Abstract: Objectives. To obtain further, and more focused, information on the efficacy and safety of the antithrombotic regimens, including triple therapy (TT) of warfarin, aspirin, and clopidogrel; dual therapy (DT) of warfarin and single antiplatelet agent (aspirin or clopidogrel); and dual-antiplatelet therapy (DAPT) of aspirin and clopidogrel, prescribed to patients on oral anticoagulation (OAC) undergoing percutaneous coronary intervention with stent (PCI-S). Background. The true efficacy and safety of TT, DT, and DAPT in OAC patients undergoing PCI-S is largely undefined. Methods. We analyzed the database of the prospective, multicenter WARfarin and coronary STENTing (WAR-STENT) registry (ClinicalTrials.gov identifier NCT00722319), only including the post-discharge period. Results. Of the 401 patients discharged alive from index hospitalization, 339 (85%), 20 (5%), and 42 (10%) were prescribed TT, DT, and DAPT, respectively. Throughout a mean follow-up of 368.3 ± 22.8 days, major adverse cardiovascular events (MACE) (including cardiovascular death, myocardial infarction, repeat revascularization, stent thrombosis, and thromboembolism), total bleeding, major bleeding, and combination of MACE plus total bleeding were comparable across the three treatment groups. The absolute rate of major bleeding with TT was 4%. The antithrombotic treatment actually ongoing at major bleeding was TT in 44%, DT in 50%, and DAPT in 6% of cases. Conclusion. In the real-world population of OAC patients undergoing PCI-S in the WAR-STENT registry, the three antithrombotic regimens of TT, DT, and DAPT showed comparable efficacy and safety. Due to several limitations, our data cannot be considered conclusive in confuting the current recommendations to prescribe TT. Further properly designed and sized studies are warranted.
J INVASIVE CARDIOL 2014;26(11):563-569
Key words: percutaneous coronary intervention, oral anticoagulation, stent
In patients on oral anticoagulation (OAC) undergoing percutaneous coronary intervention with stent (PCI-S), triple therapy (TT) of warfarin, aspirin, and clopidogrel is currently recommended throughout the period most vulnerable to stent thrombosis and recurrent coronary events (ie, 1 to 3-6 months) to prevent a major adverse cardiovascular event (MACE), including cardiovascular death, myocardial infarction, repeat revascularization, stent thrombosis, and thromboembolism.1,2 The analyses of efficacy, however, have generally yielded mixed results regarding the superiority of TT over other antithrombotic regimens, including dual therapy (DT) of OAC plus single antiplatelet agent (either aspirin or clopidogrel) and dual-antiplatelet therapy (DAPT) of aspirin and clopidogrel, with regard to the MACE rate.3-5 In contrast, the incidence of major and total bleeding has been consistently reported to be significantly increased (2- to 3-fold) with TT.3-5
Most of the data on which the current recommendations are based, however, are retrospective or derived from administrative databases, thereby not allowing evaluation of the bleeding events occurring after discharge separate from those in-hospital (which may be related more to periprocedural variables such as management of anticoagulation, vascular access site, use and dose of intraprocedural anticoagulants, and use of glycoprotein IIb/IIIa inhibitors than to the ongoing antithrombotic regimen), or to match a bleeding event to the antithrombotic regimen actually ongoing at the time of occurrence (which may not be the same as prescribed at discharge). Because of these factors, the true safety profile and absolute incidence of bleeding with the various antithrombotic regimens (especially TT) remain uncertain.
To obtain further, more focused information on the clinical outcomes of patients on OAC undergoing PCI-S, we analyzed the database of the prospective, multicenter WARfarin and coronary STENTing (WAR-STENT) registry, only including the postdischarge period.
The WAR-STENT registry is a prospective, multicenter, observational study including consecutive patients on OAC undergoing PCI-S (ClinicalTrials.gov identifier NCT00722319). The only inclusion criterion was ongoing OAC at the time of PCI-S, or when PCI-S was planned. Due to the observational design, no exclusion criteria were provided, except for the patient’s refusal to participate. At each center, patients were treated according to local policies, and were followed for 12 months. Local ethic committees approved the study protocol, and written informed consent was obtained from every patient. Outcome measures were the in-hospital and 12-month incidences of MACE, major and minor bleeding, and a combination of both.
Definitions. Outcome definitions were: (1) cardiovascular death: related to cardiac causes or thromboembolism; (2) myocardial infarction: detection of rise/fall of cardiac biomarkers with ≥1 value above 99th percentile of upper reference limit together with evidence of myocardial ischemia;6 (3) stent thrombosis: according to Academic Research Consortium classification;7 (4) stroke: permanent focal neurological deficit adjudicated by a neurologist, and confirmed by computed tomography; (5) venous thromboembolism: signs/symptoms of deep vein thrombosis or pulmonary embolism associated with a positive imaging test; and (6) major and minor bleeding: according to Thrombolysis in Myocardial Infarction (TIMI) classification.8
The analysis of the in-hospital phase has been performed separately, and previously reported.9 The present analysis is focused on the postdischarge phase, and is therefore confined to the period ranging from the date of discharge to 12-month follow-up. All patients discharged alive from the index hospitalization were included, and comparisons according to the antithrombotic regimen prescribed at discharge were performed.
Statistical analysis. Continuous variables are expressed as means ± standard deviation. Categorical variables are expressed as percentages. One-way analysis of variance or Student’s t-test were used to compare continuous variables, with the exception of patient age, and weeks of drug prescription, which were compared with Kruskal-Wallis equality-of-populations rank test or Wilcoxon rank-sum test. Chi-square test was used for comparison of categorical variables. Kappa statistic was used for the evaluation of the ongoing antithrombotic regimen at a bleeding event in relation to the regimen at discharge. The role of the antithrombotic therapies at discharge on survival from different outcomes, including MACE, MACE plus major bleeding, and MACE plus total bleeding, was estimated with Kaplan-Meier method, and differences between groups were assessed with log-rank test. The contribution of clinical and hemodynamic data to the composite outcome of MACE and major bleeding was identified by Cox’s univariate analysis. Multivariate Cox proportional hazard analysis was then performed by entering into the model variables with a P-value <.20 on univariate analysis. The proportional hazards assumption was tested by using the Schoenfeld residuals. The goodness of fit of multivariable Cox regression models was evaluated by the likelihood-ratio test. A P-value <.05 was considered statistically significant. Analyses were performed using Stata/SE 12.1 statistical software (StataCorp LP).
Out of the 411 patients consecutively included in the WAR-STENT registry at 37 Italian centers between November 2008 and June 2010, a total of 404 were discharged alive. Three out of 404 were not included in the present analysis because the prescribed antithrombotic regimen was different from either TT, DT, or DAPT. Thus, 401 patients, of whom 339 (85%), 20 (5%), and 42 (10%) were discharged on TT, DT, and DAPT, respectively, formed the population herein evaluated.
Mean duration of observation was 368.3 ± 22.8 days in the overall population, with no significant differences across the three treatment groups of TT, DT, and DAPT (368.4 ± 23.5, 364.2 ± 19.2, and 370 ± 27.3 days, respectively; P=.67). Baseline characteristics of the overall population, and of the individual treatment groups, are reported in Table 1. Non-low (ie, moderate or high) thromboembolic risk features, including atrial fibrillation with CHADS2 score ≥2, mechanical heart valve, prior cardiogenic embolism, intracardiac thrombus, and recent (<6 months) venous thromboembolism, were significantly more frequent in patients prescribed TT and DT (Table 1).
Major in-hospital data are summarized in Table 2. Bare-metal stents were implanted more often, both in the overall population, and in the individual treatment groups, with no significant differences across the TT, DT, and DAPT groups. In-hospital major bleeding was significantly more frequent in the DT group. The prescribed duration of clopidogrel at discharge was significantly longer in the DAPT group (Table 2).
At 12-month follow-up, the absolute rates of MACE, total bleeding, major bleeding, and total events (MACE plus bleeding) were 16%, 10%, 4%, and 26%, respectively, with no significant differences across the three treatment groups (Table 3). Gastrointestinal bleeding was largely the most frequent type of major bleeding, whereas nose bleeding was the most frequent type of minor bleeding (Table 4). No differences in the site of major or minor bleeding were detected across the three treatment groups (Table 4), nor were differences observed in the rate of recurrent bleeding events in the three treatment groups (Table 4).
When examining the antithrombotic regimen at bleeding, TT and DT were ongoing in nearly half of major bleeding events each, whereas TT was largely the most frequent regimen ongoing at the time of minor bleeding (Table 5). Of all major bleeding events in patients discharged on TT, only half occurred with this regimen still ongoing, whereas the other half occurred after one antiplatelet agent had already been discontinued, and DT was ongoing (Table 5). In contrast, all major bleeding events with DT and DAPT occurred with these regimens ongoing (Table 5).
No significant predictors of the combined occurrence of MACE and major bleeding were detected at both univariate and multivariate analyses. No significant differences were observed in the survival free from total events (MACE plus total bleeding), MACE, total bleeding, and MACE plus major bleeding, as estimated by Kaplan-Meier analysis (Figure 1).
In the real-world population of patients on OAC (mostly because of atrial fibrillation) undergoing PCI-S who were included in the prospective, multicenter WAR-STENT registry, the three antithrombotic regimens of TT, DT, and DAPT showed comparable efficacy and safety throughout the period from discharge to 12-month follow-up. The absolute 12-month rates of major bleeding with TT, DT, and DAPT were 4%, 5%, and 2%, respectively. Major bleeding events occurred in 44% and 50% of cases, respectively, with TT and DT actually ongoing, and in 6% with ongoing DAPT.
While acknowledging the several limitations of our data, including those inherent to observational studies (lack of randomization, and individual risk-based decision-making in treatment choices), and the limited size of our population (especially of the DT and DAPT groups), some considerations can nonetheless be made.
The observed lack of difference among the three treatment groups regarding the efficacy on MACE is likely attributable to the small size of the overall population, as well as of the individual groups, and the low absolute rate of events. Also, the significantly lower prevalence of non-low thromboembolic risk features in the DAPT group of our population may have prevented the observation of a higher incidence of MACE, namely stroke, in this group. In fact, the superiority of OAC to DAPT on stroke prevention in atrial fibrillation has been conclusively established by gold-standard, randomized, double-blind research, as it has been carried out in the ACTIVE-W study.10 Nonetheless, a comparable efficacy on MACE of TT, DT, and DAPT has been previously reported in the similar, and larger, observational AFCAS registry,11 and in a large, nationwide, administrative database.12 Recent data from the prospective, randomized WOEST study13 have even shown superior efficacy of DT (with warfarin plus clopidogrel) over TT on the occurrence of MACE. Because of the open-label design, and a size largely underpowered to reliably detect differences in efficacy endpoints, however, the WOEST study cannot be considered conclusive in establishing a superior efficacy of DT (with warfarin plus clopidogrel) over TT. Our current data do not add solid evidence in confuting the current recommendation to consider TT as the most effective antithrombotic regimen to prevent MACE in OAC patients undergoing PCI-S. Larger properly focused and designed studies are warranted to address the efficacy issue in this population.
Of greater interest, the incidence of total, major, and minor bleeding was comparable across the TT, DT, and DAPT groups. This finding may be related, at least in part, to the above-mentioned limitations of our analysis, especially when considering that a 2- to 3-fold higher risk of bleeding has been repeatedly and consistently reported with TT compared to DAPT.3-5 Although not reaching statistical significance, the occurrence of total, major, and minor bleeding was indeed 2- to 3-times lower with DAPT compared to TT in our population. No significant differences were observed in the occurrence of total, major, and minor bleeding in the TT and DT groups of our population. Although a similar finding has also been reported in the larger, observational AFCAS registry,11 it is noteworthy that the 2-fold higher incidence of total bleeding we nonetheless observed in the TT group was essentially driven by a difference in the rate of minor bleeding, whereas major bleeding events were nearly equal. Similarly, in a single-center cohort of atrial fibrillation patients prospectively observed over 12 months after PCI-S with drug-eluting stents, the difference in total bleeding events between TT and DT was essentially attributable to differences in the rate of minor bleeding.14 Of note, of all the international normalized ratios (INRs) collected throughout the 12-month follow-up in this study, 72% of them were within the 1.8-2.5 target set at discharge, with only 11% >3.0.14 Whereas such accurate data are not available for our population, it is of interest that an INR >3.0 at a bleeding event was a feature of the TT group, but not of the DT group, and that an INR >3.0 was found in nearly one-third of major bleeding events in the TT group, as opposed to <5% of minor bleeding events. When taken together, these findings suggest that supratherapeutic OAC is potentially more dangerous with multiple antithrombotic drugs, as with TT, and more capable of inducing major bleeding complications, being on the contrary minor bleeding relatively independent. The results of the WOEST study13 further reinforce the concept that TT may essentially induce more minor bleeding when compared to DT (whereas the two therapies are substantially comparable regarding major bleeding).13 Although the total bleeding rate in this study was largely and significantly lower with DT of warfarin plus clopidogrel compared to TT, this difference was essentially driven by a decrease in minor bleeding, with no significant differences in the rate of major bleeding.13
The results of the WOEST study13 also align with other observations regarding the 12-month absolute incidence of major bleeding with TT. Indeed, the 5.6% rate reported in the WOEST study perfectly matches the 5.6% observed in the prospective, observational, multicenter STENTICO registry. 15 The WOEST study13 and STENTICO registry15 both include in-hospital and postdischarge events in their 12-month rates of major bleeding; thus, their results are also comparable to the 4% observed in our population, given that an in-hospital major bleeding rate of approximately 2% has been repeatedly reported in these patients.9,15,16 Therefore, with an established rate of major bleeding of 4%-6% over 12 months, the safety of the currently recommended course of 1 to 3-6 months of TT (depending on the type of stent implanted and/or the clinical setting where PCI-S has been performed) should not be a matter of concern, as it is likely associated to an absolute risk of major bleeding of only <1% to 2%-3%. Also rather reassuring is our finding that most major bleeding events with TT were gastrointestinal, which are less likely to be fatal compared to other locations (such as intracranial), generally treatable, and largely preventable with extensive and aggressive gastric protection (however, no data are available in our registry regarding this element).
Our observations on the efficacy and safety from discharge to 12 months of the three antithrombotic regimens of TT, DT, and DAPT in OAC patients (mostly because of atrial fibrillation) undergoing PCI-S, albeit showing an overall comparability, are far from conclusive in supporting the superiority of one regimen over another. Yet, the substantial overall safety of TT is apparent. Therefore, while waiting for further data and possibly also exploring the role of combinations of newer, non-vitamin K antagonist oral anticoagulants (dabigatran, rivaroxaban, apixan, edoxaban) and/or newer antiplatelet agents (ticagrelor, prasugrel), the currently recommended TT should still be regarded as the optimal antithrombotic regimen for the short- to medium-term treatment of OAC patients who have undergone PCI-S.
Acknowledgments. The invaluable secretarial assistance of Mrs Ana Maria Rosario and Mrs Alessandra Randi, BA, is gratefully acknowledged.
- Lip GY, Huber K, Andreotti F, et al.; European Society of Cardiology Working Group on Thrombosis. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb Haemost. 2010;103(1):13-28.
- Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North American perspective. Thromb Haemost. 2011;106(4):572-584.
- Reed GW, Cannon CP. Triple oral antithrombotic therapy in atrial fibrillation and coronary artery stenting. Clin Cardiol. 2013;36(10):585-594.
- Ice DS, Shapiro TA, Gnall EM, Kowey PR. Unanswered questions in patients with concurrent atrial fibrillation and acute coronary syndrome. Am J Cardiol. 2014;113(5):888-896.
- Capodanno D, Angiolillo DJ. Management of antiplatelet and anticoagulant therapy in patients with atrial fibrillation in the setting of acute coronary syndromes or percutaneous coronary interventions. Circ Cardiovasc Interv. 2014;7(1):113-124.
- Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the redefinition of myocardial infarction. Universal definition of myocardial infarction. Circulation. 2007;116(22):2634-2653.
- Cutlip DE, Windecker S, Mehran R, et al.; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351.
- Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI), phase II trial. Ann Intern Med. 1991;115(4):256-265.
- Rubboli A, Sciahbasi A, Briguori C, et al. In-hospital management and outcome of patients on warfarin undergoing coronary stent implantation: results of the multicenter, prospective WARfarin and coronary STENTing (WAR-STENT) registry. J Invasive Cardiol. 2013;25(4):170-176.
- The ACTIVE writing group on behalf of the ACTIVE investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006:367(9526):1903-1912.
- Rubboli A, Schlitt A, Kiviniemi T, et al. One-year outcome of patients with atrial fibrillation undergoing coronary artery stenting: an analysis of the AFCAS registry. Clin Cardiol. 2014;37(6):357-364. Epub 2014 Jan 30.
- Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol. 2013:62(11):981-989.
- Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomized, controlled trial. Lancet. 201;381(9872):1107-1115. Epub 2013 Feb 13.
- Gao F, Zhou YJ, Wang ZJ, et al. Comparison of different antithrombotic regimens for patients with atrial fibrillation undergoing drug-eluting stent implantation. Circ J. 2010;74(4):701-708.
- Gilard M, Blanchard D, Helft G, et al. Antiplatelet therapy in patients with anticoagulants undergoing percutaneous coronary stenting (from STENTIng and oral antiCOagulants [STENTICO]). Am J Cardiol. 2009;104(3):338-342.
- Schlitt A, Rubboli A, Lip GY, et al. The management of patients with atrial fibrillation undergoing percutaneous coronary intervention with stent implantation: in-hospital-data from the atrial fibrillation undergoing coronary artery stenting study. Catheter Cardiovasc Interv. 2013;82(7):E864-870.
Participating investigators and centers.
Andrea Rubboli, Giuseppe Di Pasquale, Ospedale Maggiore, Bologna; Giuseppe Steffenino, Ospedale SS. Croce e Carle, Cuneo; Stefano Mistrorigo, Luigi La Vecchia, Ospedale S. Bortolo, Vicenza; Davide D’Andrea, Ospedale V. Cardarelli, Napoli; Salvatore Grasso, Ospedale V. Cervello, Palermo; Stefano Maggiolini, Ospedale L. Mandic, Merate; Alessandro Sciahbasi, Ernesto Lioy, Policlinico Casilino, Roma; Gianluca Caiazzo, Carlo Briguori, Clinica Mediterranea, Napoli; Nicoletta Franco, Giancarlo Piovaccari, Ospedale degli Infermi, Rimini; Eloisa Basile, Antonio M. Leone, Policlinico A. Gemelli, Roma; Annamaria Nicolino, Sharham Moshiri, Ospedale S. Corona, Pietra Ligure; Stefano Mameli, Ospedale S. Francesco, Nuoro; Luigi Steffanon, Alberto Benassi, Hesperia Hospital, Modena; Pierpaolo Cannarozzo, Ospedale S. Maria dei Battuti, Conegliano; Giuseppe Carosio, Ospedale SS. Antonio e Biagio, Alessandria; Paola Pasqualini, Silva Severi, Ospedale della Misericordia, Grosseto; Kenneth Ducci, Leonardo Bolognese, Ospedale S. Donato, Arezzo; Alessandro Capecchi, Leonardo G. Pancaldi, Ospedale Civile, Bentivoglio; Luigi Vignali, Diego Ardissino, Azienda Ospedaliera Universitaria, Parma; Francesco Saia, Barbara Bordoni, Antonio Marzocchi, Azienda Ospedaliera Universitaria, Bologna; Elisabetta Varani, Massimo Margheri, Ospedale S. Maria delle Croci, Ravenna; Giacomo Piccalò, Antonio Mafrici, Azienda Ospedaliera Niguarda Ca’ Granda, Milano; Paolo Calabrò, Chiara Sordelli, Seconda Università, Napoli; Simona Boarin, Marcello Galvani, Ospedale G.B. Morgagni, Forlì; Pasquale Catanzariti, Flavio Tartagni, Ospedale Bufalini, Cesena; Michela Santi, Stefano Della Casa, Ospedale Civile, Lugo; Cataldo Palmieri, Ospedale del Cuore G. Pasquinucci, Massa; Francesco Bovenzi, Ospedale Campo di Marte, Lucca; Andrea Rizzi, Claudio Cuccia, Clinica Poliambulanza, Brescia; Ferdinando Imperadore, Ospedale S. Maria del Carmine, Rovereto; Monia Monti, Marco Valgimigli, Azienda Ospedaliera Universitaria, Ferrara; Paolo Magnavacchi, Ospedale Civile, Baggiovara; Michele Dallago, Roberto Bonmassari, Ospedale S. Chiara, Trento; Paolo Sbarzaglia, Claudio Cavallini, Ospedale S. Maria della Misericordia, Perugia; Enrico Russolillo, Ospedale S. Giovanni Bosco, Napoli; Simona Lambertini, Giuseppe M. Sangiorgi, Azienda Ospedaliera Universitaria, Modena; Luigi Andrea Moroni, Paolo Rubartelli, Ospedale Villa Scassi, Genova.
From the 1Ospedale Maggiore, Bologna; 2Azienda Ospedaliera-Universitaria S. Orsola-Malpighi, Bologna; 3Ospedale S. Pertini, Roma; 4Hesperia Hospital, Modena; 5Clinica Mediterranea, Napoli; 6Seconda Università, Ospedale Monaldi, Napoli; 7Ospedale del Cuore G. Pasquinucci, Massa; 8Ospedale Poliambulanza, Brescia; 9Ospedale S. Maria del Carmine, Rovereto; 10Policlinico Casilino, Roma; 11Azienda Ospedaliera-Universitaria, Ferrara; 12Ospedale SS. Antonio e Biagio, Alessandria; 13Ospedale SS. Croce e Carle, Cuneo; 14Ospedale S. Bortolo, Vicenza; 15Ospedale G.B. Morgagni, Forlì; 16Centro Studi ANMCO, Firenze; 17Ospedale S. Donato, Arezzo; Italy.
Funding. Dr Rubboli holds a grant from the National Association of Hospital Cardiologists. ClinicalTrials.gov identifier NCT00722319
Disclosure. The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rubboli reports honoraria from Böhringer Ingelheim, Bayer Healthcare, Pfizer BMS, Astra Zeneca, and Boston Scientific; advisory board for Bayer Healthcare, Astra Zeneca, and Daiichi Sankyo. Dr Maggioni reports grants and non-financial support from Novartis, Cardiorentis, Abbott Vascular, Bayer Healthcare, and Servier. Dr Saia reports personal fees from Astra Zeneca, Eli Lilly, Terumo Europe, St. Jude Medical, and Boston Scientific; non-financial support from Abbott Vascular, Medtronic, and Edwards. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 5, 2014, provisional acceptance given May 27, 2014, final version accepted June 11, 2014.
Address for correspondence: Andrea Rubboli, MD, FESC, Division of Cardiology, Laboratory of Interventional Cardiology, Ospedale Maggiore, Largo Nigrisoli 2, 40133 Bologna, Italy. Email: email@example.com