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The new england 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 b s t r a c t

From the Uppsala Clinical Research Cen- ter, Uppsala, Sweden (L.W., C.H., S.J.); Duke Clinical Research Institute, Durham, NC (R.C.B., K.W.M., R.A.H.); Grochowski Hospital, Warsaw, Poland (A.B.); Throm- bolysis in Myocardial Infarction Study Group, Brigham and Women’s Hospital, Boston (C.P.C., B.M.S.); AstraZeneca Re- search and Development, Mölndal, Swe- den (H.E.), and Wilmington, DE ( J.H.); Århus University Hospital, Århus, Den- mark (S.H.); Universitätsklinikum Heidel- berg, Heidelberg, Germany (H.K.); World- wide Clinical Trials U.K., Nottingham, United Kingdom (A.S.); INSERM Unité 698, Assistance Publique–Hôpitaux de Paris and Université Paris 7, Paris (P.G.S.); and the University of Sheffield, Sheffield, United Kingdom (R.F.S.). Address reprint requests to Dr. Wallentin at Uppsala Clinical Research Center, University Hos- pital, 75185 Uppsala, Sweden, or at lars. wallentin@ucr.uu.se.

*The Study of Platelet Inhibition and Pa- tient Outcomes (PLATO) investigators are listed in the Appendix and the Sup- plementary Appendix, available with the full text of this article at NEJM.org.

This article (10.1056/NEJMoa0904327) was published on August 30, 2009, at NEJM. org.

Background Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphos- phate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.

Methods In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.

Results At 12 months, the primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ti- cagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other com- posite end points, as well as myocardial infarction alone (5.8% in the ticagrelor 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 death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopid- ogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not re- lated to coronary-artery bypass grafting (4.5% vs. 3.8%, P = 0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.

Conclusions In patients who have an acute coronary syndrome with or without ST-segment eleva- 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.)

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In patients who have acute coronary syndromes with or without ST-segment eleva-tion, current clinical practice guidelines1-4 recommend dual antiplatelet treatment with aspi- rin and clopidogrel. The efficacy of clopidogrel is hampered by the slow and variable transforma- tion of the prodrug to the active metabolite, modest and variable platelet inhibition,5,6 an in- creased risk of bleeding,7,8 and an increased risk of stent thrombosis and myocardial infarction in patients with a poor response.9 As compared with clopidogrel, prasugrel, another thienopyridine prodrug, has a more consistent and pronounced inhibitory effect on platelets,5,6 resulting in a lower risk of myocardial infarction and stent thrombosis, but is associated with a higher risk of major bleeding in patients with an acute coro- nary syndrome who are undergoing percutane- ous coronary intervention (PCI).10

Ticagrelor, a reversible and direct-acting oral antagonist of the adenosine diphosphate recep- tor P2Y12, provides faster, greater, and more con- sistent P2Y12 inhibition than clopidogrel.11,12 In a dose-guiding trial, there was no significant difference in the rate of bleeding with the use of ticagrelor at a dose of 90 mg or 180 mg twice daily and the rate with the use of clopidogrel at a dose of 75 mg daily. However, dose-related epi- sodes of dyspnea and ventricular pauses on Holter monitoring, which occurred more frequently with ticagrelor, led to the selection of the dose of 90 mg twice daily for further studies.13 We conducted the Study of Platelet Inhibition and Patient Out- comes (PLATO) to determine whether ticagrelor is superior to clopidogrel for the prevention of vascular events and death in a broad population of patients presenting with an acute coronary syndrome.

M e t h o d s

Study Design

PLATO was a multicenter, randomized, double- blind trial. The details of the design have been published previously.14 The executive and opera- tions committee, consisting of both academic members and representatives of the sponsor, Astra- Zeneca, designed and oversaw the conduct of the trial. An independent data and safety monitoring board monitored the trial and had access to the unblinded data. The sponsor coordinated the data management. Statistical analysis was performed by Worldwide Clinical Trials, a contract research

organization, in collaboration with investigators at the academic centers and the sponsor, all of whom had full access to the final study data. The manuscript was drafted by the chairs of the ex- ecutive and operations committee, who were aca- demic authors and who vouch for the accuracy and completeness of the reported data. The study design was approved by the appropriate national and institutional regulatory authorities and ethics committees, and all participants provided writ- ten informed consent.

Study Patients

Patients were eligible for enrollment if they were hospitalized for an acute coronary syndrome, with or without ST-segment elevation, with an onset of symptoms during the previous 24 hours. For patients who had an acute coronary syndrome without ST-segment elevation, at least two of the following three criteria had to be met: ST-seg- ment changes on electrocardiography, indicating ischemia; a positive test of a biomarker, indicat- ing myocardial necrosis; or one of several risk factors (age ≥60 years; previous myocardial infarc- tion or coronary-artery bypass grafting [CABG]; coronary artery disease with stenosis of ≥50% in at least two vessels; previous ischemic stroke, transient ischemic attack, carotid stenosis of at least 50%, or cerebral revascularization; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction, defined as a creatinine clear- ance of <60 ml per minute per 1.73 m2 of body- surface area). For patients who had an acute coronary syndrome with ST-segment elevation, the following two inclusion criteria had to be met: persistent ST-segment elevation of at least 0.1 mV in at least two contiguous leads or a new left bundle-branch block, and the intention to per- form primary PCI. Major exclusion criteria were any contraindication against the use of clopido- grel, fibrinolytic therapy within 24 hours before randomization, a need for oral anticoagulation therapy, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer.

Study Treatment

Patients were randomly assigned to receive tica- grelor or clopidogrel, administered in a double- blind, double-dummy fashion. Ticagrelor was given in a loading dose of 180 mg followed by a dose of 90 mg twice daily. Patients in the clopid- ogrel group who had not received an open-label

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loading dose and had not been taking clopidogrel for at least 5 days before randomization received a 300-mg loading dose followed by a dose of 75 mg daily. Others in the clopidogrel group contin- ued to receive a maintenance dose of 75 mg daily. Patients undergoing PCI after randomization re- ceived, in a blind fashion, an additional dose of their study drug at the time of PCI: 300 mg of clo- pid ogrel, at the investigator’s discretion, or 90 mg of ticagrelor for patients who were undergoing PCI more than 24 hours after randomization. In patients undergoing CABG, it was recommended that the study drug be withheld — in the clopid- ogrel group, for 5 days, and in the ticagrelor group, for 24 to 72 hours. All patients received acetylsalicylic acid (aspirin) at a dose of 75 to 100 mg daily unless they could not tolerate the drug. For those who had not previously been re- ceiving aspirin, 325 mg was the preferred load- ing dose; 325 mg was also permitted as the daily dose for 6 months after stent placement.

Outpatient visits were scheduled at 1, 3, 6, 9, and 12 months, with a safety follow-up visit 1 month after the end of treatment. The ran- domized treatment was scheduled to continue for 12 months, but patients left the study at their 6- or 9-month visit if the targeted number of 1780 primary end-point events had occurred by that time. Initially, patients were to be assessed by means of Holter monitoring for 7 days after randomization, until a repeat assessment at 1 month had been obtained for 2000 of the en- rolled patients.

End Points

Death from vascular causes was defined as death from cardiovascular causes or cerebrovascular causes and any death without another known cause. Myocardial infarction was defined in ac- cordance with the universal definition proposed in 2007.14,15 Evaluation for stent thrombosis was performed according to the Academic Research Consortium criteria.16 Stroke was defined as focal loss of neurologic function caused by an ischemic or hemorrhagic event, with residual symptoms lasting at least 24 hours or leading to death.

We defined major life-threatening bleeding as fatal bleeding, intracranial bleeding, intrapericar- dial bleeding with cardiac tamponade, hypo- volemic shock or severe hypotension due to bleed- ing and requiring pressors or surgery, a decline in the hemoglobin level of 5.0 g per deciliter or more, or the need for transfusion of at least

4 units of red cells. We defined other major bleeding as bleeding that led to clinically signifi- cant disability (e.g., intraocular bleeding with permanent vision loss) or bleeding either associ- ated with a drop in the hemoglobin level of at least 3.0 g per deciliter but less than 5.0 g per deciliter or requiring transfusion of 2 to 3 units of red cells. We defined minor bleeding as any bleeding requiring medical intervention but not meeting the criteria for major bleeding.

An independent central adjudication commit- tee adjudicated all suspected primary and sec- ondary efficacy end points as well as major and minor bleeding events.

Statistical Analysis

The primary efficacy variable was the time to the first occurrence of composite of death from vas- cular causes, myocardial infarction, or stroke. We estimated that 1780 such events would be re- quired to achieve 90% power to detect a relative risk reduction of 13.5% in the rate of the primary end point in the ticagrelor group as compared with the clopidogrel group, given an event rate of 11% in the clopidogrel group at 12 months. Cox proportional-hazards models were used to ana- lyze the data on primary and secondary end points. All patients who had been randomly as- signed to a treatment group were included in the intention-to-treat analyses.

The principal secondary efficacy end point was the primary efficacy variable studied in the sub- group of patients for whom invasive management was planned at randomization. Additional sec- ondary end points (analyzed for the entire study population) were the composite of death from any cause, myocardial infarction, or stroke; the com- posite of death from vascular causes, myocardial infarction, stroke, severe recurrent cardiac isch- emia, recurrent cardiac ischemia, transient isch- emic attack, or other arterial thrombotic events; myocardial infarction alone; death from cardio- vascular causes alone; stroke alone; and death from any cause.

To address the issue of multiple testing, a hierarchical test sequence was planned. The sec- ondary composite efficacy end points were test- ed individually, in the order in which they are listed above, until the first nonsignificant differ- ence was found between the two treatment groups. Other treatment comparisons were examined in an exploratory manner. No multiplicity adjust- ment was made to the confidence intervals for

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Table 1. Baseline Characteristics of the Patients, According to Treatment Group.*

Characteristic Ticagrelor Group Clopidogrel Group

Median age — yr 62.0 62.0

Age ≥75 yr — no./total no. (%) 1396/9333 (15.0) 1482/9291 (16.0)

Female sex — no./total no. (%) 2655/9333 (28.4) 2633/9291 (28.3)

Median body weight — kg (range) 80.0 (28–174) 80.0 (29–180)

Body weight <60 kg — no./total no. (%) 652/9333 (7.0) 660/9291 (7.1)

BMI — median (range)† 27 (13–68) 27 (13–70)

Race — no./total no. (%)‡

White 8566/9332 (91.8) 8511/9291 (91.6)

Black 115/9332 (1.2) 114/9291 (1.2)

Asian 542/9332 (5.8) 554/9291 (6.0)

Other 109/9332 (1.2) 112/9291 (1.2)

Cardiovascular risk factor — no./total no. (%)

Habitual smoker 3360/9333 (36.0) 3318/9291 (35.7)

Hypertension 6139/9333 (65.8) 6044/9291 (65.1)

Dyslipidemia 4347/9333 (46.6) 4342/9291 (46.7)

Diabetes mellitus 2326/9333 (24.9) 2336/9291 (25.1)

Other medical history — no./total no. (%)

MI 1900/9333 (20.4) 1924/9291 (20.7)

Percutaneous coronary intervention 1272/9333 (13.6) 1220/9291 (13.1)

Coronary-artery bypass grafting 532/9333 (5.7) 574/9291 (6.2)

Congestive heart failure 513/9333 (5.5) 537/9291 (5.8)

Nonhemorrhagic stroke 353/9333 (3.8) 369/9291 (4.0)

Peripheral arterial disease 566/9333 (6.1) 578/9291 (6.2)

Chronic renal disease 379/9333 (4.1) 406/9291 (4.4)

History of dyspnea 1412/9333 (15.1) 1358/9291 (14.6)

Chronic obstructive pulmonary disease 555/9333 (5.9) 530/9291 (5.7)

Asthma 267/9333 (2.9) 265/9291 (2.9)

Gout 272/9333 (2.9) 262/9291 (2.8)

ECG findings at study entry — no./total no. (%)

Persistent ST-segment elevation 3497/9333 (37.5) 3511/9291 (37.8)

ST-segment depression 4730/9333 (50.7) 4756/9291 (51.2)

T-wave inversion 2970/9333 (31.8) 2975/9291 (32.0)

Positive troponin I test at study entry — no./total no. (%) 7965/9333 (85.3) 7999/9291 (86.1)

Final diagnosis of ACS — no./total no. (%)

ST-elevation MI 3496/9333 (37.5) 3530/9291 (38.0)

Non–ST-elevation MI 4005/9333 (42.9) 3950/9291 (42.5)

Unstable angina 1549/9333 (16.6) 1563/9291 (16.8)

Other diagnosis or missing data§ 283/9333 (3.0) 248/9291 (2.7)

Risk factors for ST-elevation MI — no./total no. (%)

Killip class >2 25/3496 (0.7) 41/3530 (1.2)

TIMI risk score ≥3 1584/3496 (45.3) 1553/3530 (44.0)

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the hazard ratios for the ticagrelor group as compared with the clopidogrel group.

The consistency of treatment effects over time was assessed by determining the relative risk ratios for the periods from randomization to 30 days and from 31 to 360 days. Another predefined objective was to compare the two treatment groups with respect to the occurrence of stent thrombosis. The primary safety end point was the first occurrence of any major bleeding event. Additional safety end points included mi- nor bleeding, dyspnea, bradyarrhythmia, any other clinical adverse event, and results of laboratory safety tests. The consistency of effects on effi- cacy and safety end points was explored in 25 prespecified subgroups and 8 post hoc sub- groups, without adjustment for multiple com- parisons.

R e s u l t s

Study Patients and Study Drugs

We recruited 18,624 patients from 862 centers in 43 countries from October 2006 through July 2008. The follow-up period ended in February 2009, when information on vital status was avail- able for all patients except five. The two treat- ment groups were well balanced with regard to all baseline characteristics (Table 1) and non- study medications and procedures (Table 2). Both groups started the study drug at a median of 11.3 hours (interquartile range, 4.8 to 19.8) after the start of chest pain. In the clopidogrel group, taking into account both open-label and

randomized treatment, 79.1% of patients received at least 300 mg, and 19.6% at least 600 mg, of clopidogrel between the time of the index event and up to 24 hours after randomization. Prema- ture discontinuation of the study drug was slight- ly more common in the tica grelor group than in the clopidogrel group (in 23.4% of patients vs. 21.5%). The overall rate of adherence to the study drug, as assessed by the site investigators, was 82.8%, and the median duration of exposure to the study drug was 277 days (interquartile range, 179 to 365).

Efficacy

The primary end point occurred significantly less often in the ticagrelor group than in the clopid- ogrel group (in 9.8% of patients vs. 11.7% at 12 months; hazard ratio, 0.84; 95% confidence in- terval [CI], 0.77 to 0.92; P<0.001) (Table 3 and Fig. 1). The difference in treatment effect was apparent within the first 30 days of therapy and persisted throughout the study period. As shown in Table 3 (and Fig. 1 in the Supplementary Ap- pendix, available with the full text of this article at NEJM.org), the hierarchical testing of second- ary end points showed significant reductions in the ticagrelor group, as compared with the clopid- ogrel group, with respect to the rates of the com- posite end point of death from any cause, myo- cardial infarction, or stroke (10.2% vs. 12.3%, P<0.001); the composite end point of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, recurrent ischemia, transient ischemic attack, or other arterial throm-

Table 1. (Continued.)

Characteristic Ticagrelor Group Clopidogrel Group

Risk factors for non–ST-elevation MI — no./total no. (%)¶

Positive troponin I test 4418/5554 (79.5) 4455/5513 (80.8)

ST-segment depression >0.1 mV 3141/5554 (56.6) 3182/5513 (57.7)

TIMI risk score ≥5 1112/5554 (20.0) 1170/5513 (21.2)

* A positive result on testing for troponin I consisted of a troponin I level of 0.08 μg or more per liter for the first sample taken, as measured at the central laboratory with the use of the Advia Centaur TnI-Ultra Immunoassay (Siemens). ACS denotes acute coronary syndrome, ECG electrocardiographic, MI myocardial infarction, and TIMI Thrombolysis in Myocardial Infarction.

† The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. ‡ Race was self-reported. “Asian” does not include Indian or Southwest Asian ancestry. § This category includes patients with unspecified ACS or no ACS. ¶ Risk factors for non–ST-elevation MI were ascertained for patients with a final ACS diagnosis of non–ST-elevation MI or

unstable angina.

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Table 2. Randomized Treatment, Other Treatments, and Procedures, According to Treatment Group.*

Characteristic Ticagrelor Group

(N = 9333) Clopidogrel Group

(N = 9291) P Value†

Start of randomized treatment

Patients receiving treatment — no. (%) 9235 (98.9) 9186 (98.9)

Time after start of chest pain — hr 0.89

Median 11.3 11.3

IQR 4.8–19.8 4.8–19.8

Time after start of hospitalization — hr 0.75

Median 4.9 5.3

IQR 1.3–18.8 1.4–15.8

Premature discontinuation of study drug — no. (%) 2186 (23.4) 1999 (21.5) 0.002

Because of adverse event 690 (7.4) 556 (6.0) <0.001

Because of patient’s unwillingness to continue 946 (10.1) 859 (9.2) 0.04

Other reason 550 (5.9) 584 (6.3) 0.27

Adherence to study drug — no. (%)‡ 7724 (82.8) 7697 (82.8) 0.89

Exposure to study drug — days 0.11

Median 277 277

IQR 177–365 181–365

Clopidogrel administered in hospital before randomization — no. (%)

4293 (46.0) 4282 (46.1) 0.91

Clopidogrel dose given (as study drug or not) within 24 hours before or after randomization — no. (%)

0.65

No loading dose, or missing information 4937 (52.9) 94 (1.0)

300–375 mg 1921 (20.6) 5528 (59.5)

600–675 mg 1282 (13.7) 1822 (19.6)

Other dose 697 (7.5) 1339 (14.4)

Same dose as that given before index event§ 496 (5.3) 508 (5.5)

Antithrombotic treatment in hospital — no. (%)

Aspirin

Before randomization 8827 (94.6) 8755 (94.2) 0.31

After randomization 9092 (97.4) 9056 (97.5) 0.85

Unfractionated heparin 5304 (56.8) 5233 (56.3) 0.49

Low-molecular-weight heparin 4813 (51.6) 4706 (50.7) 0.21

Fondaparinux 251 (2.7) 246 (2.6) 0.89

Bivalirudin 188 (2.0) 183 (2.0) 0.83

Glycoprotein IIb/IIIa inhibitor 2468 (26.4) 2487 (26.8) 0.62

Other medication administered in hospital or at discharge — no. (%)

Organic nitrate 7181 (76.9) 7088 (76.3) 0.30

Beta-blocker 8339 (89.3) 8336 (89.7) 0.42

ACE inhibitor 7090 (76.0) 6986 (75.2) 0.22

Angiotensin-II–receptor blocker 1143 (12.2) 1125 (12.1) 0.79

Cholesterol-lowering drug (statin) 8373 (89.7) 8289 (89.2) 0.27

Calcium-channel inhibitor 2769 (29.7) 2789 (30.0) 0.61

Proton-pump inhibitor 4233 (45.4) 4128 (44.4) 0.21

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botic events (14.6% vs. 16.7%, P<0.001); myocar- dial infarction alone (5.8% vs. 6.9%, P = 0.005); and death due to vascular causes (4.0% vs. 5.1%, P = 0.001). This pattern was also reflected in a reduction in the rate of death from any cause with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). The rate of stroke did not differ sig- nificantly between the two treatment groups, al- though there were more hemorrhagic strokes with ticagrelor than with clopidogrel (23 [0.2%] vs. 13 [0.1%], nominal P = 0.10). Concerning our first secondary objective of ascertaining the ef- fect in patients for whom invasive treatment was planned, the rate of the primary end point was also lower with ticagrelor (8.9%, vs. 10.6% with clopidogrel; P = 0.003). Among patients who re- ceived a stent during the study, the rate of defi-

nite stent thrombosis was lower in the ticagrelor group than in the clopidogrel group (1.3% vs. 1.9%, P = 0.009).

The results regarding the primary end point did not show significant heterogeneity in analy- ses of the 33 subgroups, with three exceptions (Fig. 2 in the Supplementary Appendix). The ben- efit of ticagrelor appeared to be attenuated in patients weighing less than the median weight for their sex (P = 0.04 for the interaction), those not taking lipid-lowering drugs at randomization (P = 0.04 for the interaction), and those enrolled in North America (P = 0.045 for the interaction).

Bleeding

The ticagrelor and clopidogrel groups did not dif- fer significantly with regard to the rates of major

Table 2. (Continued.)

Characteristic Ticagrelor Group

(N = 9333) Clopidogrel Group

(N = 9291) P Value†

Invasive procedure performed during index hospitalization — no. (%)

Planned invasive treatment 6732 (72.1) 6676 (71.9) 0.68

Coronary angiography 7599 (81.4) 7571 (81.5) 0.91

PCI

During index hospitalization 5687 (60.9) 5676 (61.1) 0.83

Within 24 hours after randomization 4560 (48.9) 4546 (48.9) 0.93

Cardiac surgery 398 (4.3) 434 (4.7) 0.19

Invasive procedure performed during study — no. (%)

PCI 5978 (64.1) 5999 (64.6) 0.46

Stenting 5640 (60.4) 5649 (60.8) 0.61

With bare-metal stent only 3921 (42.0) 3892 (41.9) 0.87

With ≥1 drug-eluting stent 1719 (18.4) 1757 (18.9) 0.40

CABG 931 (10.0) 968 (10.4) 0.32

Time from first dose of study drug to PCI — hr 0.78

Patients with ST-elevation MI

Median 0.25 0.25

IQR 0.05–0.75 0.05–0.72

Patients with non–ST-elevation MI

Median 3.93 3.65

IQR 0.48–46.9 0.45–50.8

* ACE denotes angiotensin-converting enzyme, CABG coronary-artery bypass grafting, IQR interquartile range, and PCI percutaneous coronary intervention.

† P values were calculated with the use of Fisher’s exact test. ‡ Adherence to the study drug was defined as use of more than 80% of the study medication during each interval be-

tween visits, as assessed by the site investigator. § Patients who had been receiving clopidogrel before the study were not eligible for a loading dose of the drug at study

entry.

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bleeding as defined in the trial (11.6% and 11.2%, respectively; P = 0.43) (Fig. 2 and Table 4). There was also no significant difference in the rates of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) criteria (7.9% with ticagrelor and 7.7% with clopidogrel, P = 0.57) or fatal or life-threatening bleeding (5.8% in both groups, P = 0.70). The absence of a significant dif-

ference in major bleeding according to the trial definition was consistent among all subgroups, without significant heterogeneity, except with re- gard to the body-mass index (P = 0.05 for interac- tion) (Fig. 4 in the Supplementary Appendix). The two treatment groups did not differ significantly in the rates of CABG-related major bleeding or bleeding requiring transfusion of red cells. How-

Table 3. Major Efficacy End Points at 12 Months.*

End Point Ticagrelor

Group Clopidogrel

Group

Hazard Ratio for Ticagrelor Group

(95% CI) P Value†

Primary end point: death from vascular causes, MI, or stroke — no./total no. (%)

864/9333 (9.8) 1014/9291 (11.7) 0.84 (0.77–0.92) <0.001‡

Secondary end points — no./total no. (%)

Death from any cause, MI, or stroke 901/9333 (10.2) 1065/9291 (12.3) 0.84 (0.77–0.92) <0.001‡

Death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event

1290/9333 (14.6) 1456/9291 (16.7) 0.88 (0.81–0.95) <0.001‡

MI 504/9333 (5.8) 593/9291 (6.9) 0.84 (0.75–0.95) 0.005‡

Death from vascular causes 353/9333 (4.0) 442/9291 (5.1) 0.79 (0.69–0.91) 0.001‡

Stroke 125/9333 (1.5) 106/9291 (1.3) 1.17 (0.91–1.52) 0.22

Ischemic 96/9333 (1.1) 91/9291 (1.1) 0.74

Hemorrhagic 23/9333 (0.2) 13/9291 (0.1) 0.10

Unknown 10/9333 (0.1) 2/9291 (0.02) 0.04

Other events — no./total no. (%)

Death from any cause 399/9333 (4.5) 506/9291 (5.9) 0.78 (0.69–0.89) <0.001

Death from causes other than vascular causes 46/9333 (0.5) 64/9291 (0.8) 0.71 (0.49–1.04) 0.08

Severe recurrent ischemia 302/9333 (3.5) 345/9291 (4.0) 0.87 (0.74–1.01) 0.08

Recurrent ischemia 500/9333 (5.8) 536/9291 (6.2) 0.93 (0.82–1.05) 0.22

TIA 18/9333 (0.2) 23/9291 (0.3) 0.78 (0.42–1.44) 0.42

Other arterial thrombotic event 19/9333 (0.2) 31/9291 (0.4) 0.61 (0.34–1.08) 0.09

Death from vascular causes, MI, stroke — no./total no. (%)

Invasive treatment planned§ 569/6732 (8.9) 668/6676 (10.6) 0.84 (0.75–0.94) 0.003‡

Event rate, days 1–30 443/9333 (4.8) 502/9291 (5.4) 0.88 (0.77–1.00) 0.045

Event rate, days 31–360¶ 413/8763 (5.3) 510/8688 (6.6) 0.80 (0.70–0.91) <0.001

Stent thrombosis — no. of patients who received a stent/ total no. (%)

Definite 71/5640 (1.3) 106/5649 (1.9) 0.67 (0.50–0.91) 0.009

Probable or definite 118/5640 (2.2) 158/5649 (2.9) 0.75 (0.59–0.95) 0.02

Possible, probable, or definite 155/5640 (2.9) 202/5649 (3.8) 0.77 (0.62–0.95) 0.01

* The percentages are Kaplan–Meier estimates of the rate of the end point at 12 months. Patients could have had more than one type of end point. Death from vascular causes included fatal bleeding. Only traumatic fatal bleeding was excluded from the category of death from vas- cular causes. MI denotes myocardial infarction, and TIA transient ischemic attack.

† P values were calculated by means of Cox regression analysis. ‡ Statistical significance was confirmed in the hierarchical testing sequence applied to the secondary composite efficacy end points. § A plan for invasive or noninvasive (medical) management was declared before randomization. ¶ Patients with any primary event during the first 30 days were excluded.

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ever, in the ticagrelor group, there was a higher rate of non–CABG-related major bleeding ac- cording to the study criteria (4.5% vs. 3.8%, P = 0.03) and the TIMI criteria (2.8% vs. 2.2%, P = 0.03) (Fig. 3 in the Supplementary Appendix). With ticagrelor as compared with clopidogrel, there were more episodes of intracranial bleed- ing (26 [0.3%] vs. 14 [0.2%], P = 0.06), including fatal intracranial bleeding (11 [0.1%] vs. 1 [0.01%], P = 0.02). However, there were fewer episodes of other types of fatal bleeding in the ticagrelor group (9 [0.1%], vs. 21 [0.3%] in the clopidogrel group; P = 0.03) (Table 4).

Other Adverse Events

Dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 13.8% of patients vs. 7.8%) (Table 4). Few patients discon- tinued the study drug because of dyspnea (0.9% of patients in the ticagrelor group and 0.1% in the clopidogrel group).

Holter monitoring was performed for a me- dian of 6 days during the first week in 2866 patients and was repeated at 30 days in 1991 patients. There was a higher incidence of ven- tricular pauses in the first week, but not at day 30, in the ticagrelor group than in the clopidogrel group (Table 4). Pauses were rarely associated with symptoms; the two treatment groups did not differ significantly with respect to the inci- dence of syncope or pacemaker implantation (Table 4).

Discontinuation of the study drug due to ad- verse events occurred more frequently with ti- cagrelor than with clopidogrel (in 7.4% of pa- tients vs. 6.0%, P<0.001) (Table 2). The levels of creatinine and uric acid increased slightly more during the treatment period with ticagrelor than with clopidogrel (Table 4).

D i s c u s s i o n

PLATO shows that treatment with ticagrelor as compared with clopidogrel in patients with acute coronary syndromes significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke. A similar benefit was seen for the individual components of death from vas- cular causes and myocardial infarction, but not for stroke. The beneficial effects of ticagrelor were achieved without a significant increase in the rate of major bleeding.

The benefits of ticagrelor over clopidogrel

were seen in patients who had an acute coronary syndrome with or without ST-segment elevation. Previous trials have shown benefits of clopidogrel in the same clinical settings.8,17-19 The advantages were seen regardless of whether patients had re- ceived appropriate initiation of treatment with the

Hazard ratio, 0.84 (95% CI, 0.77–0.92)

22p3

P<0.001

100

C u

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E n

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o in

t (%

)

0 0 2 4 6 8 1210

Months

0 0 2 4 6 8 1210

Clopidogrel

Ticagrelor

No. at Risk Ticagrelor Clopidogrel

9333 9291

8628 8521

8460 8362

8219 8124

6743 6650

5161 5096

4147 4047

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Figure 1. Cumulative Kaplan–Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point.

The primary end point — a composite of death from vascular causes, myo- cardial infarction, or stroke — occurred significantly less often in the ti- cagrelor group than in the clopidogrel group (9.8% vs. 11.7% at 12 months; hazard ratio, 0.84; 95% confidence interval, 0.77 to 0.92; P<0.001).

22p3

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0 0 2 4 6 8 1210

Clopidogrel

Ticagrelor

No. at Risk Ticagrelor Clopidogrel

9235 9186

7246 7305

6826 6930

6545 6670

5129 5209

3783 3841

3433 3479

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Figure 2. Cumulative Kaplan–Meier Estimates of the Time to the First Major Bleeding End Point, According to the Study Criteria.

The time was estimated from the first dose of the study drug in the safety population. The hazard ratio for major bleeding, defined according to the study criteria, for the ticagrelor group as compared with the clopidogrel group was 1.04 (95% confidence interval, 0.95 to 1.13).

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currently recommended higher loading dose of clopidogrel and regardless of whether invasive or noninvasive management was planned.20-25 The treatment effects were the same in the short term (days 0 to 30) and in the longer term (days 31 to

360). This duration of treatment benefit has also been shown with clopidogrel.26 Thus, ticagrelor appears to expand on the previously demonstrat- ed benefits of clopidogrel across the spectrum of acute coronary syndromes.

Table 4. Safety of the Study Drugs.*

End Point Ticagrelor

Group Clopidogrel

Group

Hazard or Odds Ratio for Ticagrelor Group (95% CI)† P Value

Primary safety end points — no./total no. (%)

Major bleeding, study criteria 961/9235 (11.6) 929/9186 (11.2) 1.04 (0.95–1.13) 0.43

Major bleeding, TIMI criteria‡ 657/9235 (7.9) 638/9186 (7.7) 1.03 (0.93–1.15) 0.57

Bleeding requiring red-cell transfusion 818/9235 (8.9) 809/9186 (8.9) 1.00 (0.91–1.11) 0.96

Life-threatening or fatal bleeding, study criteria 491/9235 (5.8) 480/9186 (5.8) 1.03 (0.90–1.16) 0.70

Fatal bleeding 20/9235 (0.3) 23/9186 (0.3) 0.87 (0.48–1.59) 0.66

Nonintracranial fatal bleeding 9/9235 (0.1) 21/9186 (0.3) 0.03

Intracranial bleeding 26/9235 (0.3) 14/9186 (0.2) 1.87 (0.98–3.58) 0.06

Fatal 11/9235 (0.1) 1/9186 (0.01) 0.02

Nonfatal 15/9235 (0.2) 13/9186 (0.2) 0.69

Secondary safety end points — no./total no. (%)

Non–CABG-related major bleeding, study criteria 362/9235 (4.5) 306/9186 (3.8) 1.19 (1.02–1.38) 0.03

Non–CABG-related major bleeding, TIMI criteria 221/9235 (2.8) 177/9186 (2.2) 1.25 (1.03, 1.53) 0.03

CABG-related major bleeding, study criteria 619/9235 (7.4) 654/9186 (7.9) 0.95 (0.85–1.06) 0.32

CABG-related major bleeding, TIMI criteria 446/9235 (5.3) 476/9186 (5.8) 0.94 (0.82–1.07) 0.32

Major or minor bleeding, study criteria 1339/9235 (16.1) 1215/9186 (14.6) 1.11 (1.03–1.20) 0.008

Major or minor bleeding, TIMI criteria‡ 946/9235 (11.4) 906/9186 (10.9) 1.05 (0.96–1.15) 0.33

Dyspnea — no./total no. (%)

Any 1270/9235 (13.8) 721/9186 (7.8) 1.84 (1.68–2.02) <0.001

Requiring discontinuation of study treatment 79/9235 (0.9) 13/9186 (0.1) 6.12 (3.41–11.01) <0.001

Bradycardia — no./total no. (%)

Pacemaker insertion 82/9235 (0.9) 79/9186 (0.9) 0.87

Syncope 100/9235 (1.1) 76/9186 (0.8) 0.08

Bradycardia 409/9235 (4.4) 372/9186 (4.0) 0.21

Heart block 67/9235 (0.7) 66/9186 (0.7) 1.00

Holter monitoring — no./total no. (%)

First week

Ventricular pauses ≥3 sec 84/1451 (5.8) 51/1415 (3.6) 0.01

Ventricular pauses ≥5 sec 29/1451 (2.0) 17/1415 (1.2) 0.10

At 30 days

Ventricular pauses ≥3 sec 21/985 (2.1) 17/1006 (1.7) 0.52

Ventricular pauses ≥5 sec 8/985 (0.8) 6/1006 (0.6) 0.60

Neoplasm arising during treatment — no. of patients/ total no. (%)

Any 132/9235 (1.4) 155/9186 (1.7) 0.17

Malignant 115/9235 (1.2) 121/9186 (1.3) 0.69

Benign 18/9235 (0.2) 35/9186 (0.4) 0.02

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The incremental reduction in the risk of coro- nary thrombotic events (i.e., myocardial infarc- tion and stent thrombosis) through more-intense P2Y12 inhibition with ticagrelor is consistent with similar effects of prasugrel.10 As noted above, the benefits with ticagrelor were seen regardless of whether invasive or noninvasive management was planned; this issue has not been investigated with other P2Y12 inhibitors. Treatment with ticagrelor was also associated with an absolute reduction of 1.4 percentage points and a relative reduction of 22% in the rate of death from any cause at 1 year. This survival benefit from more-intense platelet inhibition with ticagrelor is consistent with reduc- tions in the mortality rate obtained by means of platelet inhibition with aspirin in patients who had an acute coronary syndrome27,28 and with clopidogrel in patients who had myocardial in- farction with ST-segment elevation.22 In contrast, other contemporary trials involving patients with an acute coronary syndrome have not shown sig- nificant reductions in the mortality rate with the use of clopidogrel,8 prasugrel,10 or glycoprotein IIb/IIIa inhibitors.29 The improved survival rate with ticagrelor might be due to the decrease in the risk of thrombotic events without a concomi- tant increase in the risk of major bleeding, as seen with other antithrombotic treatments in patients with an acute coronary syndrome.30-32

Since P2Y12 inhibition with ticagrelor is revers-

ible, the antiplatelet effect dissipates more rapidly than with the thienopyridines, which are irrevers- ible P2Y12 inhibitors. Therefore, less procedure- related bleeding might be expected. Although the rates of major bleeding were not lower with ticagrelor than with clopidogrel, the more-intense platelet inhibition with ticagrelor was not asso- ciated with an increase in the rate of any major bleeding. In contrast to the experience with prasugrel,10 which is also a more effective plate- let inhibitor than clopidogrel but is irreversible, there was no increased risk of CABG-related bleeding with ticagrelor. As with prasugrel,10 non–procedure-related bleeding (spontaneous bleeding), including gastrointestinal and intrac- ranial bleeding, was more common with ticagre- lor than with clopidogrel. Although the rare episodes of intracranial bleeding were often fa- tal, the rates of nonintracranial fatal bleeding, death from vascular causes, and death from any other cause were lower in the ticagrelor group than in the clopidogrel group, resulting in an overall reduction in the mortality rate with ti- cagrelor.

Dyspnea occurred more frequently with ti- cagrelor than with clopidogrel.13 Most episodes lasted less than a week. Discontinuation of the study drug because of dyspnea occurred in 0.9% of patients in the ticagrelor group. Holter moni- toring detected more ventricular pauses during

Table 4. (Continued.)

End Point Ticagrelor

Group Clopidogrel

Group

Hazard or Odds Ratio for Ticagrelor Group (95% CI)† P Value

Increase in serum uric acid from baseline value — %

At 1 mo 14±46 7±44 <0.001

At 12 mo 15±52 7±31 <0.001

1 Mo after end of treatment 7±43 8±48 0.56

Increase in serum creatinine from baseline value — %

At 1 mo 10±22 8±21 <0.001

At 12 mo 11±22 9±22 <0.001

1 Mo after end of treatment 10±22 10±22 0.59

* Plus–minus values are means ±SD. 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. The percentages for the primary and secondary safety end points are Kaplan– Meier estimates of the rate of the end point at 12 months. Patients could have more than one type of end point. CABG denotes coronary- artery bypass grafting.

† Hazard ratios are shown for all safety end points except bleeding requiring red-cell transfusion, for which odds ratios are shown. P values for the odds ratios were calculated with the use of Fisher’s exact test.

‡ 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.10

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the first week in the ticagrelor group than in the clopidogrel group,13 but such episodes were in- frequent at 30 days and were rarely associated with symptoms. There were no significant differ- ences in the rates of clinical manifestations of bradyarrhythmia between the two treatment groups.

The superiority of ticagrelor over clopidogrel with regard to the primary end point, as well as the similarity in rates of major bleeding, was consistent in 62 of 66 subgroups; the differences were significant in the remaining 4 subgroups (P<0.05 for heterogeneity). These findings may have been due to chance, given the large number of tests performed. The difference in results be- tween patients enrolled in North America and those enrolled elsewhere raises the questions of whether geographic differences between popula- tions of patients or practice patterns influenced the effects of the randomized treatments, although no apparent explanations have been found.

In conclusion, in patients who had an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor, as compared with clopidogrel, significantly reduced the rate of death from vascular causes, myocardial infarc- tion, or stroke, without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding.

Supported by AstraZeneca. Dr. Wallentin reports receiving consulting fees from Regado

Biosciences and Athera Biotechnologies; lecture fees from Boeh- ringer Ingelheim, AstraZeneca, and Eli Lilly, and grant support from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough; Dr. Becker, consulting fees from Regado Biosciences, AstraZeneca, Eli Lilly, and Bristol-

Myers Squibb and grant support from Momenta Pharmaceuticals, the Medicines Company, and Bristol-Myers Squibb; Dr. Budaj, consulting fees from Sanofi-Aventis and Eli Lilly and lecture fees from Sanofi-Aventis, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline. Dr. Cannon reports having equity ownership in Automedics Medical Systems and receiving grant support from Accumetrics, AstraZeneca, Bristol-Myers Squibb, Sanofi- Aventis, GlaxoSmithKline, Merck, Intekrin Therapeutics, Schering- Plough, Novartis, and Takeda. Drs. Emanuelsson and Horrow report being employees of AstraZeneca and having equity owner- ship in AstraZeneca; Dr. Horrow also reports receiving lecture fees from the Pharmaceutical Education and Research Institute. Dr. Husted reports receiving consulting fees from AstraZeneca, Sanofi-Aventis, and Eli Lilly and lecture fees from AstraZeneca, Sanofi-Aventis, and Bristol-Myers Squibb; Dr. Katus, consulting and lecture fees from AstraZeneca; Dr. Mahaffey, consulting fees from AstraZeneca, Bristol-Myers Squibb, Johnson and John- son, Eli Lilly, Pfizer, and Schering-Plough, lecture fees from Bayer, Bristol-Myers Squibb, Daichii Sankyo, Eli Lilly, and Sanofi- Aventis, and grant support from AstraZeneca, Portola Pharma- ceuticals, Schering-Plough, the Medicines Company, Johnson and Johnson, Eli Lilly, and Bayer; Dr. Scirica, consulting fees from AstraZeneca, Cogentus Pharmaceuticals, and Novartis, lecture fees from Eli Lilly, Daiichi Sankyo, and Sanofi-Aventis, and grant support from Astra Zeneca, Daiichi Sankyo, and Novartis. Dr. Steg reports receiving consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Endotis Pharma, GlaxoSmithKline, Medtronic, Merck Sharp and Dohme, Nycomed, Servier, the Medicines Company, Daiichi Sankyo, and Sanofi-Aventis, lecture fees from the Medicines Company, Servier, Menarini, Pierre Fabre, Boehringer Ingelheim, Bristol- Myers Squibb, Glaxo Smith Kline, Medtronic, Nycomed, and Sanofi-Aventis, and grant support from Sanofi-Aventis and hav- ing equity ownership in Aterovax. Dr. Storey reports receiving consulting fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, Teva, and Schering-Plough, lecture fees from Eli Lilly, Daiichi Sankyo, and AstraZeneca, and grant support from AstraZeneca, Eli Lilly, Daiichi Sankyo, and Schering-Plough; and Dr. Har- rington, consulting fees from Bristol-Myers Squibb, Sanofi- Aventis, Portola Pharmaceuticals, Schering-Plough, and Astra- Zeneca, lecture fees from Schering-Plough, Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly, and grant support from Millenium Pharmaceuticals, Schering-Plough, the Medicines Company, Portola Pharmaceuticals, Astra Zeneca, and Bristol-Myers Squibb. No other potential conflict of interest relevant to this article was reported.

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. Wallentin (cochair), S. James, I. Ekman; H. Emanuels- son, A. Freij, M. Thorsen; United States: R.A. Harrington (cochair), R. Becker, C. Cannon, J. Horrow; Denmark: S. Husted; Germany: H. Katus; U.K.: A. Skene (statistician), R.F. Storey; France: P.G. Steg; Steering Committee — Italy: D. Ardissino; Australia: P. Aylward; Philip- pines: N. Babilonia; France: J.-P. Bassand; Poland: A. Budaj; Georgia: Z. Chapichadze; Belgium: M.J. Claeys; South Africa: P. Commerford; the Netherlands: J.H. Cornel, F. Verheugt; Slovak Republic: T. Duris; China: R. Gao; Mexico: G.C. Armando; Germany: E. Giannitsis; United States: P. Gurbel, R. Harrington, N. Kleiman, M. Sabatine, D. Weaver; Spain: M. Heras; Denmark: S. Husted; Sweden: S. James; Hungary: M. Keltai; Norway: F. Kontny; Greece: D. Kremastinos; Finland: R. Lassila; Israel: B.S. Lewis; Spain: J.L. Sendon; Hong Kong: C. Man Yu; Austria: G. Maurer; Switzerland: B. Meier; Portugal: J. Morais; Brazil: J. Nicolau; Ukraine: A. Nikolaevich Parkhomenko; Turkey: A. Oto; India: P. Pais; Argentina: E. Paolasso; Bulgaria: D. Raev; Malaysia: D.S. Robaayah Zambahari; Russia: M. Ruda; Indonesia: A. Santoso; South Korea: K.-B. Seung; Singapore: L. Soo Teik; Czech Republic: J. Spinar; Thailand: P. Sritara; United Kingdom: R. Storey; Canada: P. Théroux; Romania: M. Vintila; Taiwan: D.W. Wu; Data Monitoring Committee — United States: J.L. Anderson (chair), D. DeMets (statistician); the Netherlands: M. Simoons; United Kingdom: R. Wilcox; Belgium: F. Van de Werf.

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