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

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Abstract: The in-hospital management of patients on warfarin undergoing coronary stent implantation (PCI-S) is variable, and the in-hospital outcome incompletely defined. To determine the adherence to the current recommendations, and the incidence of adverse events, we carried out the prospective, multicenter, observational WARfarin and coronary STENTing (WAR-STENT) registry (ClinicalTrials.gov identifier NCT00722319). All consecutive patients on warfarin undergoing PCI-S at 37 Italian centers were enrolled and followed for 12 months. Outcome measures were: major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, need for urgent revascularization, stroke, and venous thromboembolism, and major and minor bleeding. In this paper, we report the in-hospital findings. Out of the 411 patients enrolled, 92% were at non-low (ie, moderate or high) thromboembolic risk. The radial approach and bare-metal stents were used in 61% and 60% of cases, respectively. Drug-eluting stents were essentially reserved to patients with diabetes, which in turn, significantly predicted the implantation of drug-eluting stents (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.29-3.17; P=.002). The in-hospital MACE and major bleeding rates were 2.7% and 2.1%, respectively. At discharge, triple therapy (TT) of warfarin, aspirin, and clopidogrel was prescribed to 76% of patients. Prescription of TT was significantly more frequent in the non-low thromboembolic risk group. Non-low thromboembolic risk, in turn, was a significant predictor of TT prescription (OR, 11.2; 95% CI, 4.83-26.3; P<.0001). In conclusion, real-world warfarin patients undergoing PCI-S are largely managed according to the current recommendations. As a consequence, the risk of in-hospital MACE and major bleedings appears limited and acceptable.

J INVASIVE CARDIOL 2013;25(4):170-176

Key words: oral anticoagulation, antiplatelet drugs, percutaneous coronary intervention

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In patients on warfarin undergoing coronary stent implantation (PCI-S), the actual uptake of the periprocedural recommendations to prefer the radial access site, continue warfarin throughout PCI-S, avoid glycoprotein (GP) IIb/IIIa inhibitors, and prefer bare-metal stents (BMSs),^1-3 is incompletely defined. The incidence of in-hospital adverse events, which may be influenced by the above variables, is incompletely defined as well. While definite estimation of the rate of in-hospital adverse events, and especially bleeding, is of great importance for a reliable estimation of the adverse event rate recorded at the end of follow-up, no large studies focused on the in-hospital management and outcome. Moreover, the in-hospital adverse event rate has seldom been reported separately.^4-7 Finally, most of the available data derive from retrospective, single-center, and small-sized studies.^1-3

To investigate the contemporary management of patients on warfarin undergoing PCI-S, and to determine the incidence of adverse events in a real-world setting, we carried out the WARfarin and coronary STENTing (WAR-STENT) registry. In this paper, the findings of the in-hospital phase are reported, whereas the postdischarge observations will be the object of a subsequent analysis. 

Methods

The WAR-STENT registry is a prospective, multicenter, observational study including consecutive patients on warfarin undergoing PCI-S (ClinicalTrials.gov identifier NCT00722319). The only inclusion criterion was ongoing warfarin 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. Ethic committees of each participating center approved the study protocol, and written informed consent was obtained from each patient. 

Outcome measures were: (1) incidence of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction (MI), need for urgent revascularization, stroke, and venous thromboembolism; and (2) incidence of major and minor bleeding, both in-hospital and at 12 months. 

Definitions. Outcome definitions were: (1) cardiovascular death: related to cardiac causes or stroke; (2) myocardial infarction: ≥3 times increase of the upper reference limit of cardiac biomarkers unrelated to either PCI-S or coronary bypass surgery;⁸ (3) stent thrombosis: according to Academic Research Consortium classification;⁹ (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.10

Statistical analysis. The statistical analysis was performed in the overall population, and by sorting patients into 2 groups at low and non-low thromboembolic risk. Low thromboembolic risk was defined as the presence of atrial fibrillation with CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke) score <2, biological heart valve, remote (>6 months) venous thromboembolism, dilated cardiomyopathy, and left ventricular aneurysm, whereas non-low (ie, moderate or high) thromboembolic risk was defined as the presence of atrial fibrillation with CHADS2 score ≥2, mechanical heart valve, prior cardiogenic embolism, intracardiac thrombus and recent (<6 months) venous thromboembolism. Continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as percentages. Chi-square test and Student’s t-test were used to compare categorical and continuous variables, respectively. Univariate logistic regression analysis was used to identify independent predictors of procedural variables and antithrombotic regimens. Variables associated with a P-value <.05 in the univariate analysis were selected for multivariable analysis in a logistic regression model, using a stepwise elimination procedure. Results are expressed as odds ratio (OR) and 95% confidence interval (CI). A two-sided P-value <.05 was considered statistically significant.

Results

Between November 2008 and June 2010, a total of 411 consecutive patients on warfarin undergoing PCI-S at 37 Italian centers were enrolled. Baseline characteristics of the overall population, and of the low and non-low thromboembolic risk groups, are reported in Table 1. Mean duration of hospitalization was 5.0 ± 4.9 days. Most patients had non-low thromboembolic risk features. Atrial fibrillation was largely the most frequent indication for warfarin, and significantly more so in the non-low thromboembolic risk group, where the mean CHADS2 score was also significantly higher. Acute coronary syndrome, either ST-elevation or non-ST elevation, was the most frequent indication for PCI-S, with no difference in the two thromboembolic risk groups.  

The procedural characteristics are reported in Table 2. Pre-PCI-S management of anticoagulation was almost equally split in uninterrupted warfarin and heparin bridging after warfarin interruption, with no differences between the two thromboembolic risk groups. The overall preprocedural use of GP IIb/IIIa inhibitors was limited, and substantially higher in the low thromboembolic risk group. The overall intraprocedural administration of GP IIb/IIIa was more frequent, and significantly more so in patients at low thromboembolic risk. In most patients, an intravenous bolus of about 5000 U of unfractionated heparin was given at the beginning of PCI-S, with no difference between the two thromboembolic risk groups. The radial access site and BMSs were generally preferred. In about one-third of patients, however, drug-eluting stents (DESs) were implanted. At univariate analysis, the use of DES was predicted by diabetes (OR, 2.02; 95% CI, 1.29-3.17; P=.002), family history of coronary artery disease (OR, 3.41; 95% CI, 1.80-6.46; P=.0002), and previous PCI-S (OR, 2.83; 95% CI, 1.69-4.72; P<.0001), whereas a history of congestive heart failure (OR, 0.47; 95% CI, 0.24-0.94; P=.03) and increasing age (OR, 0.96; 95% CI, 0.94-0.98; P=.002) significantly decreased the likelihood of receiving a DES. Except for increasing age, the same relationship between DES implantation and diabetes (OR, 2.19; 95% CI, 1.35-3.57; P=.001), family history of coronary artery disease (OR, 3.33; 95% CI, 1.65-6.75; P=.0008), previous PCI-S (OR, 2.56; 95% CI, 1.48-4.42; P=.0008), and history of congestive heart failure (OR, 0.45; 95% CI, 0.21-0.94; P=.03) was confirmed at multivariable analysis. 

In-hospital adverse events are reported in Table 3. The overall occurrence of MACE was 2.5%, all of which were observed in the non-low thromboembolic risk group. The incidence of major bleeding was 2.1%, all of which were again observed in the non-low thromboembolic risk group. Major bleedings were accounted for by: hemoglobin drop with no overt bleeding in 5 out of 9 cases (56%); gastrointestinal bleeding in 1 (11%); and bleeding at the vascular access site in 3 (33%). All access-site bleedings were observed in patients undergoing PCI-S by the femoral approach.   

Prescriptions of the antithrombotic therapy at discharge are reported in Table 4. Triple therapy of warfarin, aspirin, and clopidogrel (TT) was the most frequent regimen, and significantly more so in the non-low thromboembolic risk group. At univariate analysis, non-low thromboembolic risk strongly predicted the prescription of TT (OR, 11.2; 95% CI, 4.83-26.3; P<.0001). Dual-antiplatelet therapy of aspirin and clopidogrel, which was prescribed to a minority of patients overall, was significantly more frequent in the low thromboembolic risk group. On average, clopidogrel was prescribed for about 6 months in the overall population, and for significantly shorter periods in the non-low thromboembolic risk group. The International Normalized Ratio (INR) was targeted to the lower end of the therapeutic range, eg, 1.8-2.5, in about one-third of patients. Of note, a reduced intensity of warfarin treatment was almost exclusively prescribed to the TT group, whereas the usual target of 2.0-3.0 was confirmed in nearly all patients discharged on warfarin and single-antiplatelet agent (Table 5). 

Discussion

The main findings of this prospective, multicenter, observational registry focusing on the in-hospital management and outcome of patients on warfarin undergoing PCI-S are: (1) most of these patients are at moderate-to-high thromboembolic risk, therefore requiring warfarin (and hence TT); (2) the incidence of adverse events is limited, and confined to patients with higher thromboembolic risk profile; and (3) both the periprocedural management and prescription of antithrombotic therapy at discharge are largely in accordance with the current recommendations. 

It is estimated that 5%-8% of patients referred for PCI-S have an indication for warfarin.^1-3 Due to the need to carefully balance the risk of thromboembolism against that of bleeding, it is important to determine what proportion of these patients has a thromboembolic risk profile not allowing warfarin to be substituted, even temporarily, by alternative regimens. In accordance with the recent expansion of the indication for warfarin also to atrial fibrillation patients at moderate risk of stroke,^11,12 our data show that the vast majority of warfarin patients referred for PCI-S have indeed an indication for warfarin, and hence for TT. 

The overall occurrence of MACE in our population was limited to 2.7%. This figure is lower than the 4.8% previously reported by our group on a small population of warfarin patients treated during our early experience,¹³ whereas it compares to 2.9% observed in the prospective, multicenter, observational STENTICO registry.⁵ The similar size, overall risk profile of the populations enrolled, and PCI-S management may account for the comparable incidence of in-hospital MACE in the STENTICO registry and the present study. Of note, in our population all MACE, as well as major bleedings, occurred in the non-low thromboembolic risk group, which therefore identifies a frail patient subset. Such a finding reinforces the known concept that patients at high thromboembolic risk are at the same time at increased hemorrhagic risk, therefore making the antithrombotic management problematic. 

The incidence of in-hospital major bleeding was 2.1%, which is again lower than 4.3% previously reported by our group,¹³ and matches with 2.1% in the STENTICO registry.⁵ Whereas the radial approach was less frequent and the periprocedural anticoagulation less standardized in our initial experience, these variables were more similar in the STENTICO registry and the present study, likely accounting for the comparable incidence of major bleeding. The low rate of in-hospital major bleeding observed in our population may be accounted for by the widespread use of those measures, such as radial approach and avoidance of GP IIb/IIIa inhibitors, as well as continuation of warfarin throughout PCI-S, both of which are recommended to minimize periprocedural bleeding.^1,2 Although it is now the most frequent strategy, uninterrupted periprocedural warfarin anticoagulation was actually adopted only in a proportion of patients, probably because a definitive superiority over warfarin interruption plus heparin bridging has not been demonstrated. Recent evidence from the large, prospective, multicenter, observational AFCAS registry, where atrial fibrillation patients undergoing PCI-S were included, confirms the absence of significant differences between the two strategies regarding both bleeding and MACE.¹⁴

The standard recommendation to administer unfractionated heparin as an intravenous bolus at the beginning of PCI-S¹⁵ was followed in about two-thirds of our population. Until very recently, no specific data were available on this issue, and highly variable strategies among interventionalists have been reported.¹⁶ The results of a recent analysis of a Finnish database, where patients undergoing PCI-S during uninterrupted therapeutic warfarin (INR, 2.0-3.5) were included, support the recommendation not to administer additional heparin unless the INR is below 2.0, as it appears associated with a significant increase of complications at the access site (which was femoral in about two-thirds of cases).¹⁷ The reported neutral effect on bleeding and adverse cardiac events,¹⁷ as well as the lesser importance of an increased risk of vascular complications when the radial approach is extensively used, may account for the common use of intraprocedural heparin in our population. 

Based on our findings, PCI-S in patients on warfarin appears associated with an acceptable risk of major bleeding complications. The femoral approach confirmed to carry an increased risk of local bleeding complications. The majority of major bleedings, however, were not access-site related, in accordance with a recent report on patients aggressively treated with antithrombotic agents undergoing PCI-S.¹⁸ Importantly, the comparable incidence of in-hospital major bleedings both in the STENTICO registry and the present study suggests that about 2% needs to be subtracted from the 12-month incidence of major bleeding when aiming to properly determine the true long-term safety profile of the antithrombotic regimens, and especially TT. 

Whereas BMSs were the preferred type implanted, as it is currently recommended,^1,2 DESs accounted for about one-third of all stents. This proportion almost perfectly matches with the population of diabetic patients, for whom DESs should be considered even in warfarin patients, due to the expected superior benefit over BMSs.^1-3 Indeed, diabetes proved a strong predictor of the implantation of a DES.

As most patients were at non-low thromboembolic risk, the finding that TT was the most frequent antithrombotic regimen prescribed at discharge is in accordance with current recommendations.^1,2 Also, TT was significantly more frequent in patients at non-low thromboembolic risk, whereas dual-antiplatelet therapy was significantly more frequent in the low thromboembolic risk group. Non-low thromboembolic risk was indeed a very potent predictor of TT prescription at discharge. The significantly shorter duration of clopidogrel prescription in the non-low thromboembolic risk group, as well as the significantly less frequent targeting of the INR to the conventional range of 2.0-3.0 in the TT group, confirms the care given to minimize the risk of bleeding during combined treatment of warfarin and dual-antiplatelet therapy. Whether these strategies will prove effective in limiting the bleeding rate during prolonged TT will be evaluated in our next outcome analysis at 12 months.

Study limitations. This study is limited by all the inherent limitations of observational studies, including individual decision-making in treatment choices. However, despite being the largest prospective study focusing on the in-hospital management and outcome of warfarin patients undergoing PCI-S, its relatively small size is the main limitation. Because of this, as well as of the low rate of both MACE and bleedings, the power to determine possible further correlations among variables is lacking.  

Conclusion

In conclusion, the periprocedural management, and the prescription of the antithrombotic therapy at discharge, of the warfarin patients undergoing PCI-S who were enrolled in our real-world WAR-STENT registry appear to be largely carried out according to the current recommendations. As a consequence, the in-hospital risk of MACE and major bleeding in this population appears limited and acceptable. Nonetheless, an in-hospital major bleeding rate of about 2% is to be expected. This figure needs to be subtracted from the long-term rate when evaluating the safety of the antithrombotic regimens, and especially TT, during follow-up.  

Acknowledgments. The invaluable secretarial assistance of Mrs Ana Maria Rosario and Mrs Alessandra Randi, BA, is gratefully acknowledged. 

Appendix

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, 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-Ospedale Monaldi, 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 Massimo Sangiorgi, Azienda Ospedaliera Universitaria, Modena; Luigi Andrea Moroni, Paolo Rubartelli, Ospedale Villa Scassi, Genova.

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From the ¹Ospedale Maggiore, Bologna, Italy, ²Policlinico Casilino, Roma, Italy, ³Clinica Mediterranea, Napoli, Italy, ⁴Ospedale Universitario, Bologna, Italy, ⁵Ospedale Pasquinucci, Massa, Italy, ⁶Ospedale Villa Scassi, Genova, Italy, ⁷Seconda Università-Ospedale Monaldi, Napoli, Italy, ⁸Policlinico Gemelli, Roma, Italy, ⁹Ospedale Degli Infermi, Rimini, Italy, ¹⁰Ospedale Universitario, Ferrara, Italy, ¹¹Ospedale S. Maria Delle Croci, Ravenna, Italy, ¹²Ospedale Civile, Lugo, Italy, ¹³Ospedale Della Misericordia, Grosseto, Italy, ¹⁴Ospedale Civile, Bentivoglio, Italy, ¹⁵Ospedale Niguarda, Milano, Italy, ¹⁶Ospedale Morgagni, Forlì, Italy, ¹⁷Ospedale S. Donato, Arezzo, Italy, and ¹⁸Centro Studi ANMCO, Firenze, 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. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted October 15, 2012, provisional acceptance given November 13, 2012, final version accepted December 27, 2012.

Address for correspondence: Andrea Rubboli, MD, FESC, Unità Operativa di Cardiologia, Laboratorio di Cardiologia Interventistica, Ospedale Maggiore, Bologna, Italy. Email: andrearubboli@libero.it