Authors: Gregory Y. H. Lip, Xianying Pan, Shital Kamble, Hugh Kawabata, Jack Mardekian, Cristina Masseria, Amanda Bruno, Hemant Phatak
Categories: Cardiology, Original Article
Source: International Journal of Clinical Practice
Doi: 10.1111/ijcp.12863
Limited data are available about the real‐world safety of non‐vitamin K antagonist oral anticoagulants (NOACs).
To compare the major bleeding risk among newly anticoagulated non‐valvular atrial fibrillation (NVAF) patients initiating apixaban, warfarin, dabigatran or rivaroxaban in the United States.
A retrospective cohort study was conducted to compare the major bleeding risk among newly anticoagulated NVAF patients initiating warfarin, apixaban, dabigatran or rivaroxaban. The study used the Truven MarketScan^®^ Commercial & Medicare supplemental US database from 1 January 2013 through 31 December 2013. Major bleeding was defined as bleeding requiring hospitalisation. Cox model estimated hazard ratios (HRs) of major bleeding were adjusted for age, gender, baseline comorbidities and co‐medications. Among 29 338 newly anticoagulated NVAF patients, 2402 (8.19%) were on apixaban; 4173 (14.22%) on dabigatran; 10 050 (34.26%) on rivaroxaban; and 12 713 (43.33%) on warfarin. After adjusting for baseline characteristics, initiation on warfarin [adjusted HR (aHR): 1.93, 95% confidence interval (CI): 1.12–3.33, P=.018] or rivaroxaban (aHR: 2.19, 95% CI: 1.26–3.79, P=.005) had significantly greater risk of major bleeding vs apixaban. Dabigatran initiation (aHR: 1.71, 95% CI: 0.94–3.10, P=.079) had a non‐significant major bleeding risk vs apixaban. When compared with warfarin, apixaban (aHR: 0.52, 95% CI: 0.30–0.89, P=.018) had significantly lower major bleeding risk. Patients initiating rivaroxaban (aHR: 1.13, 95% CI: 0.91–1.41, P=.262) or dabigatran (aHR: 0.88, 95% CI: 0.64–1.21, P=.446) had a non‐significant major bleeding risk vs warfarin.
Among newly anticoagulated NVAF patients in the real‐world setting, initiation with rivaroxaban or warfarin was associated with a significantly greater risk of major bleeding compared with initiation on apixaban. When compared with warfarin, initiation with apixaban was associated with significantly lower risk of major bleeding. Additional observational studies are required to confirm these findings.
Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice, with an estimated 70% of cases classifiable as non‐valvular atrial fibrillation (NVAF). An estimated 33 million individuals are affected by AF worldwide, including 1%–4% of adults in Australia, Europe and the United States.1 The incidence of stroke in patients with AF is nearly fivefold higher than that of the general population, resulting in significant morbidity and mortality. Also, AF‐related strokes have higher mortality, greater disability, costs, and increased incidence of recurrent stroke compared with non‐AF‐related strokes.2, 3, 4 For several decades, Vitamin K Antagonists (VKA, e.g. warfarin) were the primary oral anticoagulant used for stroke prevention in AF, being highly effective for preventing stroke and reducing all‐cause mortality in patients with AF. However, managing the proper dose of warfarin to achieve the international normalisation range (INR) of 2–3 is difficult and lack of control is associated with a significant rate of major bleeding.5 As a result, approximately 30%–50% of AF patients were undertreated with either suboptimal warfarin treatment, or given aspirin or no anticoagulation.6 In recent years, four non‐VKA oral anticoagulants (NOACs) have been approved for stroke prevention in AF. In clinical trials, all NOACs have all been shown to be at least as safe and effective as warfarin.7 These new agents do not require regular INR monitoring and have few major drug and food interactions, as compared with warfarin.7, 8 The four NOACs were approved in the United States over a period of 6 years: Dabigatran 150 mg b.i.d. was the first NOAC approved in 2010, followed by rivaroxaban 20 mg q.i.d. in 2011, apixaban 5 mg b.i.d. in 2012, and edoxaban 60 mg q.i.d. in 2015. After approval in the United States, marketing authorisation for each of the NOACs expanded globally. By 2015, when edoxaban was approved in the United States, the first three NOACs were approved for marketing in the United Kingdom, Europe and Asia. For this study, we focused on apixaban, dabigatran and rivaroxaban, as there are no real‐world data available for edoxaban in the United States. Despite evidence on the efficacy and safety of these NOACs from randomised controlled trials, little is known about the bleeding events associated with the use of NOACs among NVAF patients in real‐world settings.9 The key objectives of this study were to (i) describe the clinical and demographic patient characteristics of newly anticoagulated NVAF patients who initiated apixaban, dabigatran, rivaroxaban, and warfarin in the United States; (ii) assess unadjusted rates of first major bleeding; and (iii) compare the risk of major bleeding among newly anticoagulated NVAF patients initiating apixaban vs warfarin, dabigatran or rivaroxaban, adjusting for demographic and clinical characteristics. Further, we also assessed the risk of major bleeding among newly anticoagulated NVAF patients initiating warfarin vs apixaban, dabigatran or rivaroxaban, adjusting for demographic and clinical characteristics.
A retrospective cohort study was conducted using Truven MarketScan^®^ Commercial and Medicare supplemental data to compare the risk of major bleeding in NVAF patients newly initiated on apixaban compared with warfarin, dabigatran or rivaroxaban and patients newly initiated on warfarin compared with apixaban, dabigatran or rivaroxaban.
The Truven MarketScan^®^ (Truven Health Analytics, Ann Arbor, MI, USA) database consists of administrative healthcare claims for employees of large self‐insured companies and members of private healthcare plans in the United States. Each claim contains a unique encrypted patient identifier that is used to construct a longitudinal record of medical and pharmacy services for these people. Membership information is used to ensure that these patients are eligible for benefits during the period of the study. Medical information is obtained from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) diagnosis codes contained in the claims. Pharmacy claims include the drug dispensed using the National Drug Code coding system. Every claim contains the dates of service, provider of the service, and information about units for physician services or date medications were dispensed.
The “commercial” population of this database represents those patients who were <65 years and were not covered by Medicare (the US government program for those ≥65 years). The “Medicare Supplemental” population of the database represented those patients who were ≥65 and either participated in the Medicare program or continued to be covered by their employer's health plan. For this study, we included unique patient identifiers from both the commercial and Medical supplemental population.
NVAF (ICD‐9‐CM 427.31, 472.32 for primary or secondary diagnosis) patients ≥18 years with 1 year of baseline period with continuous enrolment were included if they were newly prescribed oral anticoagulants from 1 January 2013 to 31 December 2013. Patients included in this study were new initiators without anticoagulant treatment within 1 year prior to the initiation. Patients with evidence of valvular heart disease, thyrotoxicosis, pericarditis, mitral stenosis, VTE, heart surgery and endocarditis during the baseline period (any time prior to or on index date) were excluded. Patients with any evidence of pregnancy at any time during the baseline were excluded (Fig. 1).
Figure 1 Patient selection criteria
A new initiator (i.e. new user) was required to have at least one claim with a diagnosis of AF and at least one prescription claim for oral anticoagulant (OAC), either warfarin, apixaban, dabigatran or rivaroxaban with no prior use of anticoagulant in the baseline. Index date was defined as the date of first prescription after the NVAF diagnosis. Index drug was defined as the first anticoagulation treatment prescribed to patients included in the study.
Major bleeding on an anticoagulant was defined as bleeding requiring hospitalisation (i.e. inpatient bleeding) any time during the period of drug use or within 30 days from the last day of supply of treatment prescription. Major bleeding was identified using hospital claims, which had a bleeding diagnosis code as the first listed ICD‐9‐CM diagnosis code. ICD‐9‐CM codes are provided in Table S1. The definition of major bleeding was modified from a published administrative claims‐based algorithm10 and captures major bleeding at key sites, including but not limited to intracranial, gastrointestinal, liver, splenic and ocular haemorrhage requiring hospitalisation with a diagnosis for bleeding.
Patients were followed from the index date to the first major bleeding event, date of discontinuation from index medication, date of a switch, end of study period or interruption in continuous enrolment, whichever occurred earlier.
In the eligible population, baseline demographic and clinical categorical and continuous variables were compared across treatments using Pearson's chi‐square test and Kruskal‐Wallis test, respectively. Unadjusted rates of first major bleeding event were described as the number of bleeding events per 100 person‐years and compared using Poisson distribution using both warfarin and apixaban as the reference category. The rate of major bleeding was calculated as the number of first major bleeding events divided by the total time at risk for major bleeding within the study period. Kaplan‐Meier curves were used to present the cumulative incidence of a first major bleeding event. A Cox proportional hazards model was used to estimate the hazard ratios (HR) of major bleeding adjusted for a prespecified set of baseline demographic and clinical factors, including age, sex, region, embolic or primary ischaemic stroke, dyspepsia or stomach discomfort, congestive heart failure, coronary artery disease, diabetes, hypertension, renal disease, myocardial infarction, history of stroke or transient ischaemic attack, history of bleeding, Charlson Comorbidity Index (CCI) and baseline medications including angiotensin converting enzyme inhibitor, amiodarone, angiotensin receptor blocker, beta blocker, H2‐receptor antagonist, proton pump inhibitor and statins. We selected these baseline variables for the Cox model whose P<.2 or considered clinically important. These baseline variables were similar to baseline factors used in other recent work.11, 12, 13 All analyses were performed with sas system, version 9.2. A P<0.05 was considered statistically significant.
To assess robustness of the main study results, we conducted the following sensitivity
Among 29 338 eligible patients, 2402 (8.19%) were initiated on apixaban with a mean ± SD follow‐up of 90.37±72.06 days; 4173 (14.22%) on dabigatran with a mean follow‐up of 126.74±102.54 days; 10 050 (34.26%) on rivaroxaban with a mean follow‐up of 117.71±97.17 days; and 12 713 (43.33%) on warfarin with a mean follow‐up of 127.55±102.09 days. The mean age of apixaban, dabigatran, rivaroxaban and warfarin patients was 69.3±12.3, 66.8±12.2, 67.3±12.3, and 72.5±11.9 years, respectively. Patients initiating warfarin were older and at a higher stroke risk based on the CHA2DS2–VASc score (3.22±1.65) and had a higher CCI score of 2.37±2.33 followed by apixaban, rivaroxaban and dabigatran (P<.001 across all treatments). Compared with patients initiating rivaroxaban or dabigatran, patients initiating apixaban were older and had higher mean CHA2DS2–VASc and CCI scores. Compared with patients initiating rivaroxaban or dabigatran, apixaban patients had greater use of ACE inhibitors, amiodarone, beta blockers, statins and H2‐receptor antagonists (Tables 1 and 2).
The unadjusted incidence rate (per 100 person‐years) for major bleeding requiring hospitalisation was 4.66 for warfarin, 4.57 for rivaroxaban, 3.38 for dabigatran and 2.35 for apixaban patients (Table S3). The cumulative incidence of major bleeding for new initiations on anticoagulants is represented in Fig. 2.
Figure 2 Cumulative incidence of major bleeding requiring hospitalisation for anticoagulant initiation
After adjusting for baseline characteristics, as compared with patients newly initiated on apixaban, patients newly initiated on warfarin (HR: 1.93, 95% CI: 1.12–3.33, P=.018) or rivaroxaban (HR: 2.19, 95% CI: 1.26–3.79, P=.005) were more likely to experience a major bleeding event. Patients newly initiated on dabigatran (HR: 1.71, 95% CI: 0.94–3.10, P=.079) had a non‐significant trend for more major bleeding compared with those initiated on apixaban (Table 3).
After adjusting for baseline characteristics, as compared with patients newly initiated on warfarin, patients newly initiating apixaban (HR: 0.52, 95% CI: 0.30–0.89, P=.018) were less likely to experience a major bleeding event. There was no significant differences in major bleeding between patients newly initiated on warfarin and those initiated on rivaroxaban (HR: 1.13, 95% CI: 0.91–1.41, P=.262) or dabigatran (HR: 0.88, 95% CI: 0.64–1.21, P=.446) (Table 3 and Fig. 3). Besides OAC treatment, the factors associated with major bleeding requiring hospitalisation included the history of prior bleeding and comorbidities, including congestive heart failure, renal disease and dyspepsia or stomach discomfort (Table 3).
Figure 3 Unadjusted incidence rates of major bleeding requiring hospitalisation (per 100 person‐year) and adjusted hazard ratios for anticoagulant initiation – apixaban, rivaroxaban, and dabigatran compared with warfarin. Hazard ratios (HRs) are adjusted based on the Cox proportional hazards model adjusted age, sex, region, embolic or primary ischaemic stroke, dyspepsia or stomach discomfort, congestive heart failure, coronary artery disease, diabetes, hypertension, renal disease, myocardial infarction, history of stroke or transient ischaemic attack, history of bleeding, Charlson comorbidity Index score and baseline medications, including angiotensin converting enzyme inhibitor, amiodarone, angiotensin receptor blocker, beta blocker, H2‐receptor antagonist, proton pump inhibitor and statins.
The unadjusted incidence rate (per 100 person‐years) for major critical site bleeding in an inpatient or outpatient setting was 13.01 for warfarin compared with 8.15 for apixaban, 12.41 for rivaroxaban and 9.01 for dabigatran. These unadjusted incidence rates showed a similar pattern to the unadjusted incidence rates obtained for major bleeding requiring hospitalisation in the main analysis. After adjusting for baseline characteristics, as compared with patients newly initiated on apixaban, patients newly initiated on warfarin (HR: 1.62, 95% CI: 1.20–2.18, P=.002) or rivaroxaban (HR: 1.70, 95% CI: 1.26–2.29, P<.001) were more likely to experience a major critical site bleeding event. Patients newly initiated on dabigatran (HR: 1.28, 95% CI: 0.92–1.79, P=.144) had a numerically greater but non‐significant risk of major bleeding compared with those initiated on apixaban (Table 4). As compared with patients newly initiated on warfarin, patients newly initiated on dabigatran (HR: 0.79, 95% CI: 0.65–0.96, P=.018) or apixaban (HR: 0.62, 95% CI: 0.46–0.83, P=.002) were less likely to experience a major critical site bleeding event.
The unadjusted incidence rate (per 100 person‐years) for major bleeding requiring hospitalisation was 4.66 for dose‐adjusted warfarin compared with 2.17 for apixaban 5 mg b.i.d., 3.99 for rivaroxaban 20 mg q.i.d. and 2.98 for dabigatran 150 mg b.i.d. These unadjusted incidence rates for standard doses showed a similar pattern to the unadjusted incidence rates obtained for major bleeding requiring hospitalisation in the main analysis.
After adjusting for baseline characteristics, as compared with patients newly initiated on apixaban 5* *mg b.i.d., those patients newly initiated on dose‐adjusted warfarin (HR: 1.90, 95% CI: 1.03–3.51, P=.040) or rivaroxaban 20 mg q.i.d. (HR: 2.06, 95% CI: 1.11–3.84, P=.023) were more likely to experience a major bleeding event. Patients newly initiated on dabigatran, 150 mg b.i.d. (HR: 1.56, 95% CI: 0.79–3.04, P=.198), had a numerically greater but non‐significant risk of major bleeding compared with those initiated on apixaban 5 mg b.i.d. (Table 5). As compared with patients newly initiated on dose‐adjusted warfarin, those patients newly initiated on apixaban, 5 mg b.i.d. (HR: 0.53, 95% CI: 0.29–0.97, P=.040), were less likely to experience a major bleeding event. Patients newly initiated on dabigatran, 150 mg b.i.d. (HR: 0.82, 95% CI: 0.58–1.16, P=.262) or rivaroxaban, 20 mg q.i.d. (HR: 1.08, 95% CI: 0.85–1.39, P=.525) had a non‐significant risk of major bleeding compared with those initiated on dose‐adjusted warfarin. The third sensitivity analysis where patients were censored at 90 and 180 days showed similar results to the main analysis (Tables S3, S4 and Figs S1, S2).
In this study, we show that among newly anticoagulated NVAF patients in the real‐world US setting, initiation with rivaroxaban or warfarin was associated with a significantly greater risk of major bleeding as compared with initiation on apixaban. No prior observational study has evaluated risk of major bleeding as a comparative safety between various oral anticoagulants, apixaban and other NOACs or warfarin. The results of this study corroborates indirect treatment and network meta‐analysis findings, based on clinical trials data, that apixaban was associated with a significantly lower hazard of major bleeding compared with warfarin and rivaroxaban.14, 15, 16 Previous studies have presented the incidence and HRs of risk of major bleeding for rivaroxaban vs warfarin and dabigatran vs warfarin in real‐world settings. The findings of this study are qualitatively comparable to other real‐world studies focused on rivaroxaban vs warfarin17 and dabigatran vs warfarin.18, 19
This study used real‐world claims data from the US population to demonstrate comparative safety in an adult NVAF population newly initiated on warfarin, rivaroxaban, dabigatran or apixaban therapy. Apixaban has been available in the United States since 2013; thus, the follow‐up period on apixaban was relatively shorter compared with warfarin, rivaroxaban and dabigatran in this study. Despite major bleeding being a relatively rare event, the risk differences between the treatments groups were detected and the study was focused on newly initiated and previously anticoagulation‐naïve patients. Given that warfarin requires more time than NOACs to reach peak anticoagulant effect,20 the rate of clinical events during the initial months may reflect warfarin's lower effectiveness in preventing thrombosis events,21 and its lower likelihood of bleeding events.
Nevertheless, in this study, rivaroxaban and warfarin have demonstrated a significantly higher likelihood of bleeding risk compared with apixaban. Further, the sensitivity analyses focused on assessing major critical site bleeding in an inpatient or outpatient setting, identified based on primary or secondary ICD‐9‐CM codes. The trends remained the same except that dabigatran initiators, in addition to apixaban initiators, showed a significantly lower risk of major critical site bleeding compared with warfarin initiators. In addition, the sensitivity analysis evaluated the risk of major bleeding requiring hospitalisation, among patients newly initiated on dose‐adjusted warfarin, rivaroxaban 20 mg q.i.d., dabigatran 150 mg b.i.d., or apixaban 5 mg b.i.d., to assess the standard dose treatment effect on the risk of major bleeding requiring hospitalisation, revealed similar trends and thus, confirmed the robustness of main study findings.
Besides OACs, factors associated with the risk of major bleeding requiring hospitalisation were a history of prior bleeding and comorbidities, including congestive heart failure, renal disease and dyspepsia or stomach discomfort. Besides OACs, factors associated with the risk of major critical site bleeding in an inpatient or outpatient setting, were history of prior bleeding, higher categories of CCI, and comorbidities, including congestive heart failure, dyspepsia or stomach discomfort, myocardial infarction, renal disease and male gender (as a protective factor). These risk factors associated with major bleeding were consistent with the findings from the ARISTOTLE trial, where older age, prior haemorrhage, prior stroke or TIA, diabetes, lower creatinine clearance and decreased haematocrit level were shown to be independently associated with an increased risk of major bleeding.22 Furthermore, warfarin was preferentially initiated among older and sicker patients among newly anticoagulated NVAF patients. Among those initiating NOACs, however, apixaban patients were older and had a greater baseline clinical risk compared with those initiating dabigatran or rivaroxaban. Thus, randomised controlled trial findings are robust to variation in patient characteristics including age, baseline clinical risk and comorbid conditions.
When assessed using the standard of care warfarin as a reference comparison, we observed that the real‐world major bleeding results were in concordance with results observed in clinical trials. For patients newly initiated on dabigatran, as compared with warfarin, the risk of major bleeding was shown to be lowered by 12%–21%.18, 23 These results are generally consistent with the lower risk of major bleeding for dabigatran compared with warfarin, as demonstrated in the RE‐LY trial.24
Patients newly initiating rivaroxaban, as compared with warfarin, were numerically more likely to experience a major bleeding event but the adjusted differences in major bleeding between rivaroxaban and warfarin did not reach statistical significance. This is consistent with numerically higher adjusted risk of major bleeding with rivaroxaban compared with warfarin as demonstrated in the ROCKET‐AF trial.25 In the real‐world studies conducted using the healthcare claims database,17 a numerically higher but non‐significant risk of major bleeding was observed for rivaroxaban as compared with warfarin which is consistent with our study. Interestingly, our study showed similar crude incidence rates of major bleeding among rivaroxaban and warfarin patients (around 4.6 per 100 person‐years) although studies have shown that the mean time in therapeutic range (TTR) is relatively low in real‐world settings, usually below or around 60%.26, 27 In addition, the incidence rate of major bleeding (per 100 person‐years) was higher than previously reported in the XANTUS study (2.1; 95% CI: 1.8–2.5), Dresden NOAC registry (3.1; 95% CI: 2.2–4.3), and a retrospective claims study using the US Department of Defense health records (2.9; 95% CI: 2.61–3.13).28, 29, 30 These differences in incidence rates may be because of the difference in study design, patient selection criteria, and the definition of major bleeding.
For patients newly initiated on apixaban, compared with warfarin, there was a statistically significant reduction by 38%–48% in the risk of major bleeding. These results are consistent with the statistically significant 31% relative reduction in the risk of major bleeding for apixaban compared with warfarin, as demonstrated in the ARISTOTLE trial.31 Indeed, our study supports that the benefits of apixaban demonstrated in randomised clinical trial may also be achieved in a broad population receiving clinical care in routine practice.
A limitation of this study is that as with any retrospective observational study and common to database analysis, we can only study association between variables. As with any retrospective observational database study, there is a potential for selection bias. We conducted rigorous and thorough multivariate analyses along with sensitivity analyses for bleeding definition to ensure robustness of our findings. Comorbidities at baseline (e.g. presence of renal impairment) are determined by presence of diagnosis code in the baseline period and not based on actual lab values or clinical assessment. As is the case with any claims database, there is a potential for coding errors and missing data. Similar to any pharmacy claims data in the United States, the Truven MarketScan pharmacy claims data does not routinely capture aspirin utilisation given that aspirin is typically obtained over‐the‐counter. Thus, aspirin use was not accounted in the analyses.
Oral anticoagulant initiation criterion was based on lack of anticoagulation prescription during 1 year baseline period. It was possible that patients may have used anticoagulation or aspirin concurrently prior to the baseline period. This design limitation is consistent across all OACs studied and hence is unlikely to change results. In addition, we do not have data on quality of anticoagulation control, as reflected by TTR which can influence efficacy and safety of VKA therapy.23, 32, 33
In addition, only inpatient deaths are observed and information about mortality was not available in the database, which may have biased the survival analysis. The mean length of follow‐up for apixaban‐treated patients was approximately 1 month shorter than for the other OACs. We used survival methods to account for varying lengths of follow‐up. However, if bleeding events tend to occur later on apixaban than the other OACs, the difference in follow‐up period may have affected the results. Because of the difference in follow‐up, we conducted sensitivity analyses by limiting the follow‐up to 90 and 180 days and found the results to be generally consistent. However, larger sample size and longer follow‐up is needed to compare adequately powered events among the NOACs and warfarin.
It was also not possible to apply dose‐adjustment in this analysis for following (i) Renal function and weights are not available in claims analyses and (ii) warfarin treatment is continuously dose‐adjusted so there is no low‐ or high‐dose strategy which can be defined in a manner similar to NOACs in the study. Further, it is unclear if adjusted study results would be any different from a clinical study conducted with above variables in consideration.
The strengths of our study are that we assessed a real‐world comparative safety of newly initiating warfarin, apixaban, rivaroxaban, and dabigatran using the comprehensive Truven MarketScan^®^ claims database which incorporates all medical and pharmacy claims of patients in the United States and allows for longitudinal analysis of a nationally representative sample for the study. Medications being studied are relatively new to market and this database encompassing both commercial and Medicare lives allows for selection of the best sample size for this study. Our results are based on real‐world data and incorporate observed treatment patterns as recorded in the Marketscan database. Although Truven MarketScan^®^ database allows for selection of the nationally representative sample for this study, the results may not be necessarily generalisable to the entire NVAF population in the United States or extrapolated to other parts of the world.
In conclusion, this study demonstrates that initiation with apixaban was associated with a significantly lower risk of major bleeding as compared with initiation on warfarin among newly anticoagulated NVAF patients in the real‐world setting. Furthermore, patients initiating on rivaroxaban or warfarin had a significantly greater risk of major bleeding compared with those initiating apixaban. There was no significant difference in the risk of major bleeding among patients newly initiated on dabigatran compared with apixaban or warfarin initiators. Future analyses using a large propensity matched cohort comparing the treatment effect on the risk of major bleeding is needed to confirm the current study findings.
G.Y.H. Lip, S. Kamble, and H. Phatak conceptualised and designed the study. X. Pan and H. Kawabata collected and analysed the data. G.Y.H. Lip, S. Kamble, H. Phatak, J. Mardekian, C. Masseria and A. Bruno substantially contributed to interpretation of the data. S. Kamble, H. Phatak, G.Y.H. Lip, X. Pan, H. Kawabata, C. Masseria, A. Bruno and J. Mardekian wrote the manuscript and/or substantially contributed to critical revisions of the intellectual content. All authors agreed to the final version.
This study was sponsored by Bristol‐Myers Squibb and Pfizer. Professor Lip has served as a consultant for Bayer, Merck, Sanofi, BMS/Pfizer, Daiichi‐Sankyo, Biotronik, Medtronic, Portola and Boehringer Ingelheim and has been on the speaker's Bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi‐Sankyo, Medtronic. Ms Pan is an employee of Bristol‐Myers Squibb with ownership of stocks in Bristol‐Myers Squibb. Drs Kamble and Kawabata are employees of Bristol‐Myers Squibb with ownership of stocks in Bristol‐Myers Squibb. Drs Mardekian and Masseria are employees of Pfizer Inc. with ownership of stocks in Pfizer Inc. Drs Bruno and Phatak were employees of Bristol‐Myers Squibb, at the time of research, with ownership of stocks in Bristol‐Myers Squibb. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
This work was presented in part at the European Society of Congress (ESC) 2015, London, UK, in 29 August–2 September 2015, and an abstract was published in European Heart Journal 2015; Abstract Supplement 1085.