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Antithrombotic outcome trials in acute coronary syndromes: seeking the optimal balance between safety and efficacy

Freek W.A. Verheugt, Peter Clemmensen, Roxana Mehran, Stefan Agewall, Stuart J. Pocock, Sidney Goldstein, Christian Torp-Pedersen, Maarten L. Simoons, Jeffrey S. Borer, Yasser M. Khder, Paul Burton, Efthymios Deliargyris, John J.V. McMurray, Scott D. Berkowitz, Wendy Gattis Stough, Faiez Zannad
DOI: http://dx.doi.org/10.1093/eurheartj/eht013 1621-1629 First published online: 4 February 2013


An intricate balance exists between the safety and efficacy of antithrombotic therapies in acute coronary syndrome (ACS). Safety is largely defined by bleeding risks. Many bleeding definitions are used in clinical trials, and conclusions may differ depending on the definition applied. Bleeding risks are typically dose related, making selection of the optimal dose (or preferably, doses) to advance from phase II to III testing a critical step in drug development.1

Efficacy is defined in terms of thrombotic event reduction and is commonly assessed using composite endpoints. However, composite endpoints create interpretive challenges within and across trials, particularly when endpoint definitions vary substantially. The trade-off between benefits (reduction in thrombotic events) and risks (increase in bleeding) is important to patients and clinicians; thus, it is imperative that data are presented clearly to facilitate informed decision making. Antithrombotic drug development for ACS is a challenging area of cardiovascular medicine, a topic discussed during the 7th and 8th Global Cardiovascular Clinical Trialists (CVCT) forums in December 2010 and 2011. This manuscript highlights key points from those discussions.

Dose selection

Data from phase II trials are used to determine dose selection for phase III. However, it is not uncommon for phase II and III results to differ substantially (Tables 13). In the phase II studies of vorapaxar, prasugrel, and ticagrelor, there was no evidence of a statistically significant increase in bleeding when compared with standard therapy or placebo. However, in the larger phase III studies, an increased risk of bleeding not associated with coronary artery bypass graft (CABG) surgery was observed (Tables 2 and 3). In the phase II studies of apixaban and rivaroxaban, dose-related increases in bleeding were observed leading to the selection of lower doses for phase III. Despite the dose reduction, bleeding was still higher with these drugs when compared with placebo in the pivotal trials (Tables 2 and 3).2,3

View this table:
Table 1

Overview of recent acute coronary syndrome phase II and phase III trials

TrialStudy armsn, patients/populationLength of follow-upPrimary efficacy outcomePrimary safety (bleeding) outcome
APPRAISE6Apixaban 2.5 mg b.i.d.

Apixaban 10 mg q.d.

Apixaban 10 mg b.i.d.

Apixaban 20 mg q.d.


(all arms on top of standard therapy)

Recent ST-elevation or non-ST-elevation ACS
6 monthsCardiovascular death, MI, severe recurrent ischaemia, or ischaemic strokeIncidence of major bleeding defined by ISTH, or clinically relevant non-major bleeding
APPRAISE-23Apixaban 5 mg b.i.d.


(both arms on top of standards ACS therapy with aspirin and clopidogrel)

ACS with ≥2 high risk characteristics
240 days (apixaban)

242 days (placebo)
Cardiovascular death, MI, or ischaemic strokeTIMI major bleeding
ATLAS ACS-TIMI 465Rivaroxaban 2.5 mg b.i.d.

Rivaroxaban 5 mg b.i.d.

Rivaroxaban 10 mg b.i.d.

Rivaroxaban 5 mg q.d.

Rivaroxaban 10 mg q.d.

Rivaroxaban 20 mg q.d.


6 monthsDeath, MI, stroke, or severe recurrent ischaemia requiring revascularizationTIMI major, TIMI minor, or bleeding requiring medical attention
ATLAS ACS 2-TIMI 512Rivaroxaban 2.5 mg b.i.d.

Rivaroxaban 5 mg b.i.d.

15 526

13.1 monthsCardiovascular death, MI, or strokeTIMI major bleeding not related to CABG
TRA-PCI25Day of procedure:

Vorapaxar 10 mg load

Vorapaxar 20 mg load

Vorapaxar 40 mg load


After PCI maintenance:

Vorapaxar 0.5 mg q.d.

Vorapaxar 1 mg q.d.

Vorapaxar 2.5 mg q.d.


Non-urgent PCI or coronary angiography with planned PCI
60 days treatment with 120 day follow-upCardiovascular death, non-fatal MI, or strokeTIMI major or minor bleeding during treatment
TRACER4Vorapaxar 40 mg load, 2.5 mg q.d. maintenance

12 944

Non-ST segment elevation ACS
502 daysCardiovascular death, MI, stroke, recurrent ischaemia, or urgent coronary revascularizationComposite of GUSTO moderate or severe bleeding and TIMI major or minor bleeding or bleeding that required unplanned medical or surgical treatment or laboratory evaluation
JUMBO-TIMI 2626Prasugrel 40 mg load, 7.5 mg maintenance

Prasugrel 60 mg load, 10 mg maintenance

Prasugrel 60 mg load, 15 mg maintenance

Clopidogrel 300 mg load, 75 mg maintenance

Elective or urgent PCI
30 daysAll-cause mortality, MI, stroke, recurrent myocardial ischaemia requiring hospitalization, clinical target vessel thrombosisComposite of non-CABG TIMI major and minor bleeding
TRITON TIMI 3819Prasugrel 60 mg load, 10 mg maintenance

Clopidogrel 300 mg load, 75 mg maintenance
13 608

ACS undergoing PCI
14.5 monthsCardiovascular death, non-fatal MI, or non-fatal strokeTIMI major bleeding not related to CABG
DISPERSE-227Ticagrelor 90 mg b.i.d.

Ticagrelor 180 mg b.i.d.

Clopidogrel 300 mg load, then 75 mg q.d.

Non-ST-elevation ACS
56 daysDeath, MI, stroke, severe recurrent ischaemiaMajor plus minor bleeding but excluding minimal bleeds
PLATO20Ticagrelor 180 mg load, then 90 mg b.i.d.

Clopidogrel 300 mg load, then 75 mg q.d.
18 624

ACS (with or without ST elevation) within 24 h
277 daysDeath from vascular causes, myocardial infarction, or strokeMajor life-threatening bleeding (fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolaemic shock or severe hypotension due to bleeding and requiring pressors or surgery, a decline in the haemoglobin level of 5.0 g/dL or more, or the need for transfusion of at least 4 units of red cells)

Non-adjudicated events were also assessed according to TIMI major and minor criteria
View this table:
Table 2

Clinical and Bleeding outcomes in recent trials of antithrombotic therapy

Apixaban 2.5 mg b.i.d.Apixaban 10 mg q.d.PlaceboApixabanPlaceboP-valueRivaroxaban 5 mg b.i.d.Rivaroxaban 10 mg b.i.d.Rivaroxaban 20 mg b.i.d.PlaceboRivaroxaban 2.5 mg b.i.d.Rivaroxaban 5 mg b.i.d.PlaceboP-valuec
Ischaemic events (%)
 Primary Endpointa7.668.
 Ischaemic stroke00.
 Any revascularizationNRNRNRNRNRSevere recurrent ischaemia requiring revascularization 2%1.6%NRNRNR
aBleeding events (%)
 TIMI major bleed010. as TIMI major, TIMI minor, or requiring medical attention 4.811.014.63.3NRNRNRNR
 TIMI major bleed, non-CABG relatedNRNRNRNRNRNRNRNRNRNR1.82.40.6<0.001
 TIMI minor bleedReported as TIMI major or minor combined as major or minor combined 2.20.8<0.001NRNRNRNR0.
 ISTH major bleedReported as major or clinically relevant non-major combined 5.77.932.71.1<0.001NRNRNRNRNRNRNRNR
 ISTH clinically relevant bleedNRNRNRReported as major or clinically relevant combined 3.21.2<0.001NRNRNRNRNRNRNRNR
 Intracranial bleedNRNRNR0.30.10.03NRNRNRNR0.
 Fatal bleedNRNRNR0.10n/aNRNRNRNR0. (R 2.5 mg vs. placebo) 0.2 (R 5 mg vs. placebo)
  • NR, not reported; CTVT, clinical target vessel thrombosis.

  • aSee Table 1 for definition of primary efficacy and bleeding endpoints.

  • bOnly b.i.d. dosing arms shown due to space limitations.

  • cAll P-values are for the combined rivaroxaban dosing groups vs. placebo.

View this table:
Table 3

Clinical and bleeding outcomes in recent trials of antithrombotic therapy

Vorapaxar 10 mgVorapaxar 20 mgVorapaxar 40 mg dailyPlaceboVorapaxarPlaceboP-valuePrasugrelClopidogrelPrasugrelClopidogrelP-valueTicagrelor 90 mg b.i.d.Ticagrelor 180 mg b.i.d.ClopidogrelTicagrelorClopidogrelP-value
Ischaemic events (%)
aPrimary Endpointa855915.9170.<0.00112 weeks<0.001
 Death95595.24.90.520.5033.20.64All-cause: 2.4 CV: 1.9All-cause: 1.7 CV: 1.7All-cause: 1.3 CV:<0.001
 Ischaemic strokeNRNRNRNR1.11.40.14NRNRNRNRNRNRNR1.11.10.74
 Urgent revascularizationNRNRNRNR3.12.90.49CTVT,<0.001NRNRNRNRNRNR
aBleeding events (%)
 TIMI major bleed10 mg load: 2%, 0.5 mg maintenance: 0%20 mg load: 0%, 1.0 mg maintenance: 1%40 mg load: <1%, 2.5 mg maintenance: <1%1%3.22.1<0.001NRNRNRNRNRReported as major – fatal/life threatening but based on TIMI major criteria,
 TIMI major bleed, non-CABG relatedNRNRNRNR21.1<0.0010.
 TIMI minor bleed10 mg load: 0%, 0.5 mg maintenance: 2%20 mg load: 3%, 1.0 mg maintenance: 2%40 mg load: 3%, 2.5 mg maintenance: 2%2%Reported as major or minor, 5.23.4<0.001Reported as non-CABG TIMI major + minor, 1.71.2Reported as major or minor, as major – other but based on TIMI minor definition, as major or minor, 11.410.90.33
 Intracranial bleedNRNRNRNR0.60.2<0.001NRNR0.30.30.74NRNRNR0.30.20.06
 Fatal bleedNRNRNRNR0.20.10.15NRNR0.40.10.002NRNRNR0.30.30.66
  • NR, not reported.

  • aSee Table 1 for definition of primary efficacy and bleeding endpoints.

  • bOnly primary PCI cohort data shown.

These experiences illustrate the difficulties with choosing a dose for phase III based on phase II data. These trials were large relative to many phase II trials in other diseases, but follow-up was short and event rates low, thereby decreasing their power to be informative regarding either safety or efficacy outcomes. Small numbers (and limited power) are misleading, and conclusions drawn under these conditions are exposed to error. Most of the phase II studies showed relative increases in bleeding with the novel antithrombotic agents, and these increases became significant in the larger phase III studies that had greater power to detect such differences at typical levels of statistical significance. The phase II and phase III hazard ratios and 95% confidence intervals become more precise in the phase III trials, with more patients and longer follow-up (Figures 1 and 2).

Figure 1

Comparison of hazard ratios and 95% CI for primary efficacy outcomes in phase II and III antithrombotic acute coronary syndrome trials.

Figure 2

Comparison of hazard ratios and 95% CI for bleeding outcomes in phase II and III antithrombotic acute coronary syndrome trials Supplementary material online, Figures S1 and S2.

Endpoint selection in phase II and III may also contribute to the different observations within these trials. In both the apixaban and rivaroxaban phase II studies, the efficacy endpoint was a combination of cardiovascular death, myocardial infarction (MI), recurrent ischaemia and ischaemic stroke, while in phase III, the endpoint was cardiovascular death, MI and ischaemic stroke (Table 1). The inclusion of more (usually ‘softer’) components may be misleading if the study drug has a larger effect on the lesser important components (e.g. recurrent ischaemia) than on the components measured in phase III (e.g. cardiovascular death). It may also be misleading if the softer components add ‘noise’, i.e. additional events that are unaffected by the study agent (e.g. in TRACER,4 no significant difference was noted in the primary endpoint of cardiovascular death, MI, stroke, recurrent ischaemia with hospitalization or urgent coronary revascularization, but a statistically significant difference was observed in the composite of cardiovascular death, MI or stroke).4

Finally, phase II design is crucial if it is used to plan phase III. The ATLAS ACS TIMI 46 trial was large and completed as planned.5 Two doses were carried forward from phase II to the phase III ATLAS ACS 2-TIMI 51.2 In comparison, the phase II APPRAISE trial was smaller, and enrolment in the higher doses was stopped because of excess bleeding.6 The single dosing regimen chosen for APPRAISE-2 was not one of the doses studied in the phase II trial.3

Role of adaptive designs

Adaptive designs to explore safety (bleeding) have been proposed to overcome the limitations of phase III dose selection.7 Using an adaptive approach, seamless phase II/III studies are designed with multiple doses, and the number of dosing groups adaptively decreases during the study according to a pre-specified analysis plan at one or more unblinded interim analyses. Doses with an unfavourable risk/benefit ratio are dropped. The sample size of individual dosing groups or the overall study may be adjusted using the accruing efficacy and safety data.8,9 Another potentially useful adaptive design is sample size re-estimation based on unblinded interim results, whereby if the interim treatment difference is promising (but not as large as that originally powered for) the trial size is increased accordingly.10 Appropriate methods to control type I error for safety and efficacy, blinding of the steering committee, processes for communication between the steering and data safety monitoring committees and implementation of adaptive changes are challenges associated with these designs that remain unresolved.11

Adaptive designs will only be useful if they are accepted by the regulatory agencies. Both European and US regulators have addressed this topic, but they have not announced a final position.8,9 These designs hold promise for increasing the efficiency of clinical trials, but more research and experience are needed before their widespread adoption.79

Reporting bleeding risks

Major bleeding is an immediate safety outcome and an independent predictor of subsequent mortality among ACS patients, although whether this relationship is causal or simply identifies higher-risk patients is unknown.12,13 The impact of a bleeding event on mortality persists during the long-term follow-up, in contrast to the influence of a recurrent MI on mortality, which is mainly short term.13,14 Bleeding events, even those classified as minor, may lead to discontinuation of antithrombotic therapy, which increases the risk of recurrent ischaemic events.15 The use of transfusions also carries long-term risks.16 Importantly, bleeding events prolong hospital stays and increase costs. However, there is a marked variability in bleeding definitions used across trials (Supplementary material online, Appendix), which severely limits data interpretation.

The components of bleeding endpoints are not equal from the patient perspective (e.g. an intracranial bleed is more severe than bleeding related to instrumentation) or from the standpoint of effectiveness research. Uniform and comprehensive reporting of bleeding events and associated outcomes facilitates event-level data comparisons between agents and across trials. Relevant reporting parameters include, but are not limited to, bleed location, amount of blood loss, need for interventions and resulting disability.

In an effort to achieve consistency, the Standardized Data Collection for Cardiovascular Trials Initiative has reviewed existing bleeding definitions and posted recommendations for public comment, but the final definitions have not been announced.17 The Bleeding Academic Research Consortium (BARC) has also proposed a 5-point scoring system for bleeding (Supplementary material online, Appendix).18 Each of these definitions aims to quantify bleeding severity, but they use different criteria. Thus, various definitions applied to the same data will result in calculation of different bleeding rates. It is apparent that although efforts are being made towards adoption of consistent definitions, many options to define bleeding will be available for use in future clinical trials. Therefore, regardless of the final definitions, study results should be presented such that bleeding outcomes can be interpreted and compared across trials to achieve a comprehensive understanding of bleeding risk.

Determining therapeutic benefit and risk profiles

The optimal antithrombotic regimen should achieve the greatest reduction in thrombotic events at the lowest bleeding risk. This balance is often difficult to achieve because efficacy and safety are related to the same pharmacodynamic effect. It is further complicated by the limited ability to compare data across studies. These concepts are illustrated using several relevant clinical trials.

P2Y12 inhibitors

In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) trial, TIMI major bleeding not related to CABG was increased with prasugrel when compared with clopidogrel (Supplementary material online, Figure S1a, Tables 2 and 3).19 Further analysis revealed a statistically significant increased risk of life-threatening bleeding with prasugrel that was driven by fatal and spontaneous non-fatal events.19 In the Study of Platelet Inhibition and Patient Outcomes (PLATO) trial, there was no difference in major bleeding between groups. However, this included and was dominated by bleeding related to CABG. When the bleeding criteria used in the TRITON-TIMI 38 study were applied to PLATO (i.e. excluding CABG-related bleeding), statistically significant increases in bleeding and fatal intracranial bleeding were noted with ticagrelor (Supplementary material online, Figure S1a).

In both trials, death from vascular causes, MI or stroke was lower in patients randomized to prasugrel or ticagrelor when compared with clopidogrel (Supplementary material online, Figure S1b, Tables 2 and 3).19,20 Myocardial infarction (both spontaneous and procedure related)21 was the main contributor to the primary endpoint in both studies (Tables 2 and 3).

Factor Xa inhibitors

In ATLAS ACS 2-TIMI 51, rivaroxaban was associated with absolute increases in TIMI major non-CABG bleeding of 1.2% (2.5 mg) and 1.8% (5 mg) compared with placebo, and a 0.2% (2.5 mg b.i.d.) and 0.5% (5 mg b.i.d.) absolute increase in intracranial bleeding. Absolute reductions of 1.8% in the primary composite endpoint (cardiovascular death, MI, or stroke), 0.8% in all-cause mortality and 1.1% in MI were also observed2 (Tables 2 and 3). The exact balance between risks and benefits is uncertain due to incomplete follow-up in some patients, which caused the FDA to withhold the approval of rivaroxaban for an ACS indication pending further data.

Although definite conclusions cannot be drawn from post hoc analyses of individual components of bleeding or thrombotic outcomes that occur with a low frequency, the importance of evaluating the totality of evidence becomes clear. Clinically meaningful increases or decreases in specific thrombotic or bleeding events may be masked by an overall neutral composite result (e.g. overall bleeding composite is neutral but life-threatening or intracranial bleeding is increased). Similarly, a composite may be driven by a factor with a lower degree of clinical importance (e.g. small non-fatal MI), without effect on more important events, particularly mortality. For this reason, net clinical benefit composite endpoints are problematic, since each outcome is considered clinically equivalent, while this assumption is obviously incorrect. Similar to other types of composite endpoints, net clinical benefit composites can hide components that go in divergent directions. As with all composites, the components should be reported individually.

New methodologies are being developed to deal with these limitations of composite endpoints. One major limitation is that time-to-first event analyses do not consider subsequent events. Less clinically important events often occur first and count towards the endpoint (e.g. non-fatal MI), whereas subsequent, often more severe events, are disregarded. The win ratio approach to analysing composite endpoints gives greater priority to the more clinically important components, such as mortality.22 With this method, the most important component of the composite is determined. For example, in a composite of cardiovascular death, MI or stroke, cardiovascular death would be the most important component, followed by stroke, and then MI. Patients in the active treatment and control (or standard) treatment are matched using a risk score or risk stratification, and compared to determine which patient experienced a cardiovascular death first. If neither experienced a death, then they would be compared to determine who experienced a stroke first, and so on. The ‘win ratio’ is the number of matched pairs where patients on standard therapy had worse outcomes. An alternative unmatched ‘win ratio’ approach compares every active with every control patient using the same principles; this may be preferred if the basis of matching cannot be clearly defined in advance. Although more research is needed to validate this approach and to determine its acceptance by regulatory bodies, it is encouraging that more robust and insightful methods of analysing composite endpoints are on the horizon.

Challenges facing future trials

New therapies for ACS must be tested against evidence-based therapy as recommended in international guidelines (aspirin and a P2Y12 inhibitor, either ticagrelor, prasugrel, or clopidogrel depending on the clinical situation).23,24 The additional treatment effects are likely to be small, while the additive bleeding risks may be substantial. Very large sample sizes will be required to detect treatment effects, and the net clinical benefit may be small if bleeding risks are substantially increased. The polypharmacy of double and triple drug regimens carries important implications from the standpoints of adherence, cost, side effects, and the balance of risks and benefits. Consideration should be given to trials that evaluate novel single drugs or combinations of drugs (e.g. can newer drugs replace aspirin or P2Y12 inhibitors) rather than triple or quadruple therapy. A direct comparison of prasugrel and ticagrelor would be of interest to assess whether the observed differences in the TRITON and PLATO trials are real and reproducible. Research that aims to quantify the contribution of individual drugs would be clinically meaningful. For example, to what extent does an individual drug reduce thrombotic events and increase bleeding risk? Such research might lead to modification of current guidelines and a shift in clinical equipoise with regard to what constitutes ‘standard therapy’ for future trials. However, careful attention needs to be placed on the ethics of such designs to ensure that the best standard of care is not compromised.

Some of the points raised in this review may appear semantic, but they become clinically relevant when one applies the results of trials to clinical practice. What level of bleeding risk will patients and physicians be willing to accept to achieve which level and type of thrombotic event reduction, particularly when non-fatal MI is driven by biomarker positivity? Is thrombotic event reduction alone (reduction of MI and stent thrombosis) sufficient in the absence of any benefit on mortality? What magnitude of effect on cardiovascular or all-cause mortality should be present to outweigh bleeding risks? These questions also raise ethical concerns about treating patients with drugs associated with a significant bleeding risk for ambiguous clinical benefits. These questions remain unanswered but are critical concepts that require attention.


The development of new antithrombotic agents for the treatment of ACS and other cardiovascular diseases is a rapidly evolving and increasingly complex field. Optimizing the prevention of ischaemic events and simultaneously minimizing bleeding risks are central to improving patient outcomes. This target is often elusive because efficacy and safety are closely intertwined.

Previous advances in ACS management have reduced event rates such that mega-trials involving tens of thousands of patients are now required to achieve sufficient power to detect relatively small treatment effects. This necessitates the use of composite efficacy and safety endpoints, so that adequate numbers of events can accrue in a reasonable time frame. Investigators, regulators, and physicians are then faced with the challenges inherent in interpreting composite endpoints: effects that may differ directionally among the individual components of the composite; results that are driven by a less important or softer component; variations in efficacy and safety endpoint definitions; and competing safety outcomes. The faculty panel proposed multiple considerations for future research to address some of these challenges (Table 4). Novel, scientifically rigorous methodologies; additional analyses of existing data; and an open, cooperative dialogue among investigators, regulators, and sponsors such as occurs in CVCT meetings are needed to address these challenges and to continue bringing safe and effective new therapies to the forefront of ACS therapeutics.

View this table:
Table 4

Proposals for future research

  • Adopt uniform reporting criteria for bleeding risks, specifically BARC once validated

  • Within BARC bleeding categories, provide information on bleeding location, volume of blood, interventions, and outcome

  • If the quantity of such detailed information exceeds in-print publication limits, then the information should be publicly available as an Supplementary material online, in the clinical trial registry, or similar source

  • Components of composite endpoints should be reported separately, including MI (MI type and size)

  • The win ratio or other appropriate novel analytic methodologies should be validated in completed trial databases to gain experience with the method and to determine whether it will be an acceptable replacement for standard time-to-event analyses.

  • Adaptive designs should be considered for phase II trials to obtain more robust data to inform phase III. Efforts should focus on resolving uncertainties with regard to appropriate methodologies for data analysis and dealing with type I error.

  • To establish the optimal threshold of risk vs. benefit with regard to antithrombotic therapy, more research is needed to determine the association between different levels of bleeding and subsequent clinical outcomes and the association between thrombotic events and subsequent clinical outcomes.

  • Future research efforts should attempt to quantify the relative contribution of individual antithrombotic therapies to ischaemic event reduction and bleeding risk, in an effort to establish what should constitute ‘standard of care’ for future trials.

  • Research evaluating patient reported outcomes should focus on determining the acceptable level of risk vs. benefit from the patient's perspective, as well as the impact of triple drug therapy on the quality of life


This work was generated from discussions during the 7th and 8th Global Cardiovascular Clinical Trialists (CVCT) Forums held in Paris, France, in December 2010 and 2011. CVCT was organized by the Clinical Investigation Center (CIC) Inserm, CHU, and University Henri Poincaré of Nancy, France and funded by an unrestricted educational grant from Association de Recherche et d'Information en Cardiologie (ARISC) a non-profit educational organisation, in Nancy, France. ARISC had no involvement in preparation, review, or approval of the manuscript for publication.

Conflict of interest: F.W.A.V.: Educational and research grants from Bayer Healthcare, Roche, Eli Lilly, and Boehringer Ingelheim; Consulting honoraria from Daiichi-Sankyo, Eli Lilly, Merck, The Medicines Company, and Bayer Healthcare. P.C.: Research contracts, consulting, speakers bureau, or research and educational grants from Abbott, Astra Zeneca, Aventis, Bayer, Bristol Myers Squibb, Eli-Lilly, Fibrex, Merck, Myogen, Medtronic, Mitsubishi Pharma, The Medicines Company, Nycomed, Organon, Pfizer, Pharmacia, Sanofi-Synthelabo, Searle, and Servier. R.M.: Advisory Board of Regado Biosciences; Consultant for Janssen (Johnson & Johnson), AstraZeneca, and Abbott Laboratories; Institutional research support from Bristol Myers Squibb/Sanofi-Aventis, The Medicines Company, and Lilly/Daiichi Sankyo. S.A.: Advisory Board for AstraZeneca; Lectures for Pfizer, Siemens, Boehringer Ingelheim. S.G.: Principal investigator for a clinical trial of TAK 422 (Xa inhibitor); consulting honoraria from Takeda Pharmaceuticals.C.T.-P.: None. M.L.S.: Data Safety Monitoring Board Chairman for APPRAISE studies. J.B.: Servier, Pfizer, BioMarin, Roche, Novartis, Takeda (drug development consulting, membership on DMCs and event adjudication committees); Servier (membership on trial executive committees, membership on advisory boards, speaking); BioMarin (stock/stock options), BioTRONIK (device development consultation, membership on trial executive committee). Y.M.K.: Employee of Boehringer Ingelheim. P.B.: Employee of Johnson & Johnson. E.D.: Employee of The Medicines Company. J.J.V.M.: None. S.D.B.: Employee of Bayer HealthCare Pharmaceuticals. W.G.S.: INSERM, Centre d'Investigation Clinique, Centre Hospitalier Universitaire, Nancy, France (travel expense reimbursement to attend CVCT 2010 and 2011 and professional time related to preparation of this paper). F.Z.: Steering Committee, Pfizer, Inc.


The following individuals were speakers or panelists discussing the topic of this manuscript at the December 2010 and/or 2011 Global Cardiovascular Clinical Trialists Forum, Paris, France: Gonzalo Calvo; John Cleland; Nancy Cook-Bruns; Terry Ferguson; Lennart Forslund; Alain Gay; Stuart Kupfer; Andrea Laslop; Basil Lewis; Frank Misselwitz; Prem Pais; Vladimir Popov; James Revkin; Yves Rosenberg; Tabassome Simon; Daryl Sleep; Mohamed Sobhy; Hans Wedel.


  • The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.