to the final study data. double-dummy fashion. and more con. administered in a double- board monitored the trial and had access to the blind. a reversible and direct-acting oralfollowing three criteria had to be met: ST-seg- antagonist of the adenosine diphosphate recep. randomized. Astra­ Study Treatment Zeneca. An independent data and safety monitoring grelor or clopidogrel. a dose of 75 mg daily.

hypo­ listed above. quired to achieve 90% power to detect a relative Outpatient visits were scheduled at 1. cular causes. until a repeat assessment at The principal secondary efficacy end point was 1 month had been obtained for 2000 of the en. hierarchical test sequence was planned. or stroke. and in the ticagrelor minor bleeding events. myocardial infarction. myocardial infarction.or 9-month visit if the targeted number of lyze the data on primary and secondary end 1780 primary end-point events had occurred by points. The ran. Clopidogrel in Acute Coronary Syndromes loading dose and had not been taking clopidogrel 4 units of red cells. risk reduction of 13. 325 mg was also permitted as the daily We estimated that 1780 such events would be re- dose for 6 months after stent placement. or the need for transfusion of at least ment was made to the confidence intervals for n engl j med 361.. No multiplicity adjust- more.   Ticagrelor vs. For those who had not previously been re.11  nejm. Cox for 12 months. 2017. and death loss of neurologic function caused by an ischemic from any cause. severe recurrent cardiac isch- cordance with the universal definition proposed emia. Initially. intraocular bleeding with mg daily. randomization. patients were to be assessed signed to a treatment group were included in the by means of Holter monitoring for 7 days after intention-to-treat analyses. in the order in which they are dial bleeding with cardiac tamponade. In An independent central adjudication commit- patients undergoing CABG. for 24 to 72 hours.0 g per ceived. stroke alone. death from cardio- Consortium criteria. 3. We defined minor bleeding as any pid­ogrel. ence was found between the two treatment groups.14. ing dose. it was recommended tee adjudicated all suspected primary and sec- that the study drug be withheld — in the clopid­ ondary efficacy end points as well as major and ogrel group. but patients left the study at their proportional-hazards models were used to ana- 6. PCI more than 24 hours after randomization. For personal use only. transient isch- in 2007. No other uses without permission.org on February 12. All patients received acetylsalicylic acid (aspirin) at a dose of 75 to Statistical Analysis 100 mg daily unless they could not tolerate the The primary efficacy variable was the time to the drug. ed individually. or hemorrhagic event. 2009 1047 The New England Journal of Medicine Downloaded from nejm. permanent vision loss) or bleeding either associ- ued to receive a maintenance dose of 75 mg daily.g.0 g per deciliter but less than 5. or 90 mg bleeding requiring medical intervention but not of ticagrelor for patients who were undergoing meeting the criteria for major bleeding. for 5 days. or stroke.16 Stroke was defined as focal vascular causes alone. at the investigator’s discretion. the primary efficacy variable studied in the sub- rolled patients. . intracranial bleeding. least 3. until the first nonsignificant differ- volemic shock or severe hypotension due to bleed. 6. infarction.org  september 10. or other arterial thrombotic events. All rights reserved.0 g per deciliter or an exploratory manner. first occurrence of composite of death from vas- ceiving aspirin. an additional dose of deciliter or requiring transfusion of 2 to 3 units their study drug at the time of PCI: 300 mg of clo­ of red cells. given an event rate of domized treatment was scheduled to continue 11% in the clopidogrel group at 12 months. ing and requiring pressors or surgery. recurrent cardiac ischemia. performed according to the Academic Research myocardial infarction alone. Copyright © 2009 Massachusetts Medical Society. ated with a drop in the hemoglobin level of at Patients undergoing PCI after randomization re. the com- causes and any death without another known posite of death from vascular causes. 325 mg was the preferred load. group. intrapericar. in a blind fashion. with a safety follow-up visit end point in the ticagrelor group as compared 1 month after the end of treatment. All patients who had been randomly as- that time.15 Evaluation for stent thrombosis was emic attack. with the clopidogrel group. a lasting at least 24 hours or leading to death. a decline in Other treatment comparisons were examined in the hemoglobin level of 5. myocardial cause. The sec- We defined major life-threatening bleeding as ondary composite efficacy end points were test- fatal bleeding. group of patients for whom invasive management was planned at randomization. We defined other major for at least 5 days before randomization received bleeding as bleeding that led to clinically signifi- a 300-mg loading dose followed by a dose of 75 cant disability (e. Myocardial infarction was defined in ac. Others in the clopidogrel group contin. stroke. 9. Additional sec- End Points ondary end points (analyzed for the entire study Death from vascular causes was defined as death population) were the composite of death from any from cardiovascular causes or cerebrovascular cause.5% in the rate of the primary and 12 months. with residual symptoms To address the issue of multiple testing.

2) TIMI risk score ≥3 1584/3496 (45.2) Chronic renal disease 379/9333 (4. (%) MI 1900/9333 (20.6) 1220/9291 (13. All rights reserved.2) 114/9291 (1.org on February 12./total no. (%) 652/9333 (7.0 62.0 (29–180) Body weight <60 kg — no. .9) 265/9291 (2.org  september 10.7) Risk factors for ST-elevation MI — no.9) 262/9291 (2.8) ST-segment depression 4730/9333 (50. 2009 The New England Journal of Medicine Downloaded from nejm.2) T-wave inversion 2970/9333 (31./total no.8) ECG findings at study entry — no.8) 8511/9291 (91./total no.7) 41/3530 (1. (%) Habitual smoker 3360/9333 (36.7) Diabetes mellitus 2326/9333 (24./total no.0) 1048 n engl j med 361.1) Dyslipidemia 4347/9333 (46.5) 3530/9291 (38. (%) 1396/9333 (15.8) Other diagnosis or missing data§ 283/9333 (3.7) Hypertension 6139/9333 (65.0) 3318/9291 (35.2) 112/9291 (1. For personal use only.8) 2975/9291 (32.1) Final diagnosis of ACS — no. (%) 2655/9333 (28.1) BMI — median (range)† 27 (13–68) 27 (13–70) Race — no.* Characteristic Ticagrelor Group Clopidogrel Group Median age — yr 62.0) 660/9291 (7.1) 578/9291 (6. (%) 7965/9333 (85.1) Coronary-artery bypass grafting 532/9333 (5. According to Treatment Group.0 Age ≥75 yr — no.9) 2336/9291 (25. The n e w e ng l a n d j o u r na l of m e dic i n e Table 1.9) 530/9291 (5.2) Cardiovascular risk factor — no.0) Peripheral arterial disease 566/9333 (6.8) 554/9291 (6.0) 1482/9291 (16.5) Unstable angina 1549/9333 (16./total no.6) 4342/9291 (46. No other uses without permission.0) Female sex — no.8) 369/9291 (4.0) Non–ST-elevation MI 4005/9333 (42./total no.1) 1358/9291 (14./total no.0 (28–174) 80.11  nejm.6) 1563/9291 (16.5) 537/9291 (5.4) History of dyspnea 1412/9333 (15.6) Black 115/9332 (1.4) 1924/9291 (20. (%) Persistent ST-segment elevation 3497/9333 (37.8) Nonhemorrhagic stroke 353/9333 (3.4) 2633/9291 (28. Baseline Characteristics of the Patients.2) Congestive heart failure 513/9333 (5.1) Other medical history — no.0) 248/9291 (2.8) 6044/9291 (65.9) 3950/9291 (42.3) Median body weight — kg (range) 80.7) 574/9291 (6.7) Percutaneous coronary intervention 1272/9333 (13.0) Other 109/9332 (1.3) 7999/9291 (86.7) Asthma 267/9333 (2./total no.0) Positive troponin I test at study entry — no.1) 406/9291 (4. (%)‡ White 8566/9332 (91.3) 1553/3530 (44.9) Gout 272/9333 (2.6) Chronic obstructive pulmonary disease 555/9333 (5./total no./total no. 2017. (%) ST-elevation MI 3496/9333 (37. (%) Killip class >2 25/3496 (0.2) Asian 542/9332 (5. Copyright © 2009 Massachusetts Medical Society.5) 3511/9291 (37.7) 4756/9291 (51.

  Ticagrelor vs. after the start of chest pain. All rights reserved.3%. posite end point of death from any cause. ¶ Risk factors for non–ST-elevation MI were ascertained for patients with a final ACS diagnosis of non–ST-elevation MI or unstable angina.84.3 hours (interquartile range. 79. and 19.92.2) * A positive result on testing for troponin I consisted of a troponin I level of 0.org). Efficacy cacy and safety end points was explored in 25 The primary end point occurred significantly less prespecified subgroups and 8 post hoc sub. group.7% at 12 parisons. ogrel group (in 9.8 to 19. Additional safety end points included mi.7) TIMI risk score ≥5 1112/5554 (20. 0.8) ST-segment depression >0. nor bleeding.) Characteristic Ticagrelor Group Clopidogrel Group Risk factors for non–ST-elevation MI — no. 2017. recurrent ischemia.2% vs. at least 300 mg.5) 4455/5513 (80. For personal use only. was was the first occurrence of any major bleeding 82. 0. available with the full text of this article 2008.5%). cardial infarction.11  nejm. As shown We recruited 18. 1 in the Supplementary Ap- 43 countries from October 2006 through July pendix. § This category includes patients with unspecified ACS or no ACS. . The follow-up period ended in February at NEJM. Another ly more common in the tica­grelor group than in predefined objective was to compare the two the clopidogrel group (in 23.org on February 12. as measured at the central laboratory with the use of the Advia Centaur TnI-Ultra Immunoassay (Siemens). The overall rate of adherence to the study of stent thrombosis. bradyarrhythmia.1% of patients received compared with the clopidogrel group. treatment groups with respect to the occurrence 21. “Asian” does not include Indian or Southwest Asian ancestry. (Continued. myo- study medications and procedures (Table 2). as compared with the clopid­ ment groups were well balanced with regard to ogrel group. the hazard ratios for the ticagrelor group as randomized treatment. 2009 1049 The New England Journal of Medicine Downloaded from nejm. P<0. 4. hazard ratio. any other 179 to 365).77 to 0. The difference in treatment effect was apparent within the first 30 days of therapy and Study Patients and Study Drugs persisted throughout the study period. MI myocardial infarction. Clopidogrel in Acute Coronary Syndromes Table 1. dyspnea. often in the ticagrelor group than in the clopid­ groups.6) 3182/5513 (57. with respect to the rates of the com- all baseline characteristics (Table 1) and non.4% of patients vs.8% of patients vs. The primary safety end point drug. or other arterial throm- n engl j med 361. ECG electrocardiographic. 1). the ticagrelor group. ary end points showed significant reductions in able for all patients except five. and the median duration of exposure to event. the study drug was 277 days (interquartile range. Both groups started the study drug at a median P<0.08 μg or more per liter for the first sample taken. months. ‡ Race was self-reported. without adjustment for multiple com. myocardial infarction.001) (Table 3 and R e sult s Fig. and results of laboratory safety tests. stroke. the hierarchical testing of second- 2009. 95% confidence in- terval [CI]. clinical adverse event. No other uses without permission. In the clopidogrel severe recurrent ischemia. Prema- risk ratios for the periods from randomization ture discontinuation of the study drug was slight- to 30 days and from 31 to 360 days. or stroke (10.0) 1170/5513 (21.001).8) vascular causes.8%.624 patients from 862 centers in in Table 3 (and Fig. ACS denotes acute coronary syndrome.1 mV 3141/5554 (56. Copyright © 2009 Massachusetts Medical Society. (%)¶ Positive troponin I test 4418/5554 (79. The two treat. taking into account both open-label and transient ischemic attack. 11.org  september 10./total no. of The consistency of treatment effects over clopidogrel between the time of the index event time was assessed by determining the relative and up to 24 hours after randomization. † The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters.6% at least 600 mg. the composite end point of death from of 11. The consistency of effects on effi. 12. as assessed by the site investigators. and TIMI Thrombolysis in Myocardial Infarction. when information on vital status was avail.

7) 1822 (19.3) 0.org  september 10.* Ticagrelor Group Clopidogrel Group Characteristic (N = 9333) (N = 9291) P Value† Start of randomized treatment Patients receiving treatment — no.2) 0.0) 0.8) 7697 (82.5) 0.8) 5233 (56.5) 1339 (14. .61 Proton-pump inhibitor 4233 (45.7) 246 (2. Randomized Treatment. (%) No loading dose.4) 1999 (21.30 Beta-blocker 8339 (89.7) 8289 (89.27 Calcium-channel inhibitor 2769 (29.2) 1125 (12.9) 584 (6.31 After randomization 9092 (97.22 Angiotensin-II–receptor blocker 1143 (12.2) 0.04 Other reason 550 (5.91 no.6) 4706 (50.49 Low-molecular-weight heparin 4813 (51. 2009 The New England Journal of Medicine Downloaded from nejm.9) Time after start of chest pain — hr 0.65 or after randomization — no.3) 0.4) 0.1) 0.75 Median 4.5) 0.6) 5528 (59. (%) 2186 (23. (%) Organic nitrate 7181 (76.3 11.89 Bivalirudin 188 (2.42 ACE inhibitor 7090 (76.3) 0.4) 556 (6.62 Other medication administered in hospital or at discharge — no.89 Median 11.8 1. and Procedures.8 Time after start of hospitalization — hr 0.4) 4128 (44.8) 0.85 Unfractionated heparin 5304 (56.83 Glycoprotein IIb/IIIa inhibitor 2468 (26.3) 508 (5.8–19.7) 0.9) 7088 (76. The n e w e ng l a n d j o u r na l of m e dic i n e Table 2.7) 2789 (30.21 Fondaparinux 251 (2.1) 859 (9.11 Median 277 277 IQR 177–365 181–365 Clopidogrel administered in hospital before randomization — 4293 (46. (%) 9235 (98.8) 0.3 IQR 4. (%) Aspirin Before randomization 8827 (94.6) 8755 (94. 2017.4) 9056 (97. All rights reserved.0) 0.5) 600–675 mg 1282 (13.5) Antithrombotic treatment in hospital — no.001 Because of patient’s unwillingness to continue 946 (10.6) 0.4) Same dose as that given before index event§ 496 (5. Copyright © 2009 Massachusetts Medical Society.8 4. According to Treatment Group.7) 0. or missing information 4937 (52. No other uses without permission.4–15.0) 300–375 mg 1921 (20.2) 0.0) 6986 (75.0) 4282 (46.89 Exposure to study drug — days 0.3 IQR 1.2) 0.4) 2487 (26.8–19.0) <0. For personal use only. Other Treatments.6) Other dose 697 (7.27 Adherence to study drug — no.3–18.3) 8336 (89.9) 9186 (98.9) 94 (1.9 5.11  nejm.8 Premature discontinuation of study drug — no. (%) Clopidogrel dose given (as study drug or not) within 24 hours before 0.79 Cholesterol-lowering drug (statin) 8373 (89.1) 0.0) 183 (2.002 Because of adverse event 690 (7. (%)‡ 7724 (82.21 1050 n engl j med 361.org on February 12.

2 in the Supplementary Appendix).) Ticagrelor Group Clopidogrel Group Characteristic (N = 9333) (N = 9291) P Value† Invasive procedure performed during index hospitalization — no. All rights reserved.72 Patients with non–ST-elevation MI Median 3.1%. Among patients who re. 5.25 0.78 Patients with ST-elevation MI Median 0.001).4) 1757 (18.1%].46 Stenting 5640 (60. This pattern was also reflected in a The results regarding the primary end point reduction in the rate of death from any cause did not show significant heterogeneity in analy- with ticagrelor (4.8) 0.05–0. those not vs.68 Coronary angiography 7599 (81. § Patients who had been receiving clopidogrel before the study were not eligible for a loading dose of the drug at study entry.org on February 12. group than in the clopidogrel group (1.org  september 10. myocar. nominal P = 0. P = 0. Concerning our taking lipid-lowering drugs at randomization first secondary objective of ascertaining the ef.93 3.9) 0.8 * ACE denotes angiotensin-converting enzyme. 10. as assessed by the site investigator.32 Time from first dose of study drug to PCI — hr 0.009). the rate of the primary end point was also lower with ticagrelor (8. the rate of defi. CABG coronary-artery bypass grafting. botic events (14. efit of ticagrelor appeared to be attenuated in though there were more hemorrhagic strokes patients weighing less than the median weight with ticagrelor than with clopidogrel (23 [0.5) 0. The ticagrelor and clopidogrel groups did not dif- ceived a stent during the study.45–50. IQR interquartile range.1) 5999 (64.10).61 With bare-metal stent only 3921 (42. 1. 2009 1051 The New England Journal of Medicine Downloaded from nejm.65 IQR 0.6) 0. 2017. (%) PCI 5978 (64.3) 434 (4. planned.4) 5649 (60. and PCI percutaneous coronary intervention.7) 0. ses of the 33 subgroups.05–0. Copyright © 2009 Massachusetts Medical Society. Clopidogrel in Acute Coronary Syndromes Table 2. 13 [0. The rate of stroke did not differ sig.75 0.001).9) 0.9 0. For personal use only.19 Invasive procedure performed during study — no.0% vs. No other uses without permission.9) 4546 (48.25 IQR 0. (P = 0.9%. 16.3% vs. vs. P = 0.1) 6676 (71.40 CABG 931 (10. ‡ Adherence to the study drug was defined as use of more than 80% of the study medication during each interval be- tween visits.87 With ≥1 drug-eluting stent 1719 (18.9) 0. The ben- nificantly between the two treatment groups.0) 3892 (41.4) 0.83 Within 24 hours after randomization 4560 (48. P<0. (%) Planned invasive treatment 6732 (72.1) 0.9) 5676 (61. 5.5%. al.9) 0.045 for the interaction). (Fig.91 PCI During index hospitalization 5687 (60.003).005).93 Cardiac surgery 398 (4.9%.0) 968 (10.2%] for their sex (P = 0. 6.04 for the interaction). with three exceptions P<0. and those enrolled fect in patients for whom invasive treatment was in North America (P = 0.9%. nite stent thrombosis was lower in the ticagrelor dial infarction alone (5. P = 0.8% vs. † P values were calculated with the use of Fisher’s exact test.48–46. and death due to vascular causes (4.11  nejm.6% vs. fer significantly with regard to the rates of major n engl j med 361. .6% with Bleeding clopidogrel. P = 0.7%. (Continued. vs.001).9% with clopidogrel.04 for the interaction).4) 7571 (81.   Ticagrelor vs.

severe recurrent 1290/9333 (14.77–0.6) 0.001‡ ischemia. TIA.9) 668/6676 (10.5) 64/9291 (0.80 (0.3) 106/5649 (1.6% and 11.92) <0.003‡ Event rate.2) 0. 2009 The New England Journal of Medicine Downloaded from nejm.42–1.8) 0. The n e w e ng l a n d j o u r na l of m e dic i n e Table 3.05) 0. † P values were calculated by means of Cox regression analysis. or other arterial thrombotic event MI 504/9333 (5. Only traumatic fatal bleeding was excluded from the category of death from vas- cular causes.57) or two treatment groups did not differ significantly fatal or life-threatening bleeding (5.34–1.7) 0. MI denotes myocardial infarction.2) 23/9291 (0.62–0.02 Possible. except with re- major bleeding according to the Thrombolysis in gard to the body-mass index (P = 0.08 Recurrent ischemia 500/9333 (5. MI. ‡ Statistical significance was confirmed in the hierarchical testing sequence applied to the secondary composite efficacy end points.* Hazard Ratio for Ticagrelor Clopidogrel Ticagrelor Group End Point Group Group (95% CI) P Value† Primary end point: death from vascular causes.91) <0. was also no significant difference in the rates of without significant heterogeneity.42 Other arterial thrombotic event 19/9333 (0.91–1.84 (0.9) 0. There definition was consistent among all subgroups.71 (0.70).75–0.11  nejm.70–0. 2 and Table 4).5) 345/9291 (4.001‡ — no.org on February 12.08 Severe recurrent ischemia 302/9333 (3.88 (0. § A plan for invasive or noninvasive (medical) management was declared before randomization. .1) 0. (%) Secondary end points — no.3) 1.88 (0.04) 0.7) 0. ¶ Patients with any primary event during the first 30 days were excluded.95) 0. 2017.77 (0.05 for interac- Myocardial Infarction (TIMI) criteria (7.2) 158/5649 (2. stroke — no. The ticagrelor and 7. Death from vascular causes included fatal bleeding. The absence of a significant dif.22 Ischemic 96/9333 (1. bleeding as defined in the trial (11.01) 0. or definite 155/5640 (2. (%) Death from any cause 399/9333 (4.2) 13/9291 (0. All rights reserved.87 (0./total no. Copyright © 2009 Massachusetts Medical Society.005‡ Death from vascular causes 353/9333 (4.2) 31/9291 (0.17 (0.6) 0.001 Stent thrombosis — no.61 (0. MI.44) 0.8) 536/9291 (6. 4 in the Supplementary Appendix). or stroke 864/9333 (9.7% with clopidogrel.67 (0.045 Event rate. or stroke 901/9333 (10.9) 202/5649 (3.91) 0.9% with tion) (Fig.77–0.8% in both in the rates of CABG-related major bleeding or groups.0) 442/9291 (5.92) <0.9) 0.009 Probable or definite 118/5640 (2.04 Other events — no. MI.9) 0.01 * The percentages are Kaplan–Meier estimates of the rate of the end point at 12 months.22 TIA 18/9333 (0. and TIA transient ischemic attack./total no.0) 0.59–0.10 Unknown 10/9333 (0.3) 510/8688 (6. bleeding requiring transfusion of red cells.1) 0.org  september 10.69–0.78 (0.8) 1014/9291 (11.2) 1065/9291 (12.89) <0. Patients could have had more than one type of end point.79 (0.02) 0. MI. For personal use only.84 (0.001‡ Stroke 125/9333 (1.84 (0./total no. Major Efficacy End Points at 12 Months.9) 0.78 (0. probable. No other uses without permission.001‡ Death from vascular causes. P = 0.3) 0.93 (0.2%.6) 1456/9291 (16.69–0.82–1.50–0.75 (0.4) 0. (%) Invasive treatment planned§ 569/6732 (8. days 1–30 443/9333 (4.95) 0. P = 0.1) 2/9291 (0. (%) Definite 71/5640 (1.49–1.95) 0. ference in major bleeding according to the trial respectively./total no.52) 0.08) 0.3) 0.84 (0.8) 0.74 Hemorrhagic 23/9333 (0.77–1. days 31–360¶ 413/8763 (5.1) 91/9291 (1.81–0.74–1.75–0.001 Death from causes other than vascular causes 46/9333 (0.91) 0.8) 502/9291 (5. of patients who received a stent/ total no.09 Death from vascular causes.4) 0. stroke.43) (Fig.8) 593/9291 (6.1) 0. recurrent ischemia.95) <0.5) 506/9291 (5.5) 106/9291 (1. P = 0.94) 0. How- 1052 n engl j med 361.00) 0. (%) Death from any cause.

No other uses without permission. were achieved without a significant increase in in the same clinical settings. P = 0. 7.001 other types of fatal bleeding in the ticagrelor 10 group (9 [0. PLATO shows that treatment with ticagrelor as The time was estimated from the first dose of the study drug in the safety AUTHOR: Wallentin RETAKE 1st compared with clopidogrel in patients with acute population.03) (Fig. were seen in patients who had an acute coronary AUTHOR. defined according to the 2nd coronary syndromes significantly reduced the for FtheFIGURE: study criteria. 3 in the Supplementary Appendix). 14 [0. AUTHOR.77 to 0.org on February 12. P<0. there was a higher rate of non–CABG-related major bleeding ac. 2.org  september 10. or stroke. 0.9% The primary end point — a composite of death from vascular causes. at Risk Other Adverse Events Ticagrelor 9333 8628 8460 8219 6743 5161 4147 Dyspnea was more common in the ticagrelor Clopidogrel 9291 8521 8362 8124 6650 5096 4047 group than in the clopidogrel group (in 13. 30 0 2 4 Hazard ratio.5% vs.17-19 The advantages JOB: 36111 ISSUE: 09-10-09 the rate of major bleeding.8% vs. Months No. cagrelor groupREGthan FIGURE: F in 1 of 2 the clopidogrel group (9. 60 4 there were more episodes of intracranial bleed. myocardial EMail Line 4-C SIZE infarction. AUTHOR: Wallentin RETAKE 1st ICM or stroke — occurred significantly less often in the ti- 2nd the clopidogrel group). PLEASE NOTE: cular causes and myocardial infarction. 50 2 ing (26 [0.7% at3rd12 months. A similar benefit was seen ARTIST: ts H/T H/T 22p3 Enon Combo for the individual components of death from vas.03) and the TIMI criteria (2. 0 30 0 2 4 6 8 10 12 Discontinuation of the study drug due to ad- 20 verse events occurred more frequently with ti. for stroke.3%] vs. Please check carefully. 0.92. For personal use only. myo- of patients in the ticagrelor group and 0.Revised CASE rate of death from vascular causes. vs.03) (Table 4).95 to 1.77–0. CASE 95% confidence interval.92) 6 8 10 12 P = 0. P<0. the two treatment groups did 60 5 not differ significantly with respect to the inci- 50 dence of syncope or pacemaker implantation 40 (Table 4). All rights reserved. 2009 1053 The New England Journal of Medicine Downloaded from nejm.8%) (Table 4).06). Clopidogrel in Acute Coronary Syndromes ever. hazard ratio. Ticagrelor 90 in the ticagrelor group than in the clopidogrel 80 10 Clopidogrel group (Table 4). 3. 11.001).02).   Ticagrelor vs. REG 2 of 2 ticagrelor group as compared with the clopidogrel 3rd group was 1.13). Cumulative Kaplan–Meier Estimates of the Time to the First patients vs.4% of pa- 0 tients vs.2%. 0.8%. Cumulative Kaplan–Meier Estimates of the Time to the First Major Bleeding End Point. has been reset.8. 90 10 P = 0. 21 [0. Holter monitoring was performed for a me. 100 12 Clopidogrel cording to the study criteria (4.84.84 (95% CI. 2017.43 10 cagrelor than with clopidogrel (in 7.001) (Table 2).1%] vs. 0.11  nejm. There was a higher incidence of ven.8% of Figure 1. Ticagrelor 9235 7246 6826 6545 5129 3783 3433 Clopidogrel 9186 7305 6930 6670 5209 3841 3479 Discussion Figure 2. . Few patients discon. 0. were seen regardless of whether patients had re- The benefits of ticagrelor over clopidogrel ceived appropriate initiation of treatment with the n engl j med 361.1%].0%. Pauses were rarely associated JOB: 36111 ISSUE: 09-10-09 of Major Bleeding (%) Cumulative Incidence 70 with symptoms.1% in cardial infarction. in the ticagrelor group. Adjudicated Occurrence of the Primary Efficacy End Point. Copyright © 2009 Massachusetts Medical Society. 70 6 With ticagrelor as compared with clopidogrel.04 (95% confidence interval. 6.3%] in the clopidogrel 0 0 2 4 6 8 10 12 group. Revised Line 4-C dian of 6 days during the first week in 2866 EMail ARTIST: ts H/T H/T SIZE 22p3 Enon patients and was repeated at 30 days in 1991 Combo patients. P = 0. The levels of 0 2 4 6 8 10 12 creatinine and uric acid increased slightly more Months during the treatment period with ticagrelor than No. PLEASE NOTE: 100 15 Figure has been redrawn and type has been reset. but not syndrome with or without Figure has beenST-segment redrawn and typeelevation.01%]. there were fewer episodes of 20 P<0. According to the Study Criteria. at Risk with clopidogrel (Table 4). tinued the study drug because of dyspnea (0. including 40 0 fatal intracranial bleeding (11 [0. However. tricular pauses in the first week. but not at day 30. The ICMhazard ratio for major bleeding. 1 [0. P=0. 80 of Primary End Point (%) 8 Ticagrelor Cumulative Incidence P = 0.2%]. The beneficial effects of ticagrelor Previous trials have shownPleasebenefits check of clopidogrel carefully.8% vs.

No other uses without permission. study criteria 491/9235 (5.01) <0.01 Ventricular pauses ≥5 sec 29/1451 (2./total no.1) 76/9186 (0.33 Dyspnea — no.02 1054 n engl j med 361.3) 0.95 (0.96 Life-threatening or fatal bleeding. TIMI criteria 221/9235 (2.3) 0.8) 51/1415 (3.12 (3.2) 13/9186 (0.15) 0.8) 0.4) 906/9186 (10. This duration of treatment benefit has also clopidogrel and regardless of whether invasive or been shown with clopidogrel.41–11.02–1./total no.90–1. (%) Any 132/9235 (1.05 (0.87 Syncope 100/9235 (1. TIMI criteria‡ 946/9235 (11.08 Bradycardia 409/9235 (4.2) 1.02 Nonfatal 15/9235 (0. ticagrelor noninvasive management was planned.03.87 (0.8) 480/9186 (5.* Hazard or Odds Ticagrelor Clopidogrel Ratio for Ticagrelor End Point Group Group Group (95% CI)† P Value Primary safety end points — no.8) 177/9186 (2. TIMI criteria 446/9235 (5.03 (0.9) 79/9186 (0.66 Nonintracranial fatal bleeding 9/9235 (0.11 (1.1) 1/9186 (0.00 Holter monitoring — no.17 Malignant 115/9235 (1.8) 6/1006 (0.4) 654/9186 (7./total no.9) 0.20-25 The appears to expand on the previously demonstrat- treatment effects were the same in the short term ed benefits of clopidogrel across the spectrum of (days 0 to 30) and in the longer term (days 31 to acute coronary syndromes.60 Neoplasm arising during treatment — no. The n e w e ng l a n d j o u r na l of m e dic i n e currently recommended higher loading dose of 360).01) 0.21 Heart block 67/9235 (0.94 (0.84 (1.91–1.43 Major bleeding.07) 0.2) 0.70 Fatal bleeding 20/9235 (0.57 Bleeding requiring red-cell transfusion 818/9235 (8.5) 306/9186 (3.25 (1.2) 1.03 CABG-related major bleeding.9) 1.38) 0.10 At 30 days Ventricular pauses ≥3 sec 21/985 (2. .8) 0.1)   6.93–1.1) 21/9186 (0.4) 155/9186 (1.001 Bradycardia — no.13) 0.008 Major or minor bleeding.59) 0.4) 372/9186 (4.82–1.32 CABG-related major bleeding. 1.95–1.32 Major or minor bleeding.4) 0.11) 0.6) 0.8) 1.69 Secondary safety end points — no.7) 0.04 (0. (%) Pacemaker insertion 82/9235 (0. study criteria 619/9235 (7. (%) First week Ventricular pauses ≥3 sec 84/1451 (5. All rights reserved.87 (0.53) 0. of patients/ total no.2) 35/9186 (0.20) 0.1) 1215/9186 (14.03 Intracranial bleeding 26/9235 (0. TIMI criteria‡ 657/9235 (7./total no.06) 0.85–1.26 Thus.03 (0. study criteria 1339/9235 (16.48–1. 2009 The New England Journal of Medicine Downloaded from nejm.00 (0.03 Non–CABG-related major bleeding.1) 17/1006 (1.16) 0. study criteria 961/9235 (11.2) 0.7) 0. (%) Major bleeding.52 Ventricular pauses ≥5 sec 8/985 (0.6) 0.6) 1./total no.001 Requiring discontinuation of study treatment 79/9235 (0. Copyright © 2009 Massachusetts Medical Society.8) 1.7) 66/9186 (0.9) 1.9) 638/9186 (7.0) 0. study criteria 362/9235 (4.11  nejm.06 Fatal 11/9235 (0.2) 121/9186 (1.96–1.69 Benign 18/9235 (0. (%) Any 1270/9235 (13.58) 0.68–2.8) 1.3) 23/9186 (0.2) 1.98–3.7) 1.02) <0.8) 721/9186 (7.org  september 10.6) 929/9186 (11.3) 14/9186 (0. 2017.19 (1.9) 13/9186 (0.0) 17/1415 (1. Safety of the Study Drugs.9) 809/9186 (8. (%) Non–CABG-related major bleeding.7) 1.3) 0.3) 476/9186 (5. For personal use only.15) 0.03–1.org on February 12.9) 0. Table 4.

including gastrointestinal and intrac- platelet inhibition with aspirin in patients who ranial bleeding.28 and with lor than with clopidogrel. Discontinuation of the with other antithrombotic treatments in patients study drug because of dyspnea occurred in 0.29 The improved survival rate cagrelor. as seen lasted less than a week.30-32 of patients in the ticagrelor group.001 At 12 mo 11±22 9±22 <0. † Hazard ratios are shown for all safety end points except bleeding requiring red-cell transfusion. For personal use only. 22% in the rate of death from any cause at 1 year.org  september 10. the antiplatelet effect dissipates more rapidly nary thrombotic events (i. Although similar effects of prasugrel. CABG denotes coronary-­ artery bypass grafting.9% with an acute coronary syndrome. ‡ Major bleeding and major or minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria refer to nonadjudicated events analyzed with the use of a statistically programmed analysis in accordance with previously used definitions. which are irrevers- tion and stent thrombosis) through more-intense ible P2Y12 inhibitors.10 inhibition with ticagrelor is consistent with reduc. non–procedure-related bleeding (spontaneous tions in the mortality rate obtained by means of bleeding).4 percentage points and a relative reduction of let inhibitor than clopidogrel but is irreversible.001 At 12 mo 15±52 7±31 <0.13 Most episodes tant increase in the risk of major bleeding. with ticagrelor might be due to the decrease in Dyspnea occurred more frequently with ti- the risk of thrombotic events without a concomi. ible. the more-intense whether invasive or noninvasive management was platelet inhibition with ticagrelor was not asso- planned. this issue has not been investigated with ciated with an increase in the rate of any major other P2Y12 inhibitors. and death from any an acute coronary syndrome have not shown sig.) Hazard or Odds Ticagrelor Clopidogrel Ratio for Ticagrelor End Point Group Group Group (95% CI)† P Value Increase in serum uric acid from baseline value — % At 1 mo 14±46 7±44 <0.10 or glycoprotein overall reduction in the mortality rate with ti- IIb/IIIa inhibitors.001 1 Mo after end of treatment 10±22 10±22 0.10 which is also a more effective plate- 1. the the rates of major bleeding were not lower with benefits with ticagrelor were seen regardless of ticagrelor than with clopidogrel. The percentages for the primary and secondary safety end points are Kaplan– Meier estimates of the rate of the end point at 12 months. myocardial infarc. Although the rare clopidogrel in patients who had myocardial in. Copyright © 2009 Massachusetts Medical Society. there was no increased risk of CABG-related This survival benefit from more-intense platelet bleeding with ticagrelor.59 * Plus–minus values are means ±SD. .11  nejm. P values for the odds ratios were calculated with the use of Fisher’s exact test. other contemporary trials involving patients with death from vascular causes.10 The incremental reduction in the risk of coro. Patients could have more than one type of end point.org on February 12. than with the thienopyridines. 2009 1055 The New England Journal of Medicine Downloaded from nejm. toring detected more ventricular pauses during n engl j med 361. cagrelor than with clopidogrel.e.001 1 Mo after end of treatment 7±43 8±48 0. was more common with ticagre- had an acute coronary syndrome27. 2017. No other uses without permission.   Ticagrelor vs. Data are shown for patients who received at least one dose of the study drug for events occurring up to 7 days after permanent discontinuation of the study drug. Treatment with ticagrelor bleeding. All rights reserved. Therefore. for which odds ratios are shown. As with prasugrel. less procedure- P2Y12 inhibition with ticagrelor is consistent with related bleeding might be expected. Holter moni- Since P2Y12 inhibition with ticagrelor is revers. the rates of nonintracranial fatal bleeding. In contrast to the experience with was also associated with an absolute reduction of prasugrel.10 As noted above.56 Increase in serum creatinine from baseline value — % At 1 mo 10±22 8±21 <0.22 In contrast. tal. episodes of intracranial bleeding were often fa- farction with ST-segment elevation.. (Continued. Clopidogrel in Acute Coronary Syndromes Table 4. other cause were lower in the ticagrelor group nificant reductions in the mortality rate with the than in the clopidogrel group. resulting in an use of clopidogrel.8 prasugrel.

Dr. Norway: F. China: R. Thorsen. and Schering-Plough. Budaj. and with symptoms. lecture fees from Bayer. and tions of patients or practice patterns influenced grant support from Astra Zeneca. Astra Zeneca. Bristol-Myers Squibb. James. Vintila. GlaxoSmithKline. Australia: P. Eli Lilly. the differences Sanofi-Aventis. DeMets (statistician). Sabatine. Glaxo Smith Kline. and AstraZeneca.G. South Korea: K. D. Austria: G. Eli Lilly. Freij. S. Verheugt. Cornel. Data Monitoring Committee — United States: J. Mahaffey. Spinar. farction: a report of the American College Guidelines for the Management of Pa- et al. and grant support from Sanofi-Aventis and hav- ing equity ownership in Aterovax. Horrow. Malaysia: D. lecture whether geographic differences between popula.05 for heterogeneity). Katus. Germany: E. D.-P. consulting fees from Sanofi-Aventis and Eli Lilly and lecture fees frequent at 30 days and were rarely associated from Sanofi-Aventis. Slovak Republic: T. treatment with ticagrelor. Becker. Storey. and with clopidogrel. United States: R. Belgium: F. Nikolaevich Parkhomenko. Daiichi Sankyo. F. Storey reports receiving of death from vascular causes. France: J. Boehringer Ingelheim. Aylward. Johnson and John- son. Dr. Steg reports receiving consulting fees from AstraZeneca. significantly reduced the rate Sanofi-Aventis. R. United Kingdom: R. Kremastinos. Dr. the similarity in rates of major bleeding. Bristol-Myers Squibb. from Astra Zeneca. Gao.org on February 12. Philip- pines: N. Denmark: S. the Medicines Company. (Writing Committee to Revise the 2002 in collaboration with the American Col- 1056 n engl j med 361. Romania: M. Switzerland: B. and Bristol. Medtronic. Denmark: S. and grant support from AstraZeneca. Israel: B. Novartis. and Eli Lilly and lecture fees from AstraZeneca. Babilonia. and Bristol-Myers Squibb. Robaayah Zambahari. Raev. AstraZeneca. Sweden: S. Boehringer Ingelheim. and Astra- Dr. There were no significant differ. Pharma. in patients who had an acute Nycomed. Paolasso. Wilcox. Greece: D. The difference in results be. Morais. Lassila. Dr. Sendon. the Netherlands: M. Keltai. Sanofi- bradyarrhythmia between the two treatment Aventis. Schering-Plough. The n e w e ng l a n d j o u r na l of m e dic i n e the first week in the ticagrelor group than in the Myers Squibb and grant support from Momenta Pharmaceuticals. consulting were significant in the remaining 4 subgroups and lecture fees from AstraZeneca. Turkey: A. Boehringer Ingelheim. was Dr. In conclusion. United States: P. Wallentin (cochair). Cogentus Pharmaceuticals. Nycomed. Bristol- elevation. Eli Lilly. Bristol-Myers Squibb. Drs. . U. H. Ekman. Dr. and Sanofi-Aventis. and Eli Lilly. and Dr. Eli Lilly. Johnson and Johnson. Steering Committee — Italy: D. Gurbel. have been due to chance. Georgia: Z. Wu. and Schering-Plough. Kleiman. Daiichi overall major bleeding but with an increase in Sankyo. Portugal: J. United Kingdom: R. Théroux. coronary syndrome with or without ST-segment Servier. Brazil: J. J. Ukraine: A. Portola Pharmaceuticals. Menarini. I. Aventis. and Schering-Plough. Russia: M. Czech Republic: J. or stroke. without an increase in the rate of Teva. Ardissino. Daiichi Sankyo. Simoons. Cannon. Kontny. lecture fees from Eli Lilly. Storey.J.-B. and Bayer. myocardial infarc. and grant support from Millenium ringer Ingelheim. Medtronic. consulting Squibb. Indonesia: A. Daiichi Sankyo. and Eli Lilly. Poland: A. Boehringer Ingelheim. Intekrin Therapeutics. lecture fees from Boeh. given the large number Bristol-Myers Squibb.L. and grant support from AstraZeneca. and Schering-Plough. Horrow also reports receiving lecture with regard to the primary end point. Man Yu. Daichii Sankyo. No other potential conflict of interest relevant to this fees from Regado Biosciences. M. AstraZeneca. Van de Werf. tion. clopidogrel group. N. M. Katus.: A. consulting fees from AstraZeneca. Canada: P. and Takeda. Budaj. as well as fees from the Pharmaceutical Education and Research Institute. Adams CD. and Sanofi-Aventis. Bulgaria: D. and Bristol-Myers GlaxoSmithKline.L. AstraZeneca. Daiichi Sankyo. Armando. Servier. GlaxoSmithKline. Meier. as compared Myers Squibb. although Bayer. Belgium: M. lecture fees from Schering-Plough. Singapore: L. Steg. Eli Lilly. Antman EM. Mexico: G. Lewis. Nicolau.S. Schering-Plough. Duris. consistent in 62 of 66 subgroups. Sanofi-Aventis.13 but such episodes were in. Merck. Husted. Sanofi-Aventis. South Africa: P. consulting fees from Bristol-Myers Squibb. Dr. R. Wallentin reports receiving consulting fees from Regado Zeneca. 2009 The New England Journal of Medicine Downloaded from nejm. Emanuelsson and Horrow report being employees of AstraZeneca and having equity owner- The superiority of ticagrelor over clopidogrel ship in AstraZeneca. rington. Bristol-Myers Squibb. Dr. All rights reserved. Husted reports receiving consulting fees from AstraZeneca. Spain: J. Oto. and Novartis. consulting (P<0. the Netherlands: J. tients With Unstable Angina/Non ST-Ele- management of patients with unstable tion Task Force on Practice Guidelines vation Myocardial Infarction): developed angina/non ST-elevation myocardial in.K. Giannitsis.org  september 10. the Medicines Company. Claeys. Ruda. Biosciences and Athera Biotechnologies. Seung. Sanofi- Supported by AstraZeneca. and Bristol-Myers Squibb. Commerford. For personal use only. Dr. Pais.H. References 1. Skene (statistician). the Medicines Company. Maurer. Weaver. 2017. These findings may fees from AstraZeneca.S. Portola Pharmaceuticals. Anderson JL. Harrington (cochair). Endotis no apparent explanations have been found. Pierre Fabre. Eli Lilly. Taiwan: D. Har- the rate of non–procedure-related bleeding. Sritara.F.W. Emanuels­ son. and grant support Pharmaceuticals. Pfizer. Soo Teik. Thailand: P. the effects of the randomized treatments. appendix Members of select PLATO committees are as follows (with principal investigators at participating centers and members of other com- mittees listed in the Supplementary Appendix): Executive Committee — Sweden: L. ACC/AHA 2007 guidelines for the of Cardiology/American Heart Associa. Santoso. Bristol-Myers Squibb. R.11  nejm. Schering- groups. Schering-Plough. lecture fees from the Medicines Company. James. Anderson (chair). Aventis. No other uses without permission. Heras. Becker. France: P. Merck Sharp and Dohme. Hungary: M. Bassand. and Novartis. Finland: R. Hong Kong: C. India: P. Scirica. Husted. Chapichadze. the Medicines Company. fees from Eli Lilly. Portola Pharma- tween patients enrolled in North America and ceuticals. article was reported. GlaxoSmithKline. Daiichi Sankyo.C. Plough. Germany: H. Argentina: E. C. Spain: M. Copyright © 2009 Massachusetts Medical Society.A. Cannon reports having equity ownership in Automedics Medical Systems and receiving grant support ences in the rates of clinical manifestations of from Accumetrics. consulting fees from those enrolled elsewhere raises the questions of AstraZeneca. A. Harrington. AstraZeneca. Dr. and Sanofi- of tests performed.

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