Patients with acute coronary syndromes and a history of prior stroke are at a high risk of ischemic and bleeding events and constitute a treatment challenge. Therefore, novel and more potent antithrombotic agents need to be evaluated with regard to the balance between efficacy and safety, particularly in the most vulnerable patients. Ticagrelor provides faster, greater, and more consistent platelet inhibition than clopidogrel. The PLATelet inhibition and patient Outcomes (PLATO) trial showed that ticagrelor was superior to clopidogrel in a broad population of patients with acute coronary syndromes for the prevention of cardiovascular death, myocardial infarction, or stroke but with an increase in overall major bleeding events not associated with coronary artery bypass surgery. Among the 18 624 patients randomized in the PLATO study, 1152 (6.2%) were reported as having a history of stroke or transient ischemic attack. These patients presented higher rates of the primary composite end point (myocardial infarction, CV death, and stroke) at 1 year compared with those patients without prior stroke or transient ischemic attack. The reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results. The rates of overall PLATO-defined major bleeding events associated with coronary artery bypass graft surgery, as well as major bleeding events, were similar, and intracranial bleeding occurred infrequently in the randomized groups. In light of a favorable clinical net benefit and associated impact on mortality, the results of the present study suggest that treatment with ticagrelor should not be withheld in acute coronary syndrome patients with a history of ischemic stroke or transient ischemic attack for safety concerns if otherwise indicated.
Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack
Abstract
Background—
Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages.
Methods and Results—
We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66–1.13; interaction P=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42–0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71–1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively).
Conclusions—
Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality.
Clinical Trial Registration—
URL: http://www.clinicatrials.gov. Unique identifier: NCT00391872.
Introduction
Patients with acute coronary syndromes (ACS) with a history of stroke or transient ischemic attacks (TIAs) are at particularly high risk for recurrent cardiovascular events, including death and myocardial infarction (MI). Clopidogrel combined with aspirin has been used successfully to prevent thrombotic events in patients with ACS, but patients with prior stroke continue to have a high risk of ischemic complications and bleeding complications, including an increased risk of intracranial bleeding.1,2
Editorial see p 2821
Clinical Perspective on p 2921
Ticagrelor is an oral nonthienopyridine P2Y12 inhibitor that is active on absorption and binds directly and reversibly to the receptor, which provides faster, greater, and more consistent platelet inhibition than clopidogrel.3 The PLATelet inhibition and patient Outcomes (PLATO) trial showed that ticagrelor was superior to clopidogrel for the prevention of cardiovascular death, MI, or stroke without a significant increase in overall major bleeding in a broad population of patients with ACS.4 A higher rate of major bleeding unrelated to coronary artery bypass graft surgery was observed with ticagrelor. The rates of fatal bleeding were similar (0.3%) in both the ticagrelor and clopidogrel groups, but more patients had fatal intracranial bleeding in the ticagrelor group (11 of 9235) than in the clopidogrel group (1 of 9186).4
New and more potent antithrombotic agents need to be evaluated with regard to the balance between efficacy and safety, particularly in the most vulnerable patients. The establishment of the clinical efficacy and safety of ticagrelor versus clopidogrel in patients with prior stroke or TIA was a prespecified subgroup analysis of the PLATO trial.
Methods
The PLATO trial randomized 18 624 patients admitted to the hospital with ST-segment elevation or non–ST-segment elevation ACS with onset during the previous 24 hours to ticagrelor or clopidogrel as soon as possible after admission. Details of study design, inclusion and exclusion criteria, outcome definitions, and results have been published previously.5 For non–ST-segment elevation ACS, carotid artery disease, previous ischemic stroke, TIA, carotid stenosis, or cerebral revascularization were among the risk factors that were required for inclusion, in addition to either biomarker elevation that indicated myocardial necrosis or ST changes on the ECG. Medical history, including any prior stroke or TIA, was assessed at the time of randomization and reported in the case report form.
Ticagrelor was given in a loading dose of 180 mg followed by 90 mg twice daily. Patients randomized to clopidogrel were given a maintenance dose of 75 mg/d. Those who were clopidogrel naive received a 300-mg loading dose. All patients received acetylsalicylic acid unless intolerant to it. The randomized treatment continued for a minimum of 6 months to a maximum of 12 months, with a median duration of study treatment of 9.1 months.
The primary efficacy variable was time to first occurrence of any event from the composite of death from vascular causes, MI, or stroke, and the first secondary efficacy outcome was the primary outcome in patients who were intended to undergo invasive treatment management at the time of randomization. The primary safety variable was the time to first occurrence of any PLATO-defined major bleeding. A neurological deficit caused by an ischemic or hemorrhagic central nervous system event with symptoms that lasted at least 24 hours after onset or that led to death constituted a stroke. A focal neurological deficit that resolved spontaneously without evidence of residual deficit 24 hours after onset constituted a TIA. The study was approved by the appropriate national and institutional regulatory authorities and ethics committees, and all participants gave written informed consent.
Statistical Analysis
Patient characteristics were compared by prior history of stroke or TIA status by use of χ2 and Wilcoxon rank sum tests. We tested whether the effect of ticagrelor on the primary efficacy and safety end points was different in patients with and without a history of stroke or TIA with Cox proportional hazards regression models that included treatment group, stroke or TIA history, and the treatment-by–stroke or TIA history interaction. These models were repeated with the addition of covariates from previously developed models in the PLATO population6 (online-only Data Supplement Table I). We also tested for treatment-by–stroke or TIA history interactions for other efficacy and safety end points. Results are presented as hazard ratios (HRs) and 95% confidence intervals (CIs) for ticagrelor versus clopidogrel (unadjusted and adjusted where available) for those with and without a stroke or TIA history. For the primary efficacy and safety end points and all-cause death, the time to event is presented by treatment/stroke or TIA history group with Kaplan-Meier curves at 360 days and total number of events during the trial.
All analyses were performed according to the intention-to-treat principle with SAS version 9.1. A 2-sided probability value of 0.05 was regarded as statistically significant for overall treatment differences.
Results
Patients
Among the 18 624 patients randomized in the PLATO study, 1152 (6.2%) were reported as having a history of stroke or TIA by the investigators (Table 1). Patients with a history of stroke or TIA were older, were more often female, and had more cardiovascular risk factors than patients without a history of stroke or TIA. One quarter of the patients were >75 years old. One third of the patients had reported diabetes mellitus. The majority (70.6%) of patients with a prior stroke or TIA underwent coronary angiography during the initial hospitalization and received guideline-recommended concomitant medical therapy to a high degree (Table 2).
| Characteristic | Prior Stroke or TIA* (n=1152) | No Prior Stroke or TIA* (n=17 458) | P† | ||
|---|---|---|---|---|---|
| Ticagrelor | Clopidogrel | Ticagrelor | Clopidogrel | ||
| Age, y | 67 (59–74) | 68 (60–75) | 62 (54–70) | 62 (54–70) | <0.0001 |
| Age ≥75 y | 136 (24.1) | 152 (25.9) | 1259 (14.4) | 1329 (15.3) | <0.0001 |
| Female sex | 192 (34.0) | 197 (33.5) | 2462 (28.1) | 2433 (28.0) | <0.0001 |
| Body weight, kg | 80 (70–88) | 77 (68–86) | 80 (70–90) | 80 (70–90) | 0.0024 |
| Body weight <60 kg | 39 (6.9) | 45 (7.7) | 613 (7.0) | 615 (7.1) | 0.7511 |
| BMI, kg/m2 | 27.5 (24.9–30.9) | 27.3 (24.5–30.4) | 27.4 (24.7–30.5) | 27.3 (24.7–30.4) | 0.5212 |
| Race | 0.0034 | ||||
| Black | 7 (1.2) | 16 (2.7) | 108 (1.2) | 98 (1.1) | |
| White | 506 (89.7) | 519 (88.3) | 8053 (91.9) | 7988 (91.8) | |
| Oriental | 41 (7.3) | 47 (8.0) | 501 (5.7) | 507 (5.8) | |
| Other | 10 (1.8) | 6 (1.0) | 99 (1.1) | 106 (1.2) | |
| Cardiovascular risk factors | |||||
| Habitual smoker | 163 (28.9) | 129 (21.9) | 3197 (36.5) | 3188 (36.7) | <0.0001 |
| Hypertension | 495 (87.8) | 490 (83.3) | 5644 (64.4) | 5553 (63.8) | <0.0001 |
| Dyslipidemia | 321 (56.9) | 350 (59.5) | 4026 (46.0) | 3991 (45.9) | <0.0001 |
| Medical history | |||||
| Angina pectoris | 315 (55.9) | 335 (57.0) | 3905 (44.6) | 3802 (43.7) | <0.0001 |
| Myocardial infarction | 167 (29.6) | 181 (30.8) | 1733 (19.8) | 1743 (20.0) | <0.0001 |
| Congestive heart failure | 63 (11.2) | 67 (11.4) | 450 (5.1) | 470 (5.4) | <0.0001 |
| Percutaneous coronary intervention | 91 (16.1) | 90 (15.3) | 1181 (13.5) | 1130 (13.0) | 0.0169 |
| Coronary artery bypass graft | 58 (10.3) | 62 (10.5) | 474 (5.4) | 512 (5.9) | <0.0001 |
| Peripheral artery disease | 86 (15.2) | 70 (11.9) | 480 (5.5) | 507 (5.8) | <0.0001 |
| Chronic renal disease | 31 (5.5) | 45 (7.7) | 348 (4.0) | 361 (4.1) | <0.0001 |
| Treatment | |||||
| OL clopidogrel dose ≥600 mg before randomization | 43 (7.6) | 37 (6.3) | 1113 (12.7) | 1074 (12.3) | <0.0001 |
| Total clopidogrel (OL+IP) dose ≥600 mg, before randomization to 24 h after first dose | 79 (14.0) | 73 (12.4) | 1871 (21.4) | 1822 (20.9) | <0.0001 |
| Intended invasive treatment | 337 (59.8) | 345 (58.7) | 6388 (72.9) | 6328 (72.7) | <0.0001 |
| Baseline laboratory values | |||||
| Glucose, mmol | 6.9 (5.7–8.7) | 7.0 (5.7–9.4) | 6.9 (5.7–8.8) | 6.8 (5.7–8.7) | 0.3288 |
| Creatinine clearance, mL/min | 74.4 (57.8–88.6) | 73.4 (57.8–87.4) | 83.2 (67.0–98.9) | 82.3 (66.4–97.7) | <0.0001 |
| First central troponin I, μmol/L‡ | 1.9 (0.2–10.2) | 2.2 (0.2–11.5) | 2.0 (0.2–11.9) | 2.2 (0.2–12.2) | 0.5325 |
TIA indicates transient ischemic attack; BMI, body mass index; OL, open label; and IP, investigational product.
Values are median (25th–75th percentiles) or n (%).
*
Sixty-nine patients had both prior transient ischemic attack and prior stroke, 653 had prior nonhemorrhagic stroke only, and 430 had prior transient ischemic attack only.
†
P from χ2 or Wilcoxon rank sum test comparing patients with and without stroke or TIA.
‡
Advia Centaur TnI-Ultra Immunoassay (Siemens).
| Characteristic | Prior Stroke or TIA* (n=1152) | No Prior Stroke or TIA* (n=17 458) | P† | ||
|---|---|---|---|---|---|
| Ticagrelor | Clopidogrel | Ticagrelor | Clopidogrel | ||
| Medication from index event to end of hospitalization, n (%) | |||||
| Aspirin | 545 (96.6) | 565 (96.1) | 8514 (97.2) | 8449 (97.3) | 0.0752 |
| β-blockers | 474 (84.0) | 485 (82.5) | 7505 (85.7) | 7476 (86.1) | 0.0132 |
| ACE inhibitors and/or ARB | 505 (89.5) | 510 (86.7) | 7255 (82.8) | 7202 (82.9) | <0.0001 |
| Cholesterol lowering (statin) | 520 (92.2) | 519 (88.3) | 8232 (94.0) | 8186 (94.2) | <0.0001 |
| Calcium channel blockers | 192 (34.0) | 187 (31.8) | 1794 (20.5) | 1850 (21.3) | <0.0001 |
| Diuretics | 299 (53.0) | 309 (52.6) | 3260 (37.2) | 3124 (36.0) | <0.0001 |
| Glycoprotein IIb/IIIa inhibitors | 106 (18.8) | 116 (19.7) | 2407 (27.5) | 2408 (27.7) | <0.0001 |
| Insulin | 123 (21.8) | 144 (24.5) | 1559 (17.8) | 1513 (17.4) | <0.0001 |
| Any antidiabetic medication | 186 (33.0) | 199 (33.8) | 2242 (25.6) | 2183 (25.1) | <0.0001 |
| Procedures, n (%) | |||||
| Coronary angiography before discharge | 402 (71.3) | 411 (69.9) | 7196 (82.1) | 7159 (82.3) | <0.0001 |
| Coronary angiography during study | 435 (77.1) | 444 (75.5) | 7572 (86.4) | 7527 (86.5) | <0.0001 |
| PCI before discharge | 264 (46.8) | 270 (45.9) | 5423 (61.9) | 5405 (62.1) | <0.0001 |
| PCI during study | 289 (51.2) | 291 (49.5) | 5689 (64.9) | 5707 (65.6) | <0.0001 |
| Stenting | 260 (46.1) | 254 (43.2) | 5380 (61.4) | 5394 (62.0) | <0.0001 |
| With bare-metal stent only | 157 (27.8) | 170 (28.9) | 3764 (43.0) | 3721 (42.8) | <0.0001 |
| With ≥1 drug-eluting stent | 103 (18.3) | 84 (14.3) | 1616 (18.4) | 1673 (19.2) | 0.0280 |
| CABG before discharge | 30 (5.3) | 33 (5.6) | 435 (5.0) | 472 (5.4) | 0.6853 |
| CABG during study | 62 (11.0) | 67 (11.4) | 869 (9.9) | 901 (10.4) | 0.2494 |
| Final diagnosis, n (%) | <0.0001 | ||||
| STEMI | 149 (26.4) | 156 (26.6) | 3347 (38.3) | 3374 (38.8) | |
| NSTEMI | 271 (48.0) | 275 (46.9) | 3734 (42.7) | 3675 (42.3) | |
| Unstable angina pectoris | 128 (22.7) | 140 (23.9) | 1421 (16.2) | 1422 (16.4) | |
| Other | 16 (2.8) | 15 (2.6) | 243 (2.8) | 215 (2.5) | |
TIA indicates transient ischemic attack; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; PCI, percutaneous coronary intervention; CABG, coronary artery bypass surgery; STEMI, ST-segment elevation myocardial infarction; and NSTEMI, non–ST-segment elevation myocardial infarction.
*
Sixty-nine patients had both prior transient ischemic attack and prior stroke, 653 had prior nonhemorrhagic stroke only, and 430 had prior transient ischemic attack only.
†
P from χ2 or Wilcoxon rank sum test comparing patients with and without stroke or transient ischemic attack.
Sixty-nine patients reported both prior TIA and prior stroke, 653 had prior nonhemorrhagic stroke only, and 430 had a prior TIA only. Most patients (52%) had their cerebrovascular event >12 months before enrollment into PLATO. Five percent had their event between 6 and 12 months before and 5% of patients within 6 months of enrollment. The interval was unknown in the remaining 39% of patients.
Outcomes in Relation to Prior Stroke Status
At 1 year, patients with prior stroke or TIA had higher rates of the primary composite end point, MI, death, stroke, major bleeding, and intracranial bleeding than those patients without prior stroke or TIA. After multivariable adjustment, prior stroke or TIA remained significantly correlated with the primary composite end point, total mortality, and major bleeding not related to coronary artery bypass surgery (Table 3). End-point events with low event rates or for which models have not been developed previously in the PLATO population were not included in the multivariable analyses.
| End Point | Prior Stroke or TIA (n=1152) | No Prior Stroke or TIA (n=17 460) | Unadjusted | Adjusted | ||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | χ2 | P | HR (95% CI) | χ2 | P | |||
| Primary outcome: CV death/MI (excluding silent)/stroke | 19.9 (215) | 10.1 (1663) | 2.06 (1.78–2.37) | 98.9672 | <0.0001 | 1.65 (1.40–1.93) | 36.7953 | <0.0001 |
| CV death (includes vascular and unknown deaths) | 9.7 (102) | 4.2 (693) | 2.29 (1.86–2.82) | 61.1987 | <0.0001 | |||
| All-cause death | 10.5 (111) | 4.9 (794) | 2.18 (1.79–2.66) | 59.1666 | <0.0001 | 1.68 (1.33–2.11) | 19.7284 | <0.0001 |
| MI (excluding silent) | 11.5 (119) | 6.0 (978) | 1.92 (1.59–2.33) | 45.3974 | <0.0001 | |||
| Major bleeding (study criteria) | 14.8 (144) | 11.2 (1746) | 1.31 (1.10–1.55) | 9.5022 | 0.0021 | 1.18 (0.98–1.43) | 2.9463 | 0.0861 |
| Non–CABG-related major bleeding (study criteria) | 6.3 (60) | 4.0 (608) | 1.56 (1.20–2.04) | 10.8716 | 0.0010 | 1.38 (1.03–1.85) | 4.5464 | 0.0330 |
| Stroke | 3.4 (36) | 1.2 (195) | 2.90 (2.03–4.14) | 34.4170 | <0.0001 | |||
| Intracranial bleeding | 0.8 (8) | 0.2 (33) | 3.95 (1.82–8.55) | 12.1333 | 0.0005 | |||
TIA indicates transient ischemic attack; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; and CABG, coronary artery bypass graft surgery.
Event rates are presented as Kaplan-Meier rate at 360 days (total number of events during the trial). Variables included in the multivariable model were age, sex, prior myocardial infarction, heart failure, hypertension, smoking, height, weight, previous percutaneous coronary intervention, coronary artery bypass surgery, ST elevation or left bundle-branch block on ECG at entry, estimated creatinine clearance, heart rate, peripheral artery disease, prior tachyarrhythmia, blood pressure, and prior angina pectoris.
Outcomes in Relation to Stroke Status and Randomized Treatment
The overall results for the randomized groups were consistent with the overall PLATO trial results (Figures 1 and 2). The relative reduction of the primary end point with ticagrelor compared with clopidogrel was consistent in patients with (13%) and without (16%) prior stroke or TIA (Figure 1A). After multivariable adjustment, the HR for patients with prior stroke/TIA was 0.97 (95% CI, 0.72–1.31), with no significant treatment-by–stroke or TIA history interaction (P=0.39). This reduction was 34% in the subset of patients with a history of stroke or TIA who were intended to undergo invasive management at the time of randomization.
For all-cause death, the relative reduction with ticagrelor versus clopidogrel was 38% and 19% in patients with or without a prior history of stroke or TIA, respectively (Figure 1B), with no significant treatment-by–stroke or TIA history interaction (Figure 2). After multivariable adjustment, the HR for patients with prior stroke/TIA was 0.85 (95% CI, 0.56–1.30), with no significant treatment-by–stroke history interaction (P=0.98). Neither overall stroke rates nor hemorrhagic stroke rates displayed a significant treatment-by-subgroup interaction. The number of fatal stroke events was small, with an HR point estimate for ticagrelor versus clopidogrel of 0.43 in patients with prior stroke or TIA compared with 2.23 in patients without prior stroke or TIA. The treatment-by–stroke history interaction was nominally significant (P=0.029).
Among patients with a prior stroke or TIA, the rates of PLATO-defined major bleeding and non–coronary artery bypass graft surgery–related major bleeding were not significantly different between patients assigned to ticagrelor and clopidogrel (Figures 1C and 2), with adjusted HRs of 1.11 (95% CI, 0.77–1.59) and 1.10 (95% CI, 0.63–1.90), respectively. Intracranial bleeding occurred infrequently and with no difference between the ticagrelor and clopidogrel groups (4 patients each). These results were consistent with those of patients with prior ischemic stroke alone (n=653; data not shown).
Discussion
The present study confirms the findings from several other clinical trials and databases that patients admitted with ACS and a history of stroke or TIA have an increased risk of adverse ischemic events,7 mortality,8 and bleeding,9 even after multivariable adjustment for baseline differences. Despite good adherence to guidelines concerning pharmacological therapies and invasive procedures, patients with prior stroke or TIA demonstrated a doubled mortality rate and a 3 and 4 times higher risk for stroke and intracranial bleeding, respectively. Therefore, patients with a history of stroke constitute a real treatment challenge. Most factors that indicate high ischemic risk also indicate high bleeding risk. In this high-risk population, the balance between safety and efficacy of antithrombotic treatment is therefore particularly important.
The reduction in the primary ischemic end point (cardiovascular and total mortality) by ticagrelor compared with clopidogrel in aspirin-treated ACS patients with prior stroke or TIA was consistent with the overall PLATO population, with no apparent increase in overall bleeding and low rates of hemorrhagic stroke and intracranial bleeding. Ischemic and bleeding outcomes have been evaluated in patients with a history of stroke or TIA in several previous trials of antithrombotic agents. Clopidogrel compared with placebo nominally reduced the primary end point of cardiovascular death, MI, and stroke in the subgroup of patients with previous stroke and stable atherosclerotic disease in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.10 Outcomes of clopidogrel versus placebo in ACS patients with a history of stroke have not been reported. Dual-antiplatelet therapy with aspirin and clopidogrel in high-risk patients with recent ischemic stroke or TIA was associated with a numeric reduction of major vascular events but increased the risk of life-threatening or major bleeding compared with clopidogrel alone in the Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) trial.11
In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38),12 prasugrel reduced the primary composite ischemic end point versus clopidogrel at a cost of more frequent major bleeding events. The rate of intracranial bleeding and overall major bleeding with prasugrel versus clopidogrel was increased in the cohort of patients with prior history of stroke or TIA, which led to an overall negative net clinical benefit. Prasugrel is therefore contraindicated for this high-risk subset of patients by most regulatory authorities and guideline committees.
Recently, several trials of novel antithrombotic agents given in combination with other antiplatelets or anticoagulants have been terminated prematurely because of bleeding safety issues in general and intracranial bleeding episodes in particular. The Thrombin Receptor Antagonist –Secondary Prevention (TRA-2°P) trial13 stopped treatment during the follow-up phase in patients with a history of stroke or who experienced stroke during the course of the study because the risk of intracranial hemorrhage outweighed the potential benefit of vorapaxar in these patients (http://www.merck.com/newsroom/news-release-archive/research-and-development/2011_0113.html). The follow-up phase of treatment with vorapaxar on top of single- or dual-antiplatelet therapy14 was also stopped prematurely by the data safety monitoring board in the Thrombin Receptor Antagonist for Clinical Event Reduction in acute coronary syndrome (TRACER) trial. The APixaban for PRevention of Acute ISchemic Events 2 (APPRAISE 2) trial evaluated an oral direct coagulation factor Xa inhibitor, apixaban, compared with placebo on top of antiplatelet monotherapy or dual-antiplatelet therapy for ACS and included patients with a prior history of stroke and TIA. The trial was stopped prematurely by the data safety monitoring board because of an increase in overall bleeding events, including intracranial and fatal hemorrhage.15 The Anti-Xa Therapy to Lower cardiovascular events in Addition to Standard therapy in subjects with acute coronary syndrome (ATLAS) trial evaluated rivaroxaban, another factor Xa inhibitor, but excluded patients with a prior history of stroke or TIA on dual-antiplatelet therapy.16 Rivaroxaban reduced the primary ischemic end point and mortality but increased the bleeding incidence considerably, including intracerebral and fatal bleeding events.
Study Limitations
The present study is an underpowered subgroup analysis of the PLATO trial, with its inherent limitations. Because of the small numbers, significant interactions for the randomized treatment and outcome cannot be excluded; however, the subgroup consisted of >1000 patients, and the results are consistent with the overall trial results. For most of the ischemic end points and all stroke-related and bleeding end points, the HR in fact tended to be lower for the ticagrelor versus clopidogrel comparison in patients with a history of stroke/TIA than in patients without stroke/TIA. Thus, there was no signal of any particular increased risk with ticagrelor in this high-risk subset of patients versus other ACS patients. Randomization was not stratified for prior stroke status, which explains why unbalances between the groups may exist. Results of this exploratory analysis appear with nominal significance levels not corrected for multiplicity and should therefore be interpreted with appropriate caution.
Conclusions
ACS patients with prior stroke or TIA constitute a sizeable subgroup, develop worse outcomes, and challenge our clinical skills. The present analysis of the high-risk subgroup of patients with a history of stroke or TIA demonstrates that more potent and consistent inhibition of platelet aggregation with the reversibly binding P2Y12 receptor inhibitor ticagrelor reduced ischemic events with no significant increase in overall major bleeding complications, consistent with the overall PLATO trial results. In fact, despite the more potent antithrombotic effect, the risk of intracranial hemorrhage or fatal stroke was low, and total mortality was reduced significantly by ticagrelor. In light of a favorable clinical net benefit and associated impact on mortality, treatment with ticagrelor should not be withheld in ACS patients with a history of ischemic stroke or TIA for safety concerns if otherwise indicated.
Acknowledgments
The complete list of PLATO investigators and main study committees has been published previously. We acknowledge Ebba Bergman, PhD, Uppsala Clinical Research Center for editorial support.
Clinical Perspective
Supplemental Material
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Sources of Funding
The PLATO study was funded by AstraZeneca. Support for the analysis and interpretation of results and preparation of the manuscript was provided through funds to the Uppsala Clinical Research Center and Duke Clinical Research Institute as part of the Clinical Study Agreement.
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© 2012 American Heart Association, Inc.
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Received: 30 November 2011
Accepted: 12 April 2012
Published online: 9 May 2012
Published in print: 12 June 2012
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Dr James receives institutional research grant and honoraria from AstraZeneca, Eli Lilly, Merck, and Bristol-Myers Squibb. He also acts as an advisory board member for AstraZeneca, Eli Lilly, and Merck and receives honoraria from The Medicines Company. Dr Storey receives research grant from AstraZeneca, Eli Lilly/Daiichi Sankyo, and Merck. He receives research support from Accumetrics and Dynabyte and honoraria from AstraZeneca, Eli Lilly/Daiichi Sankyo, Merck, Novartis, The Medicines Company, Iroko, Sanofi-aventis/Merck, GlaxoSmithKline, Accumetrics, Medscape, and Eisai. He receives consultancy fees from AstraZeneca, Merck, Novartis, Accumetrics, and Eisai. Drs Khurmi and Maya are employees of and have equity ownership in AstraZeneca. Dr Husted receives advisory board fees from AstraZeneca, Bristol-Myers Squibb, and Bayer. Dr Mahaffey receives consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, Merck, Ortho/McNeill, Sanofi-aventis, and Schering-Plough (now Merck); he receives grant support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, Merck, Novartis, Portola Pharmaceuticals, Pozen, Regado Biosciences, Sanofi-aventis, Schering-Plough (now Merck), and The Medicines Company. Dr Morais receives payments from speakers' bureaus from AstraZeneca, Bayer, and MSD and honoraria from AstraZeneca, Bayer, Jaba Recordati, and MSD. Dr Lopes receives research grant from Bristol-Myers Squibb and advisory board fees from Boehringer Ingelheim and Pfizer. Dr Nicolau receives research grants, consultancy fees, and payments from speakers' bureaus from Eli Lilly and AstraZeneca. Dr Raev receives honoraria from AstraZeneca. Dr Lopez-Sendon receives research grants and honoraria from AstraZeneca, Eli-Lilly, Bayer, and Pfizer. Dr Becker receives research grants from Johnson and Johnson, Bayer, and Regado Biosciences and honoraria and consultancy fees from Johnson and Johnson, Daiichi Sankyo, and Regado Biosciences. The other authors report no conflicts.
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