Author + information
- Received February 23, 2016
- Revision received March 23, 2016
- Accepted March 25, 2016
- Published online June 14, 2016.
- Marc P. Bonaca, MD, MPHa,∗ (, )
- Deepak L. Bhatt, MD, MPHa,
- Robert F. Storey, MDb,
- Ph. Gabriel Steg, MDc,
- Marc Cohen, MDd,
- Julia Kuder, MSa,
- Erica Goodrich, MSa,
- José C. Nicolau, MD, PhDe,
- Alexander Parkhomenko, MDf,
- José López-Sendón, MDg,
- Mikael Dellborg, MDh,
- Anthony Dalby, MDi,
- Jindřich Špinar, MDj,
- Philip Aylward, MDk,
- Ramón Corbalán, MDl,
- Maria Teresa B. Abola, MDm,
- Eva C. Jensen, MD, PhDn,
- Peter Held, MD, PhDn,
- Eugene Braunwald, MDa and
- Marc S. Sabatine, MD, MPHa
- aTIMI Study Group, Brigham and Women’s Hospital Heart & Vascular Center, Boston, Massachusetts
- bDepartment of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
- cFrench Alliance for Cardiovascular Trials, Université Paris-Diderot, Paris, France
- dCardiovascular Division, Newark Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York
- eHeart Institute (InCor)–University of São Paulo Medical School, São Paulo, Brazil
- fUkranian Strazhesko Institute of Cardiology, Kiev, Ukraine
- gHospital Universitario La Paz, Instituto de Investigación La Paz, Madrid, Spain
- hDepartment of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- iLife Fourways Hospital, Randburg, South Africa
- jUniversity Hospital, Jihlavska, Brno, Czech Republic
- kDivision of Medicine, Cardiac & Critical Care Services, Flinders Medical Centre, South Australia, Australia
- lCardiovascular Division, Pontificia Universidad Católica de Chile, Santiago, Chile
- mPhilippine Heart Center, University of the Philippines College of Medicine, Manila, Philippines
- nAstraZeneca R&D, Mölndal, Sweden
- ↵∗Reprint requests and correspondence:
Dr. Marc P. Bonaca, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Background Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infarction (MI).
Objectives This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major adverse limb events in patients with PAD and a prior MI.
Methods PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin—Thrombolysis In Myocardial Infarction 54) randomized 21,162 patients with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE) (defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral revascularization for ischemia) were recorded in follow-up.
Results A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n = 404) had higher rates of MACE at 3 years than those without (n = 6,663; 19.3% vs. 8.4%; p < 0.001), which persisted after adjusting for baseline differences (adjusted hazard ratio: 1.60; 95% confidence interval: 1.20 to 2.13; p = 0.0013), and higher rates of acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater absolute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65; 95% confidence interval: 0.44 to 0.95; p = 0.026).
Conclusions Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-TIMI 54]; NCT01225562)
- acute limb ischemia
- major adverse cardiovascular events
- major adverse limb events
- peripheral arterial disease
Patients with peripheral artery disease (PAD) are at heightened risk of major adverse cardiovascular events (MACE), including myocardial infarction (MI) and stroke. The presence of concomitant symptomatic PAD in patients with coronary disease (i.e., polyvascular disease), has been associated with a further heightened risk of ischemic events and mortality beyond that associated with symptomatic disease in either vascular territory (coronary or peripheral artery) alone (1–4).
Intensive antithrombotic strategies aimed at reducing risk of MACE in patients with PAD have shown mixed results. Whereas antiplatelet monotherapy has been shown to reduce ischemic risk in patients with symptomatic PAD (4–6), the combination of aspirin and a P2Y12 inhibitor in patients with PAD undergoing lower extremity bypass surgery did not reduce a broad composite of cardiovascular and limb endpoints (7). However, larger studies evaluating the combination of aspirin and clopidogrel have shown trends of benefit for reducing MACE in patients with symptomatic vascular disease, including those with PAD (8,9). More recently, the addition of a PAR-1 antagonist, vorapaxar, was shown to reduce the risk of MACE in patients with prior MI or PAD but increase GUSTO (Global Use of Strategies to Open Occluded Arteries) moderate or severe bleeding (10). In addition to reducing MACE, vorapaxar was shown to reduce limb morbidity, including acute limb ischemia (ALI) and peripheral revascularization procedures, when added to aspirin and/or clopidogrel (11,12). These findings highlight the potential of antithrombotic therapies to reduce limb morbidity in patients with PAD.
The association of concomitant PAD with an increased risk of ischemic events is complicated by the fact that PAD is also associated with an increased risk of bleeding (13). There are many shared comorbidities that increase the risk of both PAD and bleeding, including age and renal dysfunction. In addition, it is possible that the diseased vasculature in PAD patients may be more prone to injury or procedural complications leading to bleeding. In trials of potent antithrombotic strategies for prevention in PAD, there have been significant increases in bleeding risk, particularly with full-dose anticoagulants (7,8,10,14).
The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial demonstrated that the addition of ticagrelor, a potent, reversible P2Y12 inhibitor, reduces long-term ischemic risk in patients with a history of MI. This reduction in ischemic risk was accompanied by an increase in TIMI (Thrombolysis In Myocardial Infarction) major bleeding. We therefore investigated the ischemic and bleeding risks associated with concomitant symptomatic PAD and whether the effects of ticagrelor on MACE and major adverse limb events (MALE) were modified by the presence of PAD.
The PEGASUS-TIMI 54 trial randomized patients with prior MI to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. The design (15) and primary results of the trial have been published (16). In brief, the trial enrolled 21,162 patients with a spontaneous MI occurring 1 to 3 years prior to enrollment and at least 1 of the following additional high-risk features: age ≥65 years; diabetes mellitus requiring medication; a second prior spontaneous MI; multivessel coronary artery disease; or chronic renal dysfunction, defined as a creatinine clearance <60 ml/min, as estimated by the Cockcroft-Gault equation. Patients were ineligible if there was planned use of a P2Y12 receptor antagonist or anticoagulant therapy during the study period; if they had a bleeding disorder, or a history of an ischemic stroke or intracranial bleeding, a central nervous system tumor, or an intracranial vascular abnormality; or if they had had gastrointestinal bleeding within the previous 6 months or major surgery within the previous month. The presence of PAD was determined at baseline in 21,160 patients. In addition, among patients with PAD sites were to report whether there was an ankle-brachial index (ABI) ≤0.90, a history of peripheral revascularization, or a history of claudication.
The primary efficacy endpoint was the composite of CV death, MI, or stroke (MACE). ALI was prospectively collected and adjudicated using a previously published definition that required both a clinical presentation consistent with acute ischemia and findings either on physical examination or by imaging (12). Peripheral revascularization procedures were site reported and were collected prospectively on a dedicated electronic case report form. A trained reviewer (M.P.B.), blinded to treatment assignment, identified peripheral revascularization for ischemia (e.g., chronic critical limb ischemia, ALI, or claudication). The endpoint of MALE was defined as the composite of ALI and peripheral revascularization for ischemia. Amputation was collected as a safety event and included amputations for any cause (e.g., trauma, infection, or ischemia). Due to the lack of specificity, this outcome was not included in the MALE endpoint for this analysis, but was included in a sensitivity analysis of MALE by treatment arm. The primary safety endpoint was TIMI major bleeding. Additional safety endpoints were TIMI minor bleeding, intracranial hemorrhage (ICH), and fatal bleeding. A clinical events committee blinded to treatment allocation adjudicated all primary efficacy outcomes, ALI, and bleeding events.
Baseline characteristics were summarized using medians and quartiles for continuous variables and frequencies and percentages for categorical variables. Differences were tested with the Wilcoxon rank sum test for continuous variables and with the Pearson chi-square test for categorical data. Cox proportional hazard models were used to assess the risk of MACE. Associations between PAD and the risk of MACE were adjusted for baseline clinical characteristics that differed significantly between patients with and without PAD (age, race, MI type, second prior MI, diabetes, multivessel disease, hypertension, hypercholesterolemia, smoking, congestive heart failure, chronic obstructive pulmonary disease, prior stroke/transient ischemic attack, angina, coronary artery bypass graft [CABG], time from P2Y12 withdrawal, history of percutaneous coronary intervention with stenting, estimated glomerular filtration rate, and region). Clinical predictors of MALE were evaluated in patients overall and then in those with known PAD at baseline. Clinical baseline characteristics that differed (p < 0.1) were entered into a backward model selection to identify independent predictors with variables with p values >0.05, which were removed 1 at a time until all variables remaining had a p value <0.05. Analyses of the efficacy and safety of ticagrelor were not adjusted because treatment was randomized; therefore, baseline characteristics and potential confounders were approximately balanced (Online Table 1). The proportional hazards assumption was visually examined by scaled Schoenfeld residual plot, and the validity of this assumption was not violated. Efficacy analyses were performed on an intention-to-treat basis. Safety analyses included all patients who received at least 1 dose of study drug and included all events occurring after receipt of the first dose and within 7 days of the last dose of study drug. The prognostic accuracy of the models was compared using the area under the curve derived from receiver-operating characteristic curves (C-statistic) (17). The ability of the model to enhance discrimination and correctly reclassify subjects was additionally tested with the integrated discrimination improvement and the category-free net reclassification improvement (18,19).
A total of 21,162 patients were enrolled into the PEGASUS-TIMI 54 trial with prior MI and 1,143 (5%) had known PAD at randomization. Patients with known PAD primarily had a history of claudication (65%), with approximately one-third (34%) having a history of a peripheral revascularization procedure and only 48 (∼4%) with an abnormal ABI only without prior revascularization or symptoms (Table 1). Baseline characteristics in those with and without PAD at baseline are shown in Table 1, and by treatment arm within the PAD group in Online Table 1. The presence of PAD at baseline was associated with older age, qualifying non–ST-segment elevation MI relative to ST-segment elevation MI, diabetes, renal dysfunction, smoking status, heart failure, history of stroke or transient ischemic attack, and time from last dose of P2Y12 inhibitor prior to randomization (Table 1). Patients with PAD at baseline were more likely to have multivessel coronary disease and a history of CABG, and less likely to have a history of percutaneous coronary intervention (Table 1). Use of background medical therapy, including aspirin (99.9%), statins (93%), beta-blockers (83%), and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (80.5%) was high and similar, regardless of known PAD.
PAD and risk in patients randomized to placebo
At 3 years, patients with concomitant PAD at baseline randomized to placebo had more than a 2-fold increase in the rate of MACE events relative to patients without concomitant PAD (19.3% vs. 8.4%; unadjusted hazard ratio [HR]: 2.46; 95% confidence interval [CI]: 1.92 to 3.15) (Figure 1A). Rates of the individual components of CV death, MI, or stroke, as well as all-cause mortality were also higher in patients with PAD (Figure 1B). The risk of MACE associated with PAD at baseline was highest in patients with a history of prior peripheral revascularization, followed by those with claudication but no history of revascularization, and patients with an abnormal ABI (≤0.90) alone (Figure 2). Among patients with PAD, components of MALE, including peripheral revascularization, occurred in 9.2% of patients and ALI in 1.0%, whereas (as expected) these events occurred in <1% of patients without known PAD at randomization (Figure 1B). Overall, beyond PAD history, independent predictors of MALE at baseline were prior CABG, current smoking, hypertension, chronic obstructive pulmonary disease, and diabetes (Online Table 2). For the patients with known PAD, a prior history of peripheral revascularization (HR: 3.76; 95% CI: 2.26 to 6.25; p < 0.001) was the only independent predictor of future MALE.
Patients in the placebo arm with PAD tended to have higher rates of bleeding at 3 years compared with patients without known PAD, including TIMI major bleeding (1.56% vs. 1.03%; HR: 1.47; 95% CI: 0.53 to 4.07; p = 0.46) (Figure 1B), TIMI major or minor bleeding (2.21% vs. 1.37%; HR: 1.67; 95% CI: 0.72 to 3.85; p = 0.23), and the composite of ICH or fatal bleeding (1.25% vs. 0.57%; HR: 2.05; 95% CI: 0.62 to 6.76, p = 0.24) (Figure 1B).
After adjusting for differences in baseline characteristics, patients with concomitant PAD at baseline had a significantly higher risk of MACE relative to patients without concomitant PAD (adjusted HR: 1.60; 95% CI: 1.20 to 2.13; p = 0.0013) (Figure 1A). Elements of the model before and after the addition of PAD, as well as the C-statistic change and measures of reclassification, are shown in Online Tables 3 to 5. Directionally similar results existed for the components of MACE, particularly CV death (adjusted HR: 1.84; 95% CI: 1.16 to 2.94; p = 0.0102) and stroke (adjusted HR: 2.31; 95% CI: 1.26 to 4.25; p = 0.0071). All-cause mortality was also significantly higher (adjusted HR: 2.05; 95% CI: 1.43 to 2.94; p < 0.001) (Figure 3). The adjusted risk of TIMI major bleeding (adjusted HR: 1.57; 95% CI: 0.47 to 5.22; p = 0.46) (Figure 3), TIMI major or minor bleeding (adjusted HR: 1.51; 95% CI: 0.53 to 4.30; p = 0.44), and the composite of ICH or fatal bleeding (adjusted HR: 1.97; 95% CI: 0.44 to 8.80; p = 0.37) tended to remain higher in patients with PAD.
Efficacy and safety of ticagrelor for MACE in patients with prior MI and PAD
There was no heterogeneity in the relative risk reduction with ticagrelor for MACE in patients on the basis of the presence of PAD at baseline (p interaction = 0.41) (Central Illustration). However, by nature of their greater absolute risk, patients with PAD had a numerically greater absolute risk reduction at 3 years (4.1%; 95% CI: −1.07% to 9.29%) relative to those without PAD (1.0%; 95% CI: 0.14% to 1.9%) (Central Illustration). The efficacy versus placebo was generally similar for the 2 doses of ticagrelor, but, of note, the 60-mg dose resulted in a significant reduction in CV mortality (HR: 0.47; 95% CI: 0.25 to 0.86; p = 0.014) (Table 2, Figure 4), which drove a reduction in all-cause mortality (HR: 0.52; 95% CI: 0.32 to 0.84; p = 0.0074).
Ticagrelor increased TIMI major bleeding consistently for patients with PAD (pooled doses HR: 1.32; 95% CI: 0.41 to 4.29) and without PAD (HR: 2.59; 95% CI: 1.91 to 3.52; p interaction = 0.28). Although patients with PAD randomized to placebo were at greater absolute risk of bleeding, the absolute risk increase with ticagrelor at 3 years was numerically lower for those with PAD (0.12%; 95% CI: −1.79% to 2.04%) relative to those without PAD (1.46%; 95% CI: 1.01% to 1.91%) at baseline, although events were infrequent. Secondary bleeding outcomes by baseline PAD for both ticagrelor doses are shown in Table 2. Rates of intracranial hemorrhage and fatal bleeding in patients with PAD were low.
MALE with ticagrelor
Overall, ticagrelor reduced MALE (HR: 0.65; 95% CI: 0.44 to 0.95; p = 0.026) (Figure 5), with a numerically greater relative risk reduction with the 90-mg dose (HR: 0.49; 95% CI: 0.30 to 0.81; p = 0.005) relative to the 60-mg dose (HR: 0.81; 95% CI: 0.53 to 1.24; p = 0.33) (Table 3). The effects were consistent for both a reduction in ALI (pooled doses HR: 0.56; 95% CI: 0.23 to 1.37) and peripheral revascularization for limb ischemia (pooled doses HR: 0.63; 95% CI: 0.43 to 0.93) (Online Figure 1). Results were similar in the subgroup of patients with a known history of PAD (Online Table 6) as well as when including amputation for any reason (Online Table 7).
This study demonstrates that in outpatients in stable condition with a history of MI, concomitant PAD is associated with significantly heightened risk of systemic ischemic events, limb ischemic events, bleeding, and all-cause mortality. In addition, the benefit of ticagrelor for the relative risk reduction of MACE was consistent, regardless of the presence or absence of known PAD; however, by nature of their heightened risk, patients with PAD had a particularly robust absolute risk reduction (Central Illustration). Finally, the combination of aspirin and ticagrelor reduced MALE relative to aspirin monotherapy.
The association of PAD with increased MACE risk in patients who are already at heightened risk by nature of a prior MI is complex. Possible explanations include that the presence of disease in more than 1 bed indicates a more severe form of atherosclerotic vascular disease. In addition, PAD is associated with other markers of atherothrombotic risk, including age, renal dysfunction, diabetes, and smoking. After adjustment for these baseline differences, however, PAD remained a potent marker of systemic ischemic risk. Regardless of whether PAD is a marker of a more severe vascular phenotype, an integrator of multiple adverse risk factors, or both, in practice it is an easily identifiable and potent indicator of future risk. In the current study, the magnitude of risk for MACE associated with claudication was similar to that of a history of peripheral revascularization, providing validity to this clinical indicator of PAD. These findings underscore the importance of identifying comorbid PAD in the clinic to inform future risks of both MACE and MALE.
Identification of heightened MACE risk is particularly useful if it informs clinical decision-making. The PEGASUS-TIMI 54 trial demonstrated that ticagrelor is efficacious for the reduction of MACE in patients with prior MI. Still, the need to balance ischemic efficacy and bleeding risk has created a desire to explore subgroups where ticagrelor has particularly robust efficacy. In the current analysis, we demonstrate that the presence of PAD does not modify the relative efficacy of ticagrelor. However, due to their more than 2-fold higher MACE risk, patients with PAD enjoyed a robust absolute risk reduction of 4.1% at 3 years, translating into a number needed to treat (NNT) of 25 (annualized NNT = 74). Although each dose was tested independently against placebo, and there was no formal interaction between the efficacy of either dose and the baseline presence of known PAD, the clearest benefit occurred with the 60-mg dose, with a 5.2% absolute risk reduction in MACE and NNT of 20 (annualized NNT = 58), as well as significant reductions in both CV death and all-cause mortality. At the same time, bleeding with ticagrelor appeared to be similar in patients with and without PAD. Therefore, the presence of PAD may be helpful to clinicians in identifying patients with prior MI who are likely to have a robust benefit with ticagrelor.
In addition to MACE risk, patients with PAD in the PEGASUS-TIMI 54 trial were at heightened risk of MALE. Limb revascularization for ischemia was as frequent as MI and occurred at more than twice the rate of stroke in patients with PAD. A history of peripheral revascularization was a predictor of MALE in patients with PAD in this analysis, corroborating observations from other studies (11).
To date, dual antiplatelet therapy with aspirin and clopidogrel has not been prospectively shown to be efficacious for reducing limb vascular events in patients with PAD (7). Although not powered to address this question, the current study suggests that dual antiplatelet therapy with aspirin and ticagrelor may be efficacious for reducing ALI if studied in larger, higher-risk cohorts. In addition, the reduction in the exploratory endpoint of peripheral revascularization for ischemia also supports potential antithrombotic benefits of ticagrelor on the limb circulation. Whether potent antiplatelet therapy can reduce elective revascularization for claudication, as has been observed with other mechanisms, remains unknown (11). These questions will be evaluated as secondary outcomes in the ongoing EUCLID (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [NCT01732822]) trial, which is comparing ticagrelor and clopidogrel as monotherapy for a primary endpoint of MACE.
The PAD cohort, although comprising more than 1,000 patients, was a subgroup of the PEGASUS-TIMI 54 trial and thus had more limited power for exploration of the more rare endpoints, such as ALI. In addition, patients were identified as having PAD at baseline by study investigators, but no formal screening was required, and some patients may therefore have entered the trial with undiagnosed PAD. Questionnaires to improve the ascertainment and enable adjudication of claudication as a marker of PAD were not used, thereby potentially decreasing the specificity of this baseline characteristic. Amputations were collected as safety data and were not adjudicated, thereby limiting ascertainment and specificity of this outcome. In addition, details regarding procedures typically considered in the endpoint of MALE (e.g., thrombolysis/thrombectomy) were not available, underscoring the importance of examining these outcomes in dedicated studies in patients with PAD. Finally, peripheral revascularizations were site-reported; however, they were collected on a specific case report form page with instructions.
In patients with prior MI, concomitant PAD is associated with heightened risk of ischemic vascular complications and mortality, even after adjusting for their extensive comorbidities. In these patients, the combination of ticagrelor and aspirin for long-term secondary prevention appeared to reduce ischemic risk with a particularly robust absolute risk reduction, including reductions in MACE and limb vascular events.
COMPETENCY IN PATIENT CARE: Prolonged therapy with ticagrelor reduced ischemic risk and increased bleeding in patients with prior MI, and in a subgroup analysis, those with concomitant PAD appeared to derive greater absolute benefit than those without PAD.
TRANSLATIONAL OUTLOOK: An ongoing prospective trial of ticagrelor as antiplatelet monotherapy should provide more insight into the efficacy and safety of ticagrelor monotherapy versus clopidogrel monotherapy in a broad population of patients with PAD, including those without concomitant coronary disease.
The TIMI Study Group has received significant research grant support from AstraZeneca. Dr. Bonaca has received consulting fees from AstraZeneca, Merck, Bayer, and Roche Diagnostics. Dr. Bhatt has served on the advisory board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has served on the Board of Directors of Boston VA Research Institute, and the Society of Cardiovascular Patient Care; is chair of the American Heart Association Quality Oversight Committee; has served on the data monitoring committees of Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has served as deputy editor of Clinical Cardiology; has served as vice-chair of the NCDR-ACTION Registry Steering Committee; has served as the chair of the VA CART Research and Publications Committee; has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); is a site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical; is a trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr. Storey has received grants, personal fees, and travel support from AstraZeneca; and has received personal/consultancy fees from Aspen, PlaqueTec, Correvio, The Medicines Company, Medscape, and Thermo Fisher Scientific. Dr. Steg has received research grants from Merck, Sanofi, and Servier; and has served as a consultant or speaker for Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo-Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company. Dr. Cohen has received grants and personal fees from AstraZeneca during the conduct of the study; outside of this study he has received personal fees from Merck, Janssen, Maquet, malpractice attorneys, Merck, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Lilly; and has received grants from Janssen and Edwards Lifesciences. Dr. Nicolau has received speaker/consulting honoraria and/or research grant support from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Merck, Novartis, Pfizer, and Sanofi. Dr. López-Sendón has received research grants from AstraZeneca, Lilly/Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Novartis, and Servier; and has received honoraria from AstraZeneca, Lilly/Daiichi-Sankyo, Merck, and Sanofi. Dr. Dalby has received personal fees from AstraZeneca during the conduct of the study; and has received personal fees from Aspen, Bayer, Boehringer Ingelheim, DiscoveryHealth, Lilly, Novartis, Pfizer, Sanofi, and Servier outside of the submitted work. Dr. Aylward has received a research grant, has received honoraria for speaking, and served on the advisory board of AstraZeneca. Dr. Abola has received grants and modest personal/speaker fees from and served on the local advisory board for AstraZeneca during the conduct of the study; as an investigator in other ticagrelor trials has received modest personal fees as a member of the advisory board of and as a speaker for Pfizer; has received modest personal fees as speaker for Bayer, Boehringer Ingelheim, and Daiichi-Sankyo; and has received modest investigator fees from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, and Population Health Research Institute. Dr. Jensen is an employee of AstraZeneca. Dr. Held is an employee and stockholder of AstraZeneca. Dr. Braunwald has received institutional grant support from AstraZeneca. Dr. Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, Gilead, GlaxoSmithKline, Intarcia, Merck, Novartis, Poxel, Roche Diagnostics, Sanofi, and Takeda; and has served as a consultant for Alnylam, Amgen, AstraZeneca, Cubist, CVS Caremark, Intarcia, and Merck (all ≤$10,000/year). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute limb ischemia
- coronary artery bypass graft
- confidence interval
- hazard ratio
- major adverse cardiovascular event(s)
- major adverse limb event(s)
- myocardial infarction
- peripheral artery disease
- transient ischemic attack
- Thrombolysis In Myocardial Infarction
- Received February 23, 2016.
- Revision received March 23, 2016.
- Accepted March 25, 2016.
- American College of Cardiology Foundation
- Antithrombotic Trialists' Collaboration
- Bhatt D.L.,
- Flather M.D.,
- Hacke W.,
- et al.,
- for the CHARISMA Investigators
- Cacoub P.P.,
- Bhatt D.L.,
- Steg P.G.,
- et al.,
- for the CHARISMA Investigators
- Magnani G.,
- Bonaca M.P.,
- Braunwald E.,
- et al.
- Bonaca M.P.,
- Scirica B.M.,
- Creager M.A.,
- et al.
- Bonaca M.P.,
- Gutierrez J.A.,
- Creager M.A.,
- et al.
- Bhatt D.L.,
- Peterson E.D.,
- Harrington R.A.,
- et al.,
- CRUSADE Investigators
- Bonaca M.P.,
- Bhatt D.L.,
- Braunwald E.,
- et al.