Author + information
- Received March 2, 2018
- Revision received March 2, 2018
- Accepted March 2, 2018
- Published online May 14, 2018.
- Sonia S. Anand, MD, PhDa,∗ (, )
- Francois Caron, MDa,b,
- John W. Eikelboom, MBBS, MSca,
- Jackie Bosch, MSc, PhDc,d,
- Leanne Dyal, MScd,
- Victor Aboyans, MD, PhDe,
- Maria Teresa Abola, MDf,
- Kelley R.H. Branch, MD, MScg,
- Katalin Keltai, MD, PhDh,
- Deepak L. Bhatt, MD, MPHi,
- Peter Verhamme, MDj,
- Keith A.A. Fox, MBChB, BSck,
- Nancy Cook-Bruns, MDl,
- Vivian Lanius, PhDl,
- Stuart J. Connolly, MDa and
- Salim Yusuf, DPhila
- aDepartment of Medicine, Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
- bCISSS du Bas-St-Laurent, Quebec, Canada
- cSchool of Rehabilitation Science, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
- dPopulation Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
- eDepartment of Cardiology, Dupuytren University Hospital, Limoges, France
- fDepartment of Medicine, University of Philippines/Philippine Heart Centre, Manila, Philippines
- gDepartment of Medicine, University of Washington, Seattle, Washington
- hDepartment of Medicine, Semmelweis University, Budapest, Hungary
- iDepartment of Medicine, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts
- jDepartment of Medicine, University of Leuven, Leuven, Belgium
- kUniversity of Edinburgh, Edinburgh, United Kingdom
- lBayer AG, Wuppertal, Germany
- ↵∗Address for correspondence:
Dr. Sonia S. Anand, Population Health Research Institute, McMaster University, 30 Birge Street, Hamilton, Ontario L8L 0A6, Canada.
Background Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). There is limited information on the prognosis of patients who experience MALE.
Objectives Among participants with lower extremity PAD, this study investigated: 1) if hospitalizations, MACE, amputations, and deaths are higher after the first episode of MALE compared with patients with PAD who do not experience MALE; and 2) the impact of treatment with low-dose rivaroxaban and aspirin compared with aspirin alone on the incidence of MALE, peripheral vascular interventions, and all peripheral vascular outcomes over a median follow-up of 21 months.
Methods We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. COMPASS was a randomized, double-blind placebo-controlled study of low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone. MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation.
Results A total of 128 patients experienced an incident of MALE. After MALE, the 1-year cumulative risk of a subsequent hospitalization was 61.5%; for vascular amputations, it was 20.5%; for death, it was 8.3%; and for MACE, it was 3.7%. The MALE index event significantly increased the risk of experiencing subsequent hospitalizations (hazard ratio [HR]: 7.21; p < 0.0001), subsequent amputations (HR: 197.5; p < 0.0001), and death (HR: 3.23; p < 0.001). Compared with aspirin alone, the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43% (p = 0.01), total vascular amputations by 58% (p = 0.01), peripheral vascular interventions by 24% (p = 0.03), and all peripheral vascular outcomes by 24% (p = 0.02).
Conclusions Among individuals with lower extremity PAD, the development of MALE is associated with a poor prognosis, making prevention of this condition of utmost importance. The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowered the incidence of MALE and the related complications, and this combination should be considered as an important therapy for patients with PAD. (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]; NCT01776424)
About 200 million people worldwide are estimated to experience lower extremity peripheral artery disease (PAD) (1). Patients with PAD are at high risk for the development of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) (2). The recent COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial included 27,395 participants with coronary artery disease (CAD) and/or PAD; compared with aspirin alone, rivaroxaban in combination with aspirin significantly reduced the risk of MACE by 24% (3). In the subpopulation of patients with PAD from COMPASS, MALE (including major amputation) was reduced by 46%, as was the combined outcome of MACE or MALE by 31% (4). Although the incidence of MALE is relatively low at 1% per year, the consequences of this condition can severely alter a patient’s prognosis (5).
In the present analysis of patients with lower extremity PAD from the COMPASS trial, we report the prognosis after MALE and the impact of a MALE index event on other outcomes; evaluate the baseline factors that predict the development of MALE; and evaluate the impact of the low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone on the outcomes of MALE, vascular interventions, and all vascular outcomes.
COMPASS was a multicenter, double-blind, randomized, placebo-controlled trial comparing rivaroxaban 2.5 mg twice daily with aspirin in combination or rivaroxaban 5 mg twice daily (with aspirin placebo) versus aspirin alone (with rivaroxaban placebo) for the prevention of cardiovascular death, myocardial infarction, or stroke (MACE) in patients with CAD or PAD. The details of inclusion and exclusion criteria have been previously published (3,6,7). For this analysis, we included participants with lower extremity PAD reported on their baseline case record forms as a history of previous aortofemoral bypass surgery, limb bypass surgery, percutaneous transluminal angioplasty revascularization of the iliac or infra-inguinal arteries, limb or foot amputation for arterial vascular disease, intermittent claudication confirmed by objective measures (evidence of PAD according to ankle-brachial index, ultrasound, or angiogram); we also included participants with CAD who had an ankle-brachial index <0.90 at baseline. Symptoms of limb ischemia were assessed by using the Fontaine classification at baseline (4).
Definitions of PAD outcomes in COMPASS have been previously published (4). Briefly, MALE was defined as acute or chronic limb ischemia and, in this analysis, includes all major vascular amputations. Acute limb ischemia was defined as limb-threatening ischemia that was confirmed by using limb hemodynamic parameters or imaging and led to an acute vascular intervention (pharmacological [heparin, thrombolysis], peripheral artery surgery/reconstruction, peripheral angioplasty/stent, or amputation) within 30 days of onset of symptoms. Chronic limb ischemia was defined as continuing ischemic limb, foot, or digit pain leading to hospitalization and intervention and not meeting the definition of acute limb ischemia; or participants with Fontaine classification III or IV at baseline who had a peripheral vascular intervention over the course of the trial. Major vascular amputation was defined as an amputation due to a vascular event above the forefoot. Peripheral vascular interventions were defined as interventions (including peripheral angioplasty, vascular surgery, or amputation) not meeting the definition for acute limb ischemia or chronic limb ischemia. Total peripheral vascular outcomes were defined as acute or chronic limb ischemia, a peripheral vascular intervention, or a hospitalization for other vascular reason. The PAD outcome definitions were specified in advance, and acute limb ischemia events were verified by using an algorithm; if the algorithm did not confirm acute limb ischemia, events were formally adjudicated by a vascular disease expert physician (4).
To predict the development of MALE in the univariable model, the baseline factors significant at an alpha level of 0.10 were tested in a multivariable model. The multivariable model was constructed by using a stepwise selection method with an entry level of significance of 0.10 and a selection stay level of significance of 0.10. In the final multivariable model, a factor was deemed significant if its p value was <0.05. To describe the prognosis of individuals who experienced an index MALE outcome on subsequent events of interest (i.e., hospitalizations, MACE, vascular amputations, death), the time to event from the date of the index MALE to the date of the event of interest or end of follow-up (whichever occurred first) was used to approximate the incidence rate and the cumulative incidence risk according to Kaplan-Meier estimates. Among participants who experienced >1 MALE event, the first event was considered as the index event. To estimate the incidence rate of outcomes that occurred between randomization and the occurrence of MALE or end of follow-up (whichever occurred first), the time to event from the date of randomization to the date of the event of interest was used. For participants who experienced MALE, only those events that occurred before MALE were considered; otherwise, they were censored at the day of the MALE index event. Participants without the event of interest and who did not experience MALE were censored at the end of follow-up.
The impact of the MALE index event on other events of interest (i.e., hospitalizations, MACE, vascular amputations, death) was assessed by using a stratified Cox proportional hazards models with the MALE index event modeled as a time-dependent covariate. If the interaction between antithrombotic treatment and the time-dependent covariate MALE index event was significant at an alpha level of 0.10, the impact of the MALE index event was modeled separately according to treatment group. The comparison of treatment effect of the rivaroxaban and aspirin combination or rivaroxaban alone versus aspirin on the outcomes of MALE, peripheral vascular interventions, and all peripheral vascular outcomes was calculated by using separate log-rank tests. Kaplan-Meier estimates of the cumulative risk were used to evaluate the timing of event occurrences in each of the treatment groups. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were obtained from stratified Cox proportional hazards models. No adjustments for multiple testing were made.
Baseline characteristics of participants with PAD
A total of 6,391 participants with PAD of the lower extremity were included (Table 1). This cohort was generally well treated for secondary atherosclerosis prevention with lipid-lowering medications and angiotensin-converting enzyme inhibitors or angiotensin receptor blocker medications. Overall, 1.4% of participants developed atrial fibrillation or atrial flutter during the course of follow-up, and 2.7% of participants experienced a major bleeding complication. Furthermore, 82% of participants did not permanently discontinue randomized study drug over the course of the 21-month follow-up.
Characteristics of participants who experienced MALE
The independent predictors of MALE included severe ischemia symptoms at baseline (Fontaine classification III or IV), previous limb or foot amputation at baseline, history of peripheral revascularization surgery or angioplasty, and randomization to the aspirin arm of the trial. Diabetes, current or former smoking, female sex, and history of CAD were not independently predictive of MALE (Table 2). The incidence of MALE was 3.8% in patients with PAD and a history of intervention (i.e., peripheral revascularization or amputation), compared with 1.37% among those patients with PAD and intermittent claudication with no prior intervention, and lowest (0.35%) among those with asymptomatic PAD defined as an ankle-brachial index <0.90.
Prognosis after MALE
A total of 128 (2.0%) participants experienced MALE, and the median follow-up of patients after MALE was 360 days (interquartile range: 188 to 518 days). The cumulative incidence 1-year risk after MALE of a subsequent hospitalization was 61.5%; for total vascular amputations, it was 20.5%; for death, it was 8.3%; and for MACE, it was 3.7% (Table 3, Central Illustration). The MALE index event significantly increased the risk of experiencing subsequent hospitalization (HR: 7.21; 95% CI: 5.51 to 9.43; p < 0.0001), total vascular amputations (HR: 197.5; 95% CI: 97.33 to 400.8; p < 0.0001), death (HR: 3.23; 95% CI: 1.87 to 5.56; p < 0.0001) and the composite of MACE or total vascular amputations (HR: 7.56; 95% CI: 5.14 to 11.12; p < 0.0001) (Table 4).
In addition, the increased risk due to MALE for the outcomes of death and the MACE or total vascular amputations composite was different in the participants randomized to receive the rivaroxaban and aspirin combination compared with those randomized to receive aspirin alone. Although the risk of death did not change after a MALE event in participants randomized to receive the rivaroxaban and aspirin combination, there was a 6-fold risk (HR: 5.97; 95% CI: 3.19 to 11.19) of death after a MALE event for participants randomized to receive aspirin alone. Likewise, for the composite MACE or total vascular amputation, the risk did not change after a MALE event in participants randomized to receive the rivaroxaban and aspirin combination, but the risk in participants randomized to receive aspirin alone was 10-fold (HR: 10.24; 95% CI: 6.28 to 16.70) after the MALE event, acknowledging that the follow-up time after the MALE index event for participants randomized to receive the rivaroxaban and aspirin combination was shorter because antithrombotic treatment prevents MALE index events.
By definition, participants with MALE underwent an intervention, and the types and frequency of MALE-associated interventions are shown in Figure 1. The most common procedures associated with MALE were peripheral artery angioplasty (35.9%), amputation (23.4%), and bypass surgery (21.1%). Of the 128 participants with MALE, 48 (37.5%) discontinued study drugs after the index MALE, 17 (13.3%) were given a single antiplatelet agent, 13 (10.2%) received dual antiplatelet therapy, and 3 participants (2.3%) were given an oral anticoagulant; 15 (11.7%) of 128 participants received neither an antiplatelet nor an anticoagulant.
Treatment impact of low-dose rivaroxaban versus aspirin on MALE and peripheral vascular outcomes
Compared with those participants randomized to receive aspirin alone, participants randomized to receive the rivaroxaban and aspirin combination were less likely to experience MALE (2.6% vs. 1.5%; HR: 0.57; 95% CI: 0.37 to 0.88; p = 0.01). Total and major amputations were also reduced by 58% (95% CI: 15% to 79%) and 67% (95% CI: 8% to 88%), respectively. Vascular interventions were reduced by 24% (95% CI: 3% to 40%), and total peripheral vascular outcomes were reduced by 24% (95% CI: 4% to 39%) (Table 5, Figure 2). Rivaroxaban alone compared with aspirin alone showed only a nominally significant reduction in MALE and no significant reduction in total or major amputations due to a vascular cause.
We found that the prevention of MALE is of paramount importance among individuals with lower extremity PAD. The prognosis after experiencing MALE is dire, with a 3-fold increase in death and a 200-fold increase in the risk of subsequent vascular amputation (Central Illustration). Furthermore, MALE is more common in those with a history of peripheral revascularization, amputation, severe symptomatic limb ischemia at baseline, or treatment with single antiplatelet therapy. Consistent with the overall COMPASS trial result, we found that the use of rivaroxaban 2.5 mg twice daily and aspirin was superior to aspirin alone in reducing MALE, peripheral vascular interventions, and all peripheral vascular outcomes among individuals with lower extremity PAD.
Our findings support previous studies reporting a poor prognosis after MALE. Data from the TRA 2°P-TIMI 50 (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction 50) trial of vorapaxar showed that after acute limb ischemia, the risk of amputation was 27% and mortality was 14% after a median follow-up of 2 years (5). A recent retrospective cohort study included 1,085 U.S. acute care hospitals and 31,538 patients with PAD and chronic limb ischemia who underwent peripheral artery revascularization (8). The investigators reported that 21.3% of patients had unplanned hospital readmission within 30 days of being discharged; among those readmitted, 25% had repeat revascularization or amputation, and 5.2% had died. Common reasons for readmission included procedure-related complications, complications from diabetes, sepsis, and ongoing limb ischemia. Furthermore, readmission to the hospital was costly and priced at U.S. $12,394.
Individuals who had severe or progressive PAD were at the highest risk for experiencing MALE; specifically, risk predictors of severe PAD included severe limb ischemia (Fontaine classification III or IV) at baseline, previous peripheral bypass surgery or angioplasty, and previous vascular amputation. Our findings are consistent with earlier reports from other PAD trials, including the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial and the PAD subgroup analysis of 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), in which a history of peripheral revascularization was associated with a 4-fold increase in the risk of MALE (9,10).
Aspirin therapy is the most commonly used antiplatelet agent in patients with chronic stable PAD although the limb complication event rate remains relatively high, as noted by the international REACH (Reduction of Atherothrombosis for Continued Health) registry (11). In our analysis, we showed that randomization to the aspirin-alone arm of the trial is a “risk factor” for MALE, and the outcomes for patients after MALE receiving aspirin alone were worse compared with those receiving the rivaroxaban and aspirin combination. Given the effectiveness of low-dose rivaroxaban and aspirin, this combination therapy should be considered for patients with PAD to prevent MALE and to reduce peripheral vascular interventions.
Before COMPASS, other antiplatelet or antithrombotic agents alone or in combination have produced ambiguous results in patients with PAD. Compared with aspirin, more potent antiplatelet agents such as clopidogrel alone have not shown superiority for preventing MALE or its components (acute limb ischemia or amputation) (12,13). Dual antiplatelet therapy with clopidogrel and aspirin compared with single antiplatelet therapy also did not show significantly different limb outcomes in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial (14). In contrast, the PEGASUS trial of 21,612 post–myocardial infarction patients showed that a combination of ticagrelor with aspirin compared with aspirin alone reduced acute limb ischemia or revascularization for peripheral ischemia after 3 years of follow-up (0.46% vs. 0.71%; HR: 0.65; 95% CI: 0.44 to 0.95; p = 0.026) (15). These effects were directionally consistent but were not significant in the subset of 1,143 patients with concomitant PAD over 3 years of follow-up (5.75% vs. 7.3%; p = NS) (10). Some promise was observed with vorapaxar, a protease-activated receptor-1 antagonist, that was used in addition to dual antiplatelet agents, compared with dual antiplatelet therapy alone in reducing hospitalization for acute limb ischemia and peripheral revascularization (16); the significant increase in moderate/severe bleeding has impeded its widespread use, however. For oral anticoagulant agents such as warfarin, life-threatening bleeding rates are high, and no benefit has been observed in reducing MACE or severe limb ischemia in the chronic stable PAD population included in the WAVE (Warfarin Antiplatelet Vascular Evaluation) trial (17) or in reducing graft occlusion, amputation or vascular interventions in patients after infra-inguinal bypass surgery in the Dutch BOA (Bypass Oral Anticoagulants or Aspirin) trial (18).
The variable management of patients who experienced MALE in the COMPASS trial is consistent with the lack of robust evidence regarding the optimal antithrombotic treatment after MALE occurs. We observed significant variability in the antithrombotic therapy management of patients after MALE, with 62.5% of patients continuing on randomized blinded study drug, whereas the most common nonstudy drug therapy patients were given a single antiplatelet agent, followed by dual antiplatelet therapy. The use of oral anticoagulant agents was very low and, importantly, 11.7% of patients received neither study drug nor any other antithrombotic therapy after MALE. The optimal antithrombotic treatment after MALE requires further investigation.
In contrast to the mixed results of other antithrombotic treatments in patients with PAD, the COMPASS data demonstrate prevention of both MACE and MALE outcomes with a combination of low-dose oral anticoagulant rivaroxaban with aspirin. Furthermore, in this analysis, we showed that among patients with PAD of the lower extremity, the total number of peripheral vascular interventions and outcomes are also significantly reduced by this combination treatment, which is likely to result in significant cost savings for the health care system (19). This scenario strengthens the vascular protective role of combination low-dose oral rivaroxaban used with aspirin as the most effective therapy in this population (2).
There are both strengths and limitations of the present analysis that should be considered. Strengths include that the analysis comprised a relatively large number of participants with PAD; the study reported and adjudicated incident events within the context of a double-blind trial; participants were well treated for secondary atherosclerotic risk and thus reflect contemporary therapy; and this analysis of lower extremity PAD was pre-specified. Limitations include the fact that this study was a subgroup analysis of a larger trial (which showed similar results overall) despite MALE being a pre-specified endpoint and that there was a relatively low total number of MALE cases. The incidence of MALE, however, is consistent with other large trials that have included patients with stable PAD, and the prospective evaluation in COMPASS overcomes many of the potential biases of retrospective cohorts.
Among individuals with stable lower extremity PAD, the development of MALE is associated with a dire prognosis, making its prevention of utmost importance. The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowers the incidence of both MALE and MACE and their related complications. It should therefore be considered as an important therapy to improve prognosis among patients with lower extremity PAD.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Compared with aspirin alone in patients with lower extremity PAD, the combination of aspirin plus rivaroxaban 2.5 mg twice daily prevented MALE and improved survival.
TRANSLATIONAL OUTLOOK: Further research is required to optimize the medical and surgical management of patients who experience MALE.
This study was funded by Bayer AG. Dr. Anand is supported by a Tier 1 Canada Research Chair in Ethnicity and Cardiovascular Disease and the Michael G. DeGroote Heart and Stroke Foundation Chair in Population Health. Dr. Eikelboom is supported by the Jack Hirsh Population Health Research Institute Chair in Thrombosis Research. Dr. Yusuf is supported by the Heart & Stroke Foundation/Marion W. Burke Chair in Cardiovascular Disease. Dr. Anand has received honoraria and consulting fees from Bayer and Novartis. Dr. Eikelboom has received grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi-Aventis. Dr. Aboyans has received honoraria from Bayer, Bristol-Myers Squibb, Pfizer, Novartis, Pfizer/Bristol-Myers Squibb alliance, and Merck Sharp and Dohme. Dr. Abola has received speaker fees from AstraZeneca, Bayer, and Pfizer. Dr. Branch has received grants from Bayer, Astellas, and Janssen. Dr. Bhatt is a member of the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; on the board of directors for Boston VA Research Institute and the Society of Cardiovascular Patient Care; is chair of the American Heart Association Quality Oversight Committee; a member of data monitoring committees for the Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; vice-chair, ACC Accreditation Committee), 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, including for his roles in the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] trial as the U.S. national lead investigator, steering committee member, and operations committee member), Slack Publications (chief medical editor, Cardiology Today’s Intervention), the Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees); other involvement, including Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and the VA CART Research and Publications Committee (chair); has received research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi-Aventis, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Biotronik, Boston Scientific, and St. Jude Medical (now Abbott); is a Trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, PLx Pharma, and Takeda. Dr. Verhamme has received grants and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, Sanofi, and LEO Pharma. Dr. Fox has received grants and personal fees from AstraZeneca and Bayer/Janssen; and personal fees from Lilly and Sanofi/Regeneron. Drs. Cook-Bruns and Lanius are employed by Bayer AG. Dr. Connolly has received grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Janssen, AstraZeneca, Portola, and Sanofi-Aventis. Dr. Yusuf has received research grants and honoraria and travel reimbursement for speaking from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, AstraZeneca, and Sanofi-Aventis; and research grants from Cadila. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery disease
- confidence interval
- hazard ratio
- major adverse cardiovascular event(s)
- major adverse limb events
- peripheral artery disease
- Received March 2, 2018.
- Revision received March 2, 2018.
- Accepted March 2, 2018.
- 2018 American College of Cardiology Foundation
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