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Coronary artery disease
Original article
Safety and efficacy of ticagrelor and clopidogrel in primary percutaneous coronary intervention
  1. Matthijs A Velders1,2,
  2. Jérémie Abtan3,
  3. Dominick J Angiolillo4,
  4. Diego Ardissino5,
  5. Robert A Harrington6,
  6. Anne Hellkamp7,
  7. Anders Himmelmann8,
  8. Steen Husted9,
  9. Hugo A Katus10,
  10. Bernhard Meier11,
  11. Phillip J Schulte7,12,
  12. Robert F Storey13,
  13. Lars Wallentin1,2,
  14. Philippe Gabriel Steg3,14,15,16,
  15. Stefan K James1,2
  16. on behalf of the PLATO Investigators
  1. 1Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
  2. 2Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  3. 3Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France
  4. 4Department of Medicine, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
  5. 5Azienda Ospedaliero, Universitaria di Parma, Parma, Italy
  6. 6Department of Medicine, Stanford University, Stanford, California, USA
  7. 7Duke Clinical Research Institute, Duke University, Medical Center, Durham, North Carolina, USA
  8. 8AstraZeneca Research and Development, Gothenburg, Sweden
  9. 9Medical Department, Hospital Unit West, Holstebro – Herning/Holstebro, Denmark
  10. 10Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany
  11. 11Bern University Hospital, Bern, Switzerland
  12. 12Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  13. 13Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
  14. 14INSERM-Unité 1148, Paris, France
  15. 15Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France
  16. 16NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK
  1. Correspondence to Professor Stefan K James, Department of Medical Sciences, Cardiology, Uppsala University, Uppsala Clinical Research Center, Dag Hammarskjölds väg 14B 752 37 Uppsala stefan.james{at}ucr.uu.se

Abstract

Objective The effects of ticagrelor in the subpopulation of patients with ST-elevation myocardial infarction (STEMI) were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study. However, this subgroup included patients initially or ultimately treated conservatively. The aim of this study is to compare treatment using ticagrelor with treatment using clopidogrel in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).

Methods This post-hoc subgroup analysis compared ticagrelor with clopidogrel in 4949 PLATO patients with STEMI that were treated with primary PCI within 12 h of admission. The primary endpoint was cardiovascular death, myocardial infarction or stroke. The safety endpoint consisted of any major bleeding. Secondary endpoints included stent thrombosis. The analysis was not adequately powered to establish significance of any treatment effects.

Results During a median of 286 days, the primary endpoint occurred in 7.9% of ticagrelor-treated patients versus 8.6% of clopidogrel-treated patients (HR 0.91, 95% CI 0.75 to 1.12, p=0.38). Major bleeding occurred in 6.7% in ticagrelor-treated patients versus 6.8% of clopidogrel-treated patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79). No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p=0.40) and primary safety endpoints (p=0.15) as compared with the full PLATO population. Treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37 to 0.89, p=0.013).

Conclusions In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial.

Trial registration number NCT00391872; Results.

https://doi.org/10.1136/heartjnl-2015-308963

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    Introduction

    Current guidelines recommend emergent referral of patients with ST-elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PCI), aiming at reperfusion of the culprit lesion within 60–90 min of first medical contact in case of presentation at a PCI-capable hospital.1 ,2 Efforts to decrease delay to treatment for patients with STEMI have led to marked improvements in door-to-balloon times.3 Simultaneously, the reduced time between presentation and reperfusion therapy provides new challenges for pharmacological therapy, shortening the time available for antiplatelet agents to reach efficacy.

    Ticagrelor, an oral, reversibly binding platelet P2Y12 receptor inhibitor, generates a greater and more consistent platelet inhibitory effect and has a faster onset of action compared with clopidogrel.4 Ticagrelor has been shown to reduce the rate of death from vascular causes, myocardial infarction (MI) and stroke in patients with acute coronary syndrome (ACS) compared with clopidogrel.5 In the subgroup of patients with STEMI and planned primary PCI, the effects of ticagrelor were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study population.6 However, this subgroup included patients initially or ultimately treated conservatively.

    The current post-hoc subgroup analysis of the STEMI subset sought to examine the outcomes with ticagrelor versus clopidogrel in patients with STEMI treated with primary PCI within 12 h of admission.

    Methods

    PLATO (NCT00391872) was an international, prospective, randomised, double-blind, double-dummy, event-driven trial in patients with either STEMI scheduled for primary PCI or non-ST elevation ACS that was managed invasively or medically. Details of the design, population and results have been published.5 ,7 Patients were eligible within 24 h of onset of the most recent cardiac ischaemic symptoms and randomised to receive either ticagrelor or clopidogrel before PCI. Ticagrelor-treated patients received a 180 mg loading dose followed by a maintenance dose of 90 mg twice daily. Clopidogrel-treated patients who had not already received a loading dose of open-label clopidogrel or who had not been taking clopidogrel or ticlopidine for ≥5 days before randomisation received a 300 mg loading dose followed by 75 mg once daily. The remaining patients received 75 mg clopidogrel as their first dose. At the discretion of the operator, an additional 300 mg clopidogrel/placebo at any time relative to randomisation was allowed in patients undergoing PCI. Ticagrelor loading and maintenance dose was the same in clopidogrel pretreated and naïve patients. All patients received a once-daily dose of acetylsalicylic acid unless intolerant. For patients not previously receiving acetylsalicylic acid, a loading dose of up to 325 mg was preferred (although a dose of 160–500 mg was allowed). The recommended maintenance dose was 75–100 mg/day. However, after stent placement, an acetylsalicylic acid dose up to 325 mg/day was allowed for up to 6 months. Administration of intravenous glycoprotein IIb/IIIa inhibitors was allowed at the discretion of the operator.

    Outpatient visits were scheduled after 1, 3, 6 and 12 months, with a safety follow-up visit 1 month after the end of treatment. The trial was event driven with termination of the trial either at the 6-month, 9-month or 12-month visit when the targeted number of 1780 primary endpoint events had occurred. It was recommended that study drugs be withheld in patients undergoing coronary artery bypass grafting, 5 days for clopidogrel study drug and 24–72 h for ticagrelor study drug, while maintaining the study blind.

    Patients

    Patients had to meet the following criteria for inclusion in this subanalysis: typical symptoms plus either persistent ST elevation of ≥1 mV for ≥20 min (not known to be pre-existing or resulting from a coexisting disorder) in two or more contiguous leads or new or presumed-new left bundle-branch block. Furthermore, invasive management with primary PCI had to be performed after randomisation and within the first 12 h after admission.

    Key exclusion criteria in PLATO included contraindication to clopidogrel, fibrinolytic therapy within 24 h before randomisation, need for oral anticoagulation therapy, an index event as an acute complication of PCI or PCI performed before the first study dose, and concomitant therapy with strong CYP3A inhibitors or inducers. The study protocol was approved by an independent ethics committee or institutional review board, and informed consent was required before any study procedure.

    Events

    The PLATO primary efficacy endpoint was time to first occurrence of any event from the composite of death from vascular causes (hereafter referred to as cardiovascular death), MI or stroke. Silent MI was excluded from the primary endpoint for the current analysis. The primary safety endpoint was the time to first occurrence of any major bleeding event. Safety was analysed in the population of patients who had received at least one dose of the study drug. Event definitions have been previously provided.5 ,7 In short, MI was defined in accordance with the universal definition.8 Stent thrombosis was evaluated according to Academic Research Consortium criteria based on review of charts and catheterisation laboratory reports.9 Bleeding endpoints were defined according to PLATO definitions.5 ,7 An independent blinded central adjudication committee adjudicated primary and secondary endpoints and bleeding events.

    Statistics

    Characteristics were summarised using frequencies, percentages for categorical variables and median, 25th and 75th percentiles for continuous variables. Statistical comparison was performed using Student’s t test or Wilcoxon rank-sum test. All statistical tests were two-tailed and performed at the 0.05 significance level. A Cox proportional-hazards model, with a factor for treatment group, was used to analyse the primary and secondary endpoints. Due to the randomised nature of the PLATO trial, no adjustment for baseline factors was performed. All analyses were based on intention to treat with study drug. Starting time for counting events was time of PCI. Interaction analyses were performed in the full PLATO population. A categorical variable was created, dividing patients into three categories: patients with STEMI meeting the inclusion criteria for the current study, patients with STEMI not meeting the inclusion criteria and a third category including all other non-ST elevation ACS patients. A Cox proportional-hazards model including the interaction variable was used to analyse the primary efficacy and safety endpoints according to the study drug. This post-hoc subgroup analysis of the PLATO trial was not adequately powered to establish significance of any treatment effects.

    Results

    Patients

    In the total PLATO population of 18 624 patients with ACS, 7544 patients met the criteria for STEMI at entry. Of these patients, 4949 underwent primary PCI within 12 h. Online supplementary figure S1 shows the study flow chart. Baseline characteristics are shown in table 1. Virtually all patients (98.2%) showed persistent ST-segment elevation on ECG at randomisation, with a minority of patients (4.1%) presenting with a left bundle-branch block configuration. Furthermore, most patients had positive high-sensitivity troponin T levels at randomisation.

    View this table:
    Table 1

    Baseline characteristics according to randomised treatment

    Intervals between symptom onset, admission, randomisation and PCI were balanced between treatment arms (table 2). Additionally, procedural characteristics were balanced in accordance with the general PLATO population. Median duration of study treatment was 286 days for patients in the ticagrelor arm and 287 days for patients in the clopidogrel arm.

    View this table:
    Table 2

    Characteristics of index hospitalisation and follow-up according to randomised treatment

    Efficacy

    Efficacy endpoints according to randomised treatment are shown in figure 1 and online supplementary table S1. The primary efficacy endpoint occurred in 7.9% of ticagrelor patients and 8.6% of clopidogrel patients during follow-up (HR 0.91, 95% CI 0.75 to 1.12, p=0.38) (figure 1 and 2A). Interaction analysis in the full PLATO population showed no significant interaction for the primary efficacy endpoint when compared with other PLATO patients (interaction p=0.40). Secondary endpoints also showed numerically lower rates in the ticagrelor group, although statistical significance was not reached in these underpowered subgroup analyses. Definite ST occurred in 1.4% of patients treated with ticagrelor and 2.3% of patients treated with clopidogrel (HR 0.58, 95% CI 0.37 to 0.89, p=0.013) (figure 1 and 2B). Acute ST (within 24 h of PCI) occurred in 0.5% of patients treated with ticagrelor and in 0.2% of patients treated with clopidogrel. Early ST (up to 30 days after PCI) occurred in 1.0% and 1.6% of patients treated with ticagrelor and clopidogrel, respectively. Late ST (between 30 days and 1 year after PCI) occurred in 0.4% and 0.7% of patients treated with ticagrelor and clopidogrel, respectively. Furthermore, rates of definite/probable ST and definite/probable/possible ST were reduced in patients treated with ticagrelor compared with clopidogrel, corresponding to a non-statistically significant numerical reduction in the occurrence of MI in the ticagrelor (3.9%) as compared with the clopidogrel group (5.0%) (HR 0.77, 95% CI 0.58 to 1.02, p=0.064 (figure 1)). Stroke was the only efficacy endpoint that showed a numerically lower rate in the clopidogrel group although the low numbers of events limit meaningful conclusions.

    Figure 1
    Figure 1

    Efficacy endpoints according to randomised treatment. For each treatment group, 12-month Kaplan–Meier rates (95% CI) (number of events) are shown. Start time for counting events is the time of PCI. HRs and p values are from Cox models. Silent MI is excluded from MI endpoint. CVD, cardiovascular death; MI, myocardial infarction; PCI, percutaneous coronary intervention; ST, stent thrombosis.

    Figure 2
    Figure 2

    (A) Primary efficacy endpoint according to randomised treatment. (B) Definite ST according to randomised treatment. Kaplan–Meier curves showing the occurrence of the composite efficacy endpoint and definite ST during 12-month follow-up. For definite ST, the occurrence of definite ST during the first 30 days is shown in the top right corner. PCI, percutaneous coronary intervention; ST, stent thrombosis.

    There was no significant interaction within the primary PCI population regarding the effect of ticagrelor on the primary endpoint according to whether or not patients were pretreated with open-label clopidogrel (p=0.11).

    Safety

    Figure 3 and online supplementary table S2 show the safety endpoints according to randomised treatment. Major bleeding occurred in 6.7% of ticagrelor patients compared with 6.8% of clopidogrel patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79) (figures 3 and 4). Interaction analysis in the full PLATO population showed no significant interaction for major bleeding compared with other PLATO patients (interaction p=0.15). The rates of other bleeding endpoints were similar between the treatment groups. Patients assigned ticagrelor in comparison to clopidogrel experienced significantly more dyspnoea (12.7% vs 8.2%, HR 1.65 (95% CI 1.37 to 1.99), p<0.0001).

    Figure 3
    Figure 3

    Safety endpoints according to randomised treatment. All bleeding endpoints are PLATO definitions. For each treatment group, 12-month Kaplan–Meier rates (95% CI) (number of events) are shown. Start time for counting events is the time of PCI. HRs and p values are from Cox models. CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and Patient Outcomes study.

    Figure 4
    Figure 4

    Primary safety endpoint according to randomised treatment. Kaplan–Meier curve showing the occurrence of the safety endpoint of any major bleeding during 12-month follow-up. PCI, percutaneous coronary intervention.

    Discussion

    In this post-hoc subgroup analysis of patients with STEMI treated with primary PCI within 12 h of admission, the association of ticagrelor versus clopidogrel with the primary efficacy endpoint was consistent with the overall PLATO population. Despite the small number of events, patients randomised to ticagrelor experienced a significant reduction in the occurrence of the secondary endpoint of stent thrombosis, which is a sensitive marker of the effect of platelet inhibition. Furthermore, no interaction was observed for rates of any major bleeding with ticagrelor versus clopidogrel compared with the full PLATO population. These results therefore support the superior efficacy and similar safety of ticagrelor as compared with clopidogrel in patients with STEMI treated with primary PCI.

    In accordance with the current analysis, a comparable substudy of the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38) trial showed a consistent treatment effect of prasugrel compared with clopidogrel in patients treated with primary PCI for STEMI.10 ,11 The magnitude of risk reduction with use of the newer P2Y12 receptor inhibitors compared with clopidogrel in a setting of primary PCI appeared to be less marked compared with use of these agents in the full ACS population (figure 5). Of note, no definite conclusions can be drawn due to the post-hoc nature of these substudies. These findings may at least partly be explained by the study population, as patients undergoing primary PCI and recruited into trials tend to be younger with lower long-term risk compared with other patients with ACS.12 Furthermore, the limited ability to detect periprocedural MI in patients with ongoing STEMI due to high baseline and increasing levels of biomarkers makes evaluation of influence on early MI impossible which hampers ascertainment of ischaemic complications in the periprocedural phase and likely results in underestimation of the effects of the newer antiplatelet agents.8 The relatively late separation of the curves for the primary efficacy endpoint in this substudy seems to support this notion.

    Figure 5
    Figure 5

    Treatment effect of ticagrelor and prasugrel compared with clopidogrel in the PLATO and TRITON-TIMI 38 trials. In PLATO, pretreatment with 300–600 mg clopidogrel was allowed. In TRITON-TIMI 38, patients pretreated with clopidogrel before randomisation were excluded, but pretreatment with the study drug (a loading dose of 300 mg for clopidogrel) was allowed up to 24 h before planned primary PCI in patients with STEMI. *Based on the initial ECG and/or final diagnosis; †based on the initial ECG; ‡data extracted from references 10 and 11. PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and Patient Outcomes study; STE-ACS, ST elevation acute coronary syndrome; STEMI, ST-elevation myocardial infarction; TRITON-TIMI 38, Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38.

    Finally, pharmacokinetics may influence the efficacy of antiplatelet agents in patients with STEMI, as the interval between drug administration and reperfusion therapy is generally short.3 Pharmacologic studies showed a greater and more consistent platelet inhibitory effect and a faster onset of action of ticagrelor compared with clopidogrel in patients with ACS.4 However, it has been noted that effective platelet inhibition 2 h after loading doses of ticagrelor and prasugrel is achieved in up to two-thirds of patients with STEMI.13 ,14 Commonly performed cotreatment with morphine may further negatively influence the rate of absorption of P2Y12 inhibitors, including ticagrelor among patients with STEMI.13 Attempts to improve platelet inhibition using higher loading doses in a setting of primary PCI have failed to show effect.15 ,16 However, administration of crushed ticagrelor tablets reduced platelet reactivity up to 50% at 1 h compared with integral tablets.17 ,18 Furthermore, prehospital compared with in-hospital administration of ticagrelor loading dose reduced rates of acute stent thrombosis in the ATLANTIC (Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery) study.19 These findings suggest that alternative modes of administration may enhance the early clinical benefit of ticagrelor.

    Pretreatment with clopidogrel may improve outcome in patients treated with primary PCI as compared with in-hospital loading with clopidogrel, and was commonly performed in this substudy.20 ,21 In contrast, TRITON-TIMI 38 excluded patients pretreated with clopidogrel before randomisation.11 Additional antiplatelet effect is commonly obtained with the use of parenteral glycoprotein IIb/IIIa inhibitors with potentially greater benefit in patients with short duration from symptom onset to PCI.1 ,2 ,22 ,23 Despite common use of clopidogrel pretreatment and glycoprotein IIb/IIIa inhibitors, no safety concerns were observed in this substudy, supporting the coadministration of these agents in patients treated with ticagrelor. In accordance with findings of previous PLATO analyses, use of ticagrelor was associated with an increased frequency of dyspnoea.5 ,6

    Limitations

    The current study was a post-hoc analysis of the subset of patients with STEMI, which in turn is a subset of the total population included in the PLATO trial. Furthermore, the use of primary PCI was a postrandomisation variable and as such, randomised therapy may influence the population surviving to receive PCI and the use of PCI. Therefore these results can only be interpreted as descriptive and hypothesis-generating. Proposed guidelines on publishing of subgroup analyses of clinical trials have stated that interaction analyses should be used to evaluate treatment effect in individual subgroups.24 Presence of statistical significance of primary endpoints does not provide a reliable assessment of the efficacy or safety of ticagrelor in patients with STEMI treated with primary PCI, which, given the lack of significant interaction, is best assessed by the results of the overall trial rather than by the results observed within the sub-subgroup.25 The analysis of the primary PCI subset of the STEMI subgroup was not preplanned as part of the original statistical analysis plan. In addition, this subpopulation was underpowered to provide reliable estimates of possible differences in treatment effects compared with the main trial.

    Conclusions

    In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial.

    Key messages

    What is already known on this subject?

    • Ticagrelor reduces the rate of death from vascular causes, myocardial infarction and stroke in patients with acute coronary syndromes compared with clopidogrel. In a ST-elevation myocardial infarction setting, limited time between loading dose and reperfusion therapy shortens the time available for antiplatelet agents to reach efficacy. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, the effect of ticagrelor was consistent in patients with ST-elevation myocardial infarction, but a substantial number of these patients were initially or ultimately treated conservatively.

    What might this study add?

    • The current analysis focused on the subpopulation of patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Findings for the primary efficacy and safety endpoints were consistent with the full PLATO population.

    How might this impact on clinical practice?

    • This study supports the similar safety and superior efficacy of ticagrelor compared with clopidogrel in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention.

    Acknowledgments

    Ebba Bergman, PhD, at Uppsala Clinical Research Center, Uppsala, Sweden, provided editorial assistance.

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    View Abstract

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Contributors Lead authors (MAV and SKJ), members of the Executive Committee (RAH, SH, HAK, RFS, LW, PGS and SKJ) and national coordinators (DA, RAH, SH, BM, RFS and SKJ) designed the PLATO trial and supervised the conduct of the trial. DJA, DA, BM, RFS and SKJ were principal investigators recruiting patients to the PLATO trial. All coauthors were involved in the planning and data interpretation of the analyses for this manuscript. The statistical analyses in this substudy were performed at Duke Clinical Research Institute, Duke University, Medical Center, Durham, North Carolina, USA (AH and PJS). All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The first draft of the manuscript was written by the lead authors (MAV and SKJ), which thereafter was revised by all coauthors until agreement to submit was reached.

    • 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.

    • Competing interests MAV: institutional research grants from AstraZeneca. JA: nothing to disclose. DJA: investigator initiated grants, consulting fees and sponsored research grants from AstraZeneca, Eli Lilly/DSI, The Medicines Company, Merck; sponsored research grants from Gilead, Osprey, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, CSL Behring; consulting fees from Sanofi, Abbott Vascular; data and safety monitoring board member for CeloNova, Johnson & Johnson, St Jude. DA: research grants, personal fees and non-financial support from AstraZeneca, Bayer, GlaxoSmithKline, Eli Lilly & Company, Pfizer, Novartis; personal fees from Boehringer Ingelheim, Johnson & Johnson, Daiichi Sankyo, Boston Scientific, Bristol-Myers Squibb, Menarini, Sanofi-Aventis. RAH: research grants from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck, NHLBI, Portola, Regado, Sanofi-Aventis, Novartis, CSL-Behring, The Medicines Company; consultant for Vida Health, Vox Media, Apo Pharma, Medtronic, Merck, WebMD, Gilead Sciences, Johnson & Johnson, Myocardia, Orexigen, Adverse Events, Amgen, Daiichi-Lilly, Janssen, Novartis, The Medicines Company; stockholder in Element Sciences, MyoKardia; other from Evidint, Regardo, Scanadu; non-commercial relationship with American Heart Association. AH: employee of and having stock ownership in AstraZeneca. SH: advisory board member and research support from Pfizer; advisory board member for AstraZeneca, Bristol-Myers Squibb, Bayer; research support from GlaxoSmithKline, Boehringer Ingelheim. HAK: grants and personal fees from Roche Diagnostics, AstraZeneca, Bayer Health; personal fees from Daiichi Sankyo. BM: nothing to disclose. PJS: nothing to disclose. RFS: institutional research grant, consultancy fees, speaker fees, travel support from AstraZeneca and named by the company as an inventor on a patent pending related to discoveries made during the PEGASUS-TIMI 54 study but has no personal financial interest in this; institutional research grant, consultancy fees and speaker fees from Daiichi Sankyo/Eli Lilly; consultancy fees, speaker fees and consumables from Accumetrics; institutional research grant and consultancy fees from Merck; honoraria from Medscape; consultancy fees from Aspen, Correvio, Plaque Tec, Roche, The Medicines Company, Thermo Fisher Scientific, Regeneron, Sanofi-Aventis; travel support from Medtronic. LW: institutional research grant, consultancy and lecture fees, travel support and honoraria from GlaxoSmithKline; institutional research grants, consultancy and lecture fees and travel support from AstraZeneca, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim; institutional research grant from Merck & Co., Roche; consultancy fees from Abbott; holds two patents involving GDF-15. PGS: honoraria and non-financial support from AstraZeneca, Sanofi, Servier; honoraria from Amarin, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Merck-Sharpe-Dohme, Novartis, Pfizer, Medtronic, Janssen, The Medicines Company, CSL-Behring, GlaxoSmithKline; institution research grants from Sanofi, Servier; stockholder in Aterovax. SKJ: institutional research grant, honoraria and consultant/advisory board fee from AstraZeneca; institutional research grant and consultant/advisory board fee from Medtronic; institutional research grants from Terumo Inc., Vascular Solutions; honoraria from The Medicines Company; consultant/advisory board fees from Daiichi Sankyo, Janssen, Sanofi.

    • Patient consent Obtained.

    • Ethics approval The study protocol was reviewed and approved by the appropriate national, independent ethics committee or institutional review board.

    • Provenance and peer review Not commissioned; externally peer reviewed.