Author + information
- Received July 6, 2017
- Revision received November 5, 2017
- Accepted November 25, 2017
- Published online January 29, 2018.
- Sameer Bansilal, MD, MSa,
- Marc P. Bonaca, MD, MPHb,
- Jan H. Cornel, MD, PhDc,
- Robert F. Storey, MDd,
- Deepak L. Bhatt, MD, MPHb,
- Ph. Gabriel Steg, MDe,f,
- Kyungah Im, PhDb,
- Sabina A. Murphy, MPHb,
- Dominick J. Angiolillo, MD, PhDg,
- Robert G. Kiss, MDh,
- Alexander N. Parkhomenko, MD, PhDi,
- Jose Lopez-Sendon, MD, PhDj,
- Daniel Isaza, MDk,
- Assen Goudev, MD, DScl,
- Frederic Kontny, MD, PhDm,n,
- Peter Held, MD, PhDo,
- Eva C. Jensen, MD, PhDo,
- Eugene Braunwald, MDb,
- Marc S. Sabatine, MD, MPHb,∗ ( and )
- A.J. Oude Ophuis, MD, PhDc,p
- aZena and Michael Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- bTIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- cDepartment of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar and Dutch Network for Cardiovascular Research (WCN), the Netherlands
- dDepartment of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
- eDHU (Département Hospitalo-Universitaire)-FIRE (Fibrosis, Inflammation, REmodelling), Hôpital Bichat, AP-HP (Assistance Publique–Hôpitaux de Paris), Université Paris-Diderot, Sorbonne–Paris Cité, and FACT (French Alliance for Cardiovascular clinical Trials), an F-CRIN network, INSERM U-1148, Paris, France
- fNational Heart and Lung Institute, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, Imperial College, London, United Kingdom
- gDivision of Cardiology, University of Florida College of Medicine, Jacksonville, Florida
- hDepartment of Cardiology, Military Hospital, Budapest, Hungary
- iEmergency Cardiology Department, Institute of Cardiology, Kiev, Ukraine
- jHospital Universitario La Paz, Madrid, Spain
- kFundacion Cardioinfantil, Instituto de Cardiología, Bogotá, Cundinamarca, Colombia
- lMedical University Sofia, Queen Ioanna Hospital, Sofia, Bulgaria
- mDepartment of Cardiology, Stavanger University Hospital, Stavanger, Norway
- nDrammen Heart Center, Drammen, Norway
- oAstraZeneca Research and Development, Mölndal, Sweden
- pDepartment of Cardiology, CWZ Hospital, Nijmegen, the Netherland
- ↵∗Address for correspondence:
Dr. Marc Sabatine, TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Office Level One, 350 Longwood Avenue, Boston, Massachusetts 02115.
Background Patients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events.
Objectives The authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in 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.
Methods Patients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months.
Results A total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HRadj]: 1.24; p = 0.026) and for coronary events (7.67% vs. 5.34%, HRadj: 1.49; p = 0.0005). In patients with MVD, ticagrelor reduced the risk of MACE (7.94% vs. 9.37%, HR: 0.82; p = 0.004) and coronary events (6.02% vs. 7.67%, HR: 0.76; p < 0.0001), including a 36% reduction in coronary death (HR: 0.64; 95% confidence interval: 0.48 to 0.85; p = 0.002). In this subgroup, ticagrelor increased the risk of TIMI major bleeding (2.52% vs. 1.08%, HR: 2.67; p < 0.0001), but not ICH or fatal bleeds.
Conclusions Patients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562)
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 evaluated the benefit of long-term treatment with 2 doses of ticagrelor (60 mg and 90 mg twice daily) compared with placebo in patients treated with low-dose aspirin who had a history of myocardial infarction (MI) between 1 and 3 years before randomization and who also had additional risk factors for recurrent atherothrombotic events. Ticagrelor reduced the risk of major adverse cardiovascular (CV) events (MACE) (CV death, MI, or stroke), with an increase in nonfatal major bleeding (1).
Patients with multivessel coronary artery disease (MVD) have more advanced atherosclerosis, with higher rates of in-hospital events, as well as recurrent atherothrombotic coronary events and death (2–6). Significant debate has centered on revascularization strategies in MVD patients; less attention has been paid to the intensity and duration of antithrombotic therapy. Recently, data from multiple small trials have provided some evidence of reduction in major ischemic events with more intense and longer duration antiplatelet therapy in patients with MVD (7).
In this pre-specified analysis from the PEGASUS-TIMI 54 trial, we evaluated the efficacy and safety of long-term ticagrelor therapy in patients with prior MI and MVD.
The design and primary overall results of PEGASUS-TIMI 54 have been previously published (8). Patients with a history of MI 1 to 3 years previously and ≥1 additional atherothrombotic risk factor (age >65 years, diabetes mellitus requiring medication, second prior spontaneous MI, chronic renal dysfunction, or MVD) were randomized to ticagrelor (90 mg or 60 mg twice daily) versus placebo, on a background of low-dose aspirin and followed for a median of 33 months. For this pre-specified analysis examining patients stratified by presence or absence of MVD, we defined MVD as presence of >50% stenosis in ≥2 separate major coronary territories at the time of the index event (with or without prior revascularization).
The primary efficacy endpoint was MACE, consisting of the composite of CV death, MI, or stroke. We also examined the composite endpoint of coronary events (defined as coronary-related death, MI, or definite stent thrombosis), and individual components of MACE and coronary events. The primary safety endpoint was Thrombolysis In Myocardial Infarction (TIMI) major bleeding (9). Other safety endpoints included intracranial hemorrhage (ICH) or fatal bleeding.
The data were analyzed with both ticagrelor groups combined, as well as separately. Baseline characteristics between groups were compared using the chi-square test for categorical variables and the Wilcoxon test for continuous variables. The independent risk associated with presence of MVD was assessed using multivariable modeling in the placebo arm of the trial; covariates included age, sex, race, region, type of presenting MI, history of diabetes, history of hypercholesterolemia, smoking status, history of congestive heart failure, history of peripheral arterial disease, history of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), and glomerular filtration rate. Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated using a Cox proportional hazards model to evaluate the treatment effect of ticagrelor. We constructed models that evaluated the interaction between randomized treatment group and the presence of MVD subgroup. A 2-sided p value ≤0.05 was considered significant for all analyses.
Of 21,162 patients randomized in the PEGASUS-TIMI 54 trial, 12,558 (59.4%) had a history of MVD. Patient characteristics stratified by MVD status are shown in Table 1. Although the MVD group had a higher prevalence of hyperlipidemia, current smoking, peripheral artery disease (PAD), ST-segment elevation MI, and prior revascularization (PCI/CABG), as a function of the trial inclusion criteria, the non-MVD subgroup contained a higher prevalence of other high-risk features such as diabetes mellitus, hypertension, reduced renal function, and congestive heart failure, and were likely higher risk than typical patients without MVD.
Risk of CV events and bleeding in patients with and without MVD
In patients in the placebo arm, the risk of MACE was higher in patients with MVD versus no MVD (3-year Kaplan-Meier [KM] rate 9.37% vs. 8.57%; adjusted HR [HRadj]: 1.24; 95% CI: 1.03 to 1.50; p = 0.026). Likewise, the risk of coronary events was higher in patients with MVD (7.67% vs. 5.34%; HRadj: 1.49; 95% CI: 1.19 to 1.87; p = 0.0005) (Figure 1). The incidence of TIMI major bleeding was similar in patients with (1.08%) and without (1.03%) MVD (Figure 1).
There was consistent relative risk reduction with ticagrelor for MACE in patients with MVD (pooled ticagrelor vs. placebo, HR: 0.82; 95% CI: 0.72 to 0.94) (Figure 2) and in those without MVD (pooled ticagrelor vs. placebo, HR: 0.87; 95% CI: 0.74 to 1.03; pinteraction = 0.61) (Figure 2). Given the higher absolute risk of MACE in patients with MVD, the magnitude of the absolute risk reduction with ticagrelor (1.43%; number needed to treat for 3 years [NNT3yr] = 70) tended to be greater than in patients without MVD (0.97%; NNT3yr = 103).
In terms of coronary events, the HR with ticagrelor was 0.76 (95% CI: 0.66 to 0.88) in patients with MVD and 0.95 (95% CI: 0.77 to 1.16) in patients without MVD (pinteraction = 0.09). Again, given the higher absolute risk of coronary events in patients with MVD, the magnitude of the absolute risk reduction tended to be greater in those with MVD (1.65%; NNT3yr = 60 pooled ticagrelor) than in those without (0.17%, NNT3yr = 588 pooled ticagrelor) (Figures 2 and 3). In patients with MVD, there were large reductions in the individual components, including a 36% reduction in coronary death (HR: 0.64; 95% CI: 0.48 to 0.85), a 21% reduction in MI (HR: 0.79; 95% CI: 0.67 to 0.93), a 41% reduction in definite stent thrombosis (HR: 0.59; 95% CI: 0.37 to 0.94), and a 54% reduction with the 90-mg dose (HR: 0.46; 95% CI: 0.25 to 0.84) (Figure 2). The number of stent thrombosis events were very low for the non-MVD group resulting in extremely wide CIs for the ticagrelor versus placebo comparison. Ticagrelor tended to have a beneficial effect on the rate of coronary revascularization (PCI or CABG) in patients with MVD (HR: 0.88; 95% CI: 0.78 to 1.01; as compared with HR: 1.03; 95% CI: 0.82 to 1.29 in patients without MVD, pinteraction = 0.25).
Ticagrelor increased TIMI major bleeding to a similar degree (both relative and absolute risk) in those with (3-year KM rate 2.52% vs. 1.08%; HR: 2.67; 95% CI: 1.81 to 3.93) and without MVD (3-year KM rate 2.36% vs. 1.03%; HR: 2.27; 95% CI: 1.44 to 3.58; pinteraction = 0.58) (Figure 3). Ticagrelor did not significantly increase the rate of ICH or fatal bleeding either in patients with MVD (3-year KM rate 0.67% vs. 0.63%; HRadj: 1.21; 95% CI: 0.69 to 2.12) or without MVD (3-year KM rate 0.67% vs. 0.56%; HRadj: 1.20; 95% CI: 0.61 to 2.38; pinteraction = 0.98) (Figure 3).
In this pre-specified analysis from the PEGASUS-TIMI 54 trial, we report multiple clinically relevant findings: 1) In patients with prior MI, the presence of MVD is associated with a higher risk of MACE and coronary ischemic events; and 2) this atherothrombotic risk is reduced significantly by ticagrelor, with a robust impact on coronary heart disease-related death, MI, and stent thrombosis (Central Illustration). Only 60 patients with MVD needed to be treated with ticagrelor for 3 years to prevent 1 coronary event.
Patients with MVD, not only represent an advanced state of atherosclerosis quantitatively in the coronary and other vascular beds, but also show qualitatively greater endothelial dysfunction, higher grades of platelet reactivity, higher fibrinogen levels, and increased thrombin activation (2–6,10,11). These factors may cumulatively lead to worse clinical outcomes manifested as increased rates of in-hospital and long-term mortality, recurrent MIs, and repeat revascularization (12,13).
It has become clear that background medical therapy plays a critical role with regard to risk reduction in high-risk patients (14). We have previously shown larger absolute benefits for ticagrelor therapy in high-risk subjects such as those with type 2 diabetes or PAD (15,16). An analysis from a pooled dataset of 6 randomized trials (N = 9,577) evaluating the efficacy and safety of long-term dual antiplatelet therapy (DAPT) with aspirin and clopidogrel (>1 year) versus short-term DAPT (3 to 6 months) in patients undergoing complex PCI (>50% subjects with MVD), showed that long-term DAPT provided significant reduction in major ischemic events (7).
Along with duration of therapy, potency of the antiplatelet therapy is also critically important. In a modest-sized trial of 3,000 patients, Lee et al. (17) showed that adding cilostazol to aspirin and clopidogrel for patients undergoing multivessel stenting may be an efficacious strategy. In a secondary analysis from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial (N = 9,478), DAPT with clopidogrel and aspirin versus monotherapy with aspirin in subjects with prior MI, stroke, or symptomatic PAD led to a lower rate of CV death, MI, and stroke (18). In the MI subgroup (n = 16,897) of the TRA2P-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), addition of the platelet inhibitor vorapaxar to aspirin led to a reduction in MACE, notably recurrent MI and stroke (19).
These prior studies provide conceptual support for our current observations of the benefit of long-term, potent P2Y12 inhibition. Indeed, in line with the data in the acute setting from the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial, it is reasonable to consider ticagrelor for patients with MVD to be initiated upon presentation for an acute coronary syndrome and to be continued for long-term therapy (20). The ongoing COMPLETE (Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI) (N = 3,900) (21), TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) (N = 9,000) (22), and GLOBAL-LEADERS (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation) (N = 16,000) (23) trials will give more insight into the specific efficacy of ticagrelor in patients with MVD, including the concept of long-term ticagrelor monotherapy.
Because clinicians debate which therapies are best matched to their patients, and multiple empiric approaches exist, efforts are being made to inform this decision with more data and creation of aids such as the DAPT score (24). Our data suggest that patients with more extensive atherosclerotic disease might benefit from more intensive antithrombotic therapy with ticagrelor.
Limitations of the present analysis include that the MVD subgroup was not specifically powered for the primary endpoint or for individual secondary endpoints, although this was a pre-specified subgroup. Adjustments were not made for multiple comparisons, because these subgroup analyses were viewed as hypothesis-generating. It is also important to realize that as a function of the trial inclusion criteria, the non-MVD subgroup contained other high-risk features and were likely higher risk than typical patients without MVD. However, despite this factor, patients with MVD remained at significantly increased risk even after adjusting for potential confounders.
Patients with prior MI and MVD are at heightened ischemic risk, predominantly coronary risk, relative to those without MVD. In patients with prior MI and MVD, ticagrelor reduces the risk of MACE, with particular benefit for coronary events, notably coronary death.
COMPETENCY IN MEDICAL KNOWLEDGE: Prolonged DAPT with ticagrelor and aspirin in patients with prior MI and multivessel coronary disease reduces ischemic events, including death.
TRANSLATIONAL OUTLOOK: Additional studies are needed to compare the safety and efficacy of prolonged ticagrelor monotherapy versus dual antiplatelet therapy in patients with multivessel disease.
Dr. Angiolillo is the recipient of funding from the Scott R. MacKenzie Foundation and the National Institute of Health/National Center for Advancing Translational Sciences Clinical and Translational Science Award to the University of Florida UL1 TR000064 and National Institutes of Health/National Human Genome Research Institute U01 HG007269, outside the submitted work. Dr. Bansilal has served on advisory boards of AstraZeneca, Merck, and Janssen; has received speaking or consulting fees from AstraZeneca and Janssen; has received research support from AstraZeneca; and is currently an employee of Bayer LLC, but not at the time of this research. Dr. Bonaca has received grant support to the TIMI Study Group from AstraZeneca and Merck; and has been a consultant to Aralez, AstraZeneca, Bayer, and Merck. Dr. Cornel has received personal fees from Merck, Eli Lilly, and AstraZeneca. Dr. Storey has received research grants and honoraria from AstraZeneca; research grants from PlaqueTec; and consultancy fees from Actelion, AstraZeneca, Avacta, Bayer, Bristol-Myers Squibb/Pfizer, Novartis, PlaqueTec, The Medicines Company, and Thermo Fisher Scientific. Dr. Bhatt has served on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has served on the board of directors of the Boston VA Research Institute and the Society of Cardiovascular Patient Care; served as chair of the American Heart Association Quality Oversight Committee; has served on data monitoring committees for the Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and 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 other relationships with Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and 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, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has been a site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical (now Abbott); has been a trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, PLx Pharma, and Takeda. Dr. Steg has received research grants from Merck, Sanofi, and Servier; and speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, and Servier. Dr. Im and Ms. Murphy have received research grant support to their institution from AstraZeneca. Dr. Angiolillo has received individual fees or honoraria for consulting from Amgen, AstraZeneca, Bayer, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, and Sanofi; and for participating in review activities from CeloNova and St. Jude Medical; and has institutional payments for grants from Amgen, AstraZeneca, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Matsutani Chemical Industry Co., Merck, Novartis, and Renal Guard Solutions. Dr. Kiss has served on speakers bureaus for Bayer AG, Pfizer, Boehringer Ingelheim, and Merck Sharp & Dohme. Dr. Parkhomenko has received grants and personal fees from Pfizer, Bayer, Janssen, AstraZeneca, Sanofi, and Merck Sharp & Dohme outside the submitted work. Dr. Lopez-Sendon has received grants from Portola Pharmaceuticals, Pfizer, GlaxoSmithKline, Bayer; and grants and personal fees from Merck, AstraZeneca, Menarini, Merck Sharp & Dohme, and Sanofi. Dr. Goudev has received speaking honoraria and advisory board fees from AstraZeneca. Dr. Kontny has received honoraria for consultancy/advisory board membership from AstraZeneca and Merck & Co.; and lecture fees from Novartis. Drs. Held and Jansen are employees of AstraZeneca. Dr. Braunwald has received research grant support to his institution from AstraZeneca. Dr. Sabatine has received research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research Development, MedImmune, Merck, Novartis, Pfizer, Poxel, and Takeda (all >$10,000 per year); and has been a consultant for Amgen, CVS Caremark, Esperion, Intarcia, Ionis, MedImmune, and Merck (all ≤$10,000 per year except Amgen, Esperion, and Ionis). Dr. Oude Ophuis has received personal fees from TIMI during the conduct of the study; grant support and personal fees from Boston Scientific and Abbott; personal fees from AstraZeneca and Merck Sharp & Dohme; and nonfinancial support from Biosensor, WCN, and Vascular Research Network outside the submitted work. Dr. Isaza has reported that he has no relationships relevant to the contents of this paper to disclose. Michael S. Lee, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- coronary artery bypass graft
- confidence interval
- dual antiplatelet therapy
- hazard ratio
- intracranial hemorrhage
- major adverse cardiovascular event(s)
- myocardial infarction
- multivessel disease
- number needed to treat for 3 years
- peripheral artery disease
- percutaneous coronary intervention
- Thrombolysis In Myocardial Infarction
- Received July 6, 2017.
- Revision received November 5, 2017.
- Accepted November 25, 2017.
- 2018 American College of Cardiology Foundation
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