Journal of the American College of Cardiology Vol. 63, No. 11, 2014� 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.049

EDITORIAL COMMENT

Vorapaxar in PatientsUndergoing CoronaryArtery Bypass Grafting

Insights From a Subgroup Analysis*

Ori Ben-Yehuda, MD

New York, New York

Subgroup analyses play an important role in the interpre-tation of clinical trials. Consistency of a treatment effectacross different demographic and baseline characteristics isof the greatest importance, as an overall positive result maynot translate to be of benefit in all subgroups. The mostimportant subgroups, such as those categorized by sex, age,diabetes status, and prior myocardial infarction (MI), areusually reported in the primary publication, followed bya host of other publications, with only the imagination andacademic stamina limiting the number of possible analyses.

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But subgroup analyses are fraught with pitfalls (1,2).Both false positive (type 1) and false-negative (type 2) errorsare more likely in subgroup analyses, the former due tomultiple testing and the latter due to small sample size. Theproblem with subgroup analyses was memorably high-lighted 25 years ago when the ISIS-2 (International Studyof Infarct Survival-2) trial investigators showed that aspirintherapy in the treatment of suspected MI appeared to beharmful in the subgroup born under the astrological sign ofGemini or Libra, although it was beneficial in loweringmortality and reducing recurrent MIs in the overall study(3). No such astrological effect was seen with streptokinase.More recently, a subgroup analysis of the ATHENA (APlacebo-Controlled, Double Blind, Parallel Arm Trial toAssess the Efficacy of Dronedarone 400 mg bid for thePrevention of Cardiovascular Hospitalization or Deathfrom any Cause in Patients with Atrial Fibrillation/AtrialFlutter) trial suggested a benefit in patients with permanentatrial fibrillation (4). Subsequently, however, the PALLAS

*Editorials published in the Journal of the American College of Cardiology reflect the

views of the authors and do not necessarily represent the views of JACC or the

American College of Cardiology.

From the Cardiovascular Research Foundation, New York, New York. Dr. Ben-

Yehuda has reported that he has no relationships relevant to the contents of this paper

to disclose.

(Permanent Atrial Fibrillation Outcome Study UsingDronedarone on Top of Standard Therapy) trial (5) notonly failed to show any benefit, but was prematurelystopped due to a statistically significant increase in mor-tality, stroke, and heart failure, highlighting the potentialdanger of subgroup analyses influencing clinical care andforming the basis of phase 3 studies.

How, then, should we approach subgroup analyses, par-ticularly when one subgroup is at odds with the overallfindings of the study? Beyond a hefty grain of salt, certainsubgroup analyses are more believable. The larger thesubgroup, the more believable the result; indeed, we shouldbe looking at the power of the subgroup itself. A rule ofthumb is to limit subgroup analyses to those that maintainat least 40% to 50% power for the endpoint of interest (2). Ina study with 90% power, this rule would preclude analyzingsubsets comprising fewer than 30% of the original cohort.Additional questions include whether the analysis was pre-defined, whether a formal test of interaction is significant,and whether there is biological plausibility for the diver-gent findings. And finally, even if all these conditions aremet, subgroup analyses should be viewed as hypothesis-generating and not overinterpreted.

It is with these caveats and limitations in mind that weshould examine the subgroup analysis by Whellan et al. (6)from the TRACER (Thrombin Receptor Antagonist forClinical Event Reduction in Acute Coronary Syndrome)trial published in this issue of the Journal. The TRACERtrial (7) was a large (n ¼ 12,944) phase 3 study of vora-paxar in acute coronary syndrome. Vorapaxar, a protease-activated-receptor 1 antagonist, inhibits the activation ofplatelets by thrombin. Thrombin is considered the mostpotent platelet agonist. Vorapaxar showed promise in phase2 trials in patients with stable percutaneous coronary inter-vention and acute coronary syndromes. Importantly, in thephase 2 trials (8,9), there was no increased bleeding asassessed by the Thrombolysis In Myocardial Infarction(TIMI) bleeding score, despite concomitant dual antiplatelettherapy in the majority of patients. Vorapaxar was thereforetouted as a potential blockbuster with anti-ischemic effects,but no increase in bleeding. Two large phase 3 trials weresubsequently carried out, the TRACER trial (8) in patientswith acute coronary syndrome and the TRA 2P–TIMI 50(Thrombin Receptor Antagonist in Secondary Preventionof Atherothrombotic Ischemic Events–Thrombolysis InMyocardial Infarction 50) trial (10) in patients with priorMI, ischemic stroke, or peripheral arterial disease.

The TRACER trial failed to meet its primary quadrupleendpoint (cardiovascular death, MI, stroke, or ischemia-driven revascularization or hospitalization), but did meetthe secondary triple endpoint of cardiovascular death, MI,or stroke with a hazard ratio (HR) of 0.89 (p ¼ 0.02). Mostimportantly, in divergence with the phase 2 data, there wasa significant increase in major bleeding, including intracra-nial hemorrhage, which was increased from 0.2% in theplacebo group to 1.1% in the vorapaxar group (HR: 3.39).

JACC Vol. 63, No. 11, 2014 Ben-YehudaMarch 25, 2014:1058–60 Vorapaxar and CABG

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The subgroup analysis by Whellan et al. (6) looked at1,312 patients from the trial who underwent coronary arterybypass graft (CABG) surgery during the index hospitaliza-tion and showed a 45% reduction in the primary quadrupleendpoint for the TRACER trial. Most important, there wasno significant increase in major CABG-related bleeding.These findings (part of a pre-specified subgroup analysis)differ significantly from the non-CABG group, with a pvalue for interaction of 0.012.

Based on the relatively small number of patients in theCABG subgroup, the skeptic would be inclined to dismissthe findings, despite the significant p value for interaction,as this subgroup appears a priori to be underpowered, withonly 10.8% of the study population. Even the markedbenefit (seen with an HR of 0.55) should be viewed withcaution. Indeed, to be statistically significant, effects insmall-sized subgroups have to be of greater magnitude (2).

Is there biological plausibility in the results? Thrombingeneration is increased during surgery in general and on-pump bypass surgery in particular. At the site of wounds,such thrombin generation is beneficial and necessary forhemostasis, but when there is systemic generation ofthrombin, such as that during bypass, a host of coagulationdisorders may ensue, with both increased bleeding andthrombosis (11). It is therefore plausible that in the settingof CABG surgery, vorapaxar would reduce thrombin-relatedplatelet activation and reduce ischemic events, which inturn may reduce perioperative MIs and thrombotic graftfailure.

The most important finding of the CABG subgroupanalysis was not, however, that it met the primary endpointof the TRACER trial. After all, the main trial was stoppedprematurely, showed a trend toward a reduction in theprimary endpoint with a p value of 0.07, and met the similarsecondary composite endpoint, consistent with an anti-ischemic effect. An anti-ischemic effect was also shown inthe even larger trial, the TRA 2P–TIMI 50 trial, in patientspost-MI. Rather it is the lack of major CABG-relatedbleeding and a lower, albeit still increased rate overplacebo of 2-year TIMI major bleeding that is remarkable.One possibility is of a type II error (false negative) as theCABG subgroup was not powered for this important safetyendpoint. A more intriguing possibility is that the CABGsubgroup had a lower risk of bleeding due to the expectedlylower use of clopidogrel in this group. At discharge, clopi-dogrel use in the patients undergoing CABG was only 18%versus 84% in the non-CABG group. Clopidogrel was alsoheld prior to CABG, with only 39% receiving the drugwithin 5 days of surgery, and probably a smaller percentagecloser to surgery.

Withholding concomitant clopidogrel treatment, how-ever, is unlikely to prevent the most dreaded risk of treat-ment with vorapaxar, namely intracranial hemorrhage in allpatients. In the TRA 2P–TIMI 50 trial, there was a markedincrease in intracranial hemorrhage in subjects with a historyof stroke, leading the data and safety monitoring board to

discontinue study treatment in this group 2 years into thestudy. This group, as with the CABG subgroup in theTRACER trial, had a low use of thienopyridines (mostlyclopidogrel) at 24%. It would appear that with vorapaxar,intracranial bleeding is also dependent on the patient’sunderlying substrate. Thrombin generation, which is trig-gered by release of anionic phospholipids in brain injury,may be particularly important in preventing intracranialhemorrhage.

Is there a second act in store for vorapaxar, once consid-ered a potential blockbuster? Is there a future for the conceptof protease-activated receptor 1 inhibition, whether in asurgical population or in a wider acute coronary syndromeor percutaneous coronary intervention population? Manyuncertainties remain, including the correct dose of the drug,either as monotherapy, in addition to aspirin or in additionto dual antiplatelet therapy. Interestingly in the phase2 study of vorapaxar, both the 1 mg and 2.5 mg maintenancedoses led to at least 80% inhibition of thrombin receptoragonist peptide (TRAP)-induced platelet inhibition in100% of patients, both at 30 and 60 days (9). Based on thephase 2 data, the 2.5 mg dose was chosen for the phase3 program in anticipation that major bleeding would notbe increased, an expectation which was not confirmed. Thephase 2 program also indicated that the drugwould not lead toincreased bleeding, even in the presence of dual antiplatelettherapy. Given the clear finding of increased bleeding in thephase 3 program, thereby changing the anticipated benefit/risk ratio for the drug, the possibility of using the drug in theabsence of a P2Y12 blocker is intriguing.

Decades after the introduction of aspirin into routineuse, and more than 15 years after the availability of clopi-dogrel, we are still defining the proper dose and use ofthese important antiplatelet drugs. Vorapaxar is presentlyundergoing evaluation by the Food and Drug Administra-tion for the treatment of patients with a history of priorMI and no prior stroke and transient ischemic attack (12).Given the issues of bleeding associated with the drug, evenif approved, its proper use will entail a difficult task ofidentifying the patient in whom the benefit outweighs therisk. The study by Whellan et al. (6) adds an interestinghypothesis to the inevitable debate.

Reprint requests and correspondence: Dr. Ben-Yehuda,Cardiovascular Research Foundation, 111 East 59th Street,New York, New York 10022. E-mail: obenyehuda@crf.org.

REFERENCES

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4. Nieuwlaat R, Hohnloser SH, Connolly SJ. Effect of dronedarone inpatients with permanent atrial fibrillation during the ATHENA study.Eur Heart J 2011;32: Suppl:618.

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12. Merck & Co. press release. Merck Announces FDA Acceptance ofNew Drug Application for Vorapaxar, Investigational Anti-Thrombotic Medicine. July 24, 2013. Available at: http://www.mercknewsroom.com/press-release/research-and-development-news/merck-announces-fda-acceptance-new-drug-application-vora. Accessed October6, 2013.

Key Words: bypass - coronary disease - myocardial infarction -

platelets - thrombin.