Author + information
- Received August 20, 2007
- Revision received October 29, 2007
- Accepted November 20, 2007
- Published online February 26, 2008.
- Juan M. Ruiz-Nodar, MD, PhD⁎,
- Francisco Marín, MD, PhD†,‡,
- José Antonio Hurtado, MD†,‡,
- José Valencia, MD, PhD⁎,
- Eduardo Pinar, MD, PhD†,‡,
- Javier Pineda, MD, PhD⁎,
- Juan Ramón Gimeno, MD, PhD†,‡,
- Francisco Sogorb, MD, PhD⁎,
- Mariano Valdés, MD, PhD† and
- Gregory Y.H. Lip, MD, FACC, FESC§,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Gregory Y. H. Lip, University Department of Medicine, City Hospital, Birmingham B18 7QH, United Kingdom.
Objectives This study was designed to review outcomes in relation to antithrombotic therapy management strategies for patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) with stenting.
Background There is limited evidence on the optimal antithrombotic therapy management strategies for patients with AF who undergo PCI with stenting.
Methods We reviewed 426 patients (70.9% men, mean age 71.5 ± 8.5 years) with AF undergoing PCI with stenting between 2001 and 2006. We recorded clinical and demographic characteristics of the patients, stroke risk factors, and antithrombotic therapy use before PCI and at discharge. Clinical follow-up was performed, and all bleeding episodes, thromboembolism, and major adverse cardiac events (MACE) (i.e., death, acute myocardial infarction, or target lesion revascularization) were recorded.
Results The most commonly associated comorbidities were hypertension (74.5%), diabetes mellitus (40.2%), chronic renal failure (14.9%), and congestive heart failure (26.7%); 80% of patients had ≥2 stroke risk factors. Of the drugs prescribed at discharge, aspirin plus clopidogrel were used in 174 patients (40.8%), whereas 213 patients (50%) were discharged with triple therapy (coumarins, aspirin, and clopidogrel). Complete follow-up was achieved in 87.5% (median 594 days; range 0 to 2,190). The incidence of adverse events was high (36.6%), with major bleeding in 12.3%, thromboembolic events in 4.2%, and MACE in 32.3%. All-cause mortality was high (22.6%). In a multivariate analysis, non-anticoagulation with coumarins increased mortality (17.8% vs. 27.8%; hazard ratio [HR] = 3.43; 95% confidence interval [CI] 1.61 to 7.54; p = 0.002) and MACE (26.5% vs. 38.7%; HR = 4.9; 95% CI 2.17 to 11.1; p < 0.01) In a Cox-regression analysis, non-anticoagulation (p < 0.01) and age (p = 0.02) were independent predictors of MACE.
Conclusions Patients with AF undergoing PCI with stenting represent a high-risk population because of age, comorbidities, and presence of stroke risk factors. These patients have a high mortality and MACE rate, which is reduced by anticoagulation therapy.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and its association with stroke and thromboembolism is well recognized. In high-risk patients with nonvalvular AF, anticoagulation with coumarins is recommended to reduce the risk of stroke and thromboembolic events (1). In patients with stable coronary artery disease, treatment with aspirin or clopidogrel is recommended for cardiovascular prevention (2), whereas dual antiplatelet therapy with aspirin plus clopidogrel is advised following presentation with an acute coronary syndrome (ACS) or following coronary artery stent deployment (3,4). The recommended duration of dual antiplatelet therapy varies, ranging from 4 weeks following bare-metal stent implantation during elective angioplasty to at least 6 to 12 months with drug-eluting stents (DES), in view of the risk of late stent thrombosis, and for 12 months following a presentation with ACS (4–6).
A management problem arises when a patient in whom long-term anticoagulation with coumarins is recommended as thromboprophylaxis because AF subsequently presents with ACS and/or undergoes percutaneous coronary intervention (PCI) and/or stenting. Coumarin monotherapy is a poor therapeutic choice in post-stent patients, with a high rate of adverse cardiac complications after stent implantation (7). However, anticoagulation with coumarins in coronary artery disease subjects may provide a similar degree of “vascular protection” to antiplatelet therapy, at least in the post-ACS setting (8). In contrast, the use of “aspirin plus coumarins” or “triple therapy” (aspirin, clopidogrel, and coumarins) is associated with more bleeding complications (8,9).
A delicate balance between risk of recurrent cardiac ischemia (either post-ACS or from stent thrombosis), stroke/thromboembolic complications, and the risk of major bleeding is therefore needed. Unfortunately, there is a lack of published evidence on the optimal antithrombotic management strategy in anticoagulated AF patients who present with an ACS and/or undergo PCI/stenting and hence require antiplatelet therapy. The 2006 American College of Cardiology/American Heart Association/European Society of Cardiology guidelines on AF management (10) acknowledge that no adequate studies specifically address this issue in patients who also require chronic anticoagulation because of AF and suggest that the maintenance regimen should be a combination of clopidogrel and coumarins for 9 to 12 months, after which warfarin may be continued as monotherapy in the absence of a subsequent coronary event (10). Other authorities (11) have suggested an antithrombotic management schema based on ACS presentation, perceived bleeding risk, and the type of stent used. None of these strategies have been tested in prospective randomized trials.
Given that randomized trials are unlikely to provide the answer in the short term, registry data may give some insight into the important management question. In this article, our objective was to present a case series of 426 patients with AF undergoing PCI with stenting from registry data available from 2 teaching hospitals, with particular attention to clinical and demographic characteristics of the patients, stroke risk factors, and antithrombotic therapy use before PCI and at discharge, as well as bleeding, thromboembolism, and major adverse cardiac events (MACE) (i.e., death, acute myocardial infarction, target lesion revascularization) at follow-up.
We conducted a retrospective 2-center registry analysis based on a search of our computerized PCI/stenting database of those patients diagnosed with AF that underwent PCI with at least 1 stent implanted over a 5-year period (January 2001 to December 2006); all of the outcome data were collected post hoc. We included patients from Hospital General Universitario of Alicante, which is a teaching hospital serving a population of approximately 800,000 that has 5 interventional cardiologists and performs 1,300 PCI procedures a year. The second hospital was Hospital Virgen de la Arricaca, Murcia, which has 7 interventional cardiologists serving a population of 1,100,000 and performs 1,400 PCI procedures a year. We recorded clinical and demographic characteristics of the patients, stroke risk factors, and antithrombotic therapy use before PCI and at discharge. Stroke risk of our patients was assessed by the CHADS2 (1 point each for the presence of Congestive heart failure, Hypertension, Age 75 years or older, and Diabetes mellitus and by assigning 2 points for history of Stroke or transient ischemic attack) score (12). Clinical follow-up was performed, and all bleeding episodes, thromboembolism, and MACE were recorded.
Patients with a preexisting diagnosis of permanent, persistent, or paroxysmal AF and those who developed new-onset AF during their current admission were included in this analysis. The type of stent implanted was recorded, and, since May 2002, DES were routinely available for use in both our hospitals. Individual patient management decisions, such as the type of revascularization performed or the type of stent implanted, were decided by the interventional cardiologist and/or the responsible cardiologist. The regimen of oral anticoagulation and/or antiplatelet drugs at discharge was again decided by the responsible clinical cardiologist on the basis of type of AF, stroke/thromboembolic risk factors, comorbidities, revascularization procedure, and the type of stent used.
At discharge, patients were followed up as part of the usual routine for each center. Telephone follow-up was also performed to confirm the antithrombotic therapy regimen followed after discharge, as well as to ascertain any episodes of bleeding, stroke/thromboembolism, and/or MACE. Clinical records of patients with hospital readmissions and/or outpatient clinic interviews were also reviewed for further information to validate our registry database.
End point definitions
For the follow-up analysis, the primary end point was defined as the occurrence of MACE episodes, including death, MI, or target vessel revascularization. A secondary safety end point was major adverse events (MAE), which included the occurrence of any MACE, major bleeding complications, and/or stroke during the follow-up period. Myocardial infarction was defined as either the development of pathologic Q waves in at least 2 contiguous leads with an elevated creatine kinase-MB fraction level or, in the absence of pathologic Q waves, an elevation in creatine kinase-MB levels to more than twice upper limit of normal. Major bleeding was defined as a decrease in the blood hemoglobin level of more than 5.0 g/dl (including the period around the coronary interventional procedure), the need for the transfusion of 2 or more units of blood, the need for corrective surgery, the occurrence of an intracranial or retroperitoneal hemorrhage, or any combination of these events (13).
Continuous variables were tested for normal distribution by the Kolmogorov-Smirnov test. The normal distributed continuous variables are shown as mean ± SD, and those nonparametrically distributed are shown as median (interquartile range). Discrete variables are presented as frequencies (percentages). The comparison of discrete variables was done via the chi-square test or (when the 2 × 2 table had <5 patients) the Fisher test. Comparisons of the groups for continuous variables were performed with the unpaired t test for independent samples that were parametrically distributed; for nonparametric variables, the Mann-Whitney U test was used.
Survival analyses were initially conducted using a Kaplan-Meier analysis and compared by the log-rank test. Second, we performed a stepwise Cox proportional hazard model analysis, considering the presence of any event as an end point and introducing influencing variables as age, type of AF, different cardiovascular risk factors (e.g., hypertension, diabetes, heart failure, and so on), use of DES, diameter and total length of stent, and antithrombotic therapy at discharge. In the multivariate model, we also included those variables that showed a p value <0.15 in the univariate analysis when comparing patients with and without oral anticoagulation at discharge. All p values were 2-sided, and a p value of <0.05 was considered statistically significant.
We reviewed 426 patients (70.9% men, mean age 71.5 ± 8.5 years) with AF undergoing PCI with stents between 2001 and 2006. Of the 426 patients, 256 (60.1%) had permanent AF and 170 (39.9%) had paroxysmal AF (Table 1). The population was older, with diabetes mellitus in 40%, hypertension in 74.5%, heart failure or impaired cardiac function in 47%, and previous coronary events in 44%. There was at least 1 risk factor for stroke/thromboembolism in 96% of the patients, and 80% had ≥2 stroke risk factors. Specifically, 93% of the patients had a CHADS2 score of ≥1, whereas 69% had a CHADS2 score of ≥2. At least 1 DES was used in 40% of the patients, and complete revascularization was only achieved in 60% (Table 2).
Antithrombotic drug regimen at discharge
Of the drugs prescribed at discharge, dual antiplatelet therapy (aspirin plus clopidogrel) was prescribed in 174 (40.8%), whereas 213 (50.0%) were discharged with triple therapy (coumarins, aspirin, and clopidogrel). Furthermore, 15 patients (3.6%) were receiving a single antiplatelet drug, whereas 24 (5.6%) were taking coumarins plus 1 antiplatelet drug (Table 3). There was wide variability in the antithrombotic therapy regimen and duration of treatment used by the 2 hospitals and between the interventional cardiologists. Of the patients discharged with triple therapy, there was no consistency in the duration of treatment, with either coumarins or 1 antiplatelet agent being stopped at 1 month following PCI where bare-metal stents were used and between 3 and 12 months when a DES was used. Ticlopidine was used in a very small number of patients (n = 13), and thus, numbers were included within the clopidogrel group.
In the patients with permanent AF, the antithrombotic drug regimen most commonly used was triple therapy (55.8%), in comparison with patients with paroxysmal AF, where dual antiplatelet therapy predominated (49.5%). Characteristics of the population treated with coumarins at discharge in relation to those not treated with such drugs are shown in Table 4. Those discharged taking coumarins were a higher risk population, given the higher proportion of hypertension and previous embolism and a higher number of stroke/thromboembolism risk factors.
Complete follow-up was achieved in 88% of the cohort (median 595 days; range 0 to 2,190 days). The incidence of adverse events was high (35%), with major bleeding in 12.3%, thromboembolic events in 4.2%, and MACE in 32.3% (Table 5). All-cause mortality was also high (22.6%). In a multivariate Cox regression analysis, nonanticoagulation with coumarins significantly increased mortality (17.8% vs. 27.8%; hazard ratio [HR] = 3.43; 95% confidence interval [CI] 1.61 to 7.54; p = 0.002) and MACE (26.5% vs. 38.7%; HR = 4.9; 95% CI 2.17 to 11.1; p = 0.001).
Among the patients who were prescribed oral anticoagulants at discharge, there was a nonsignificant increase in major bleeding (14.9% vs. 9.0%; p = 0.19) (Fig. 1A) (log-rank test p = 0.64) but a significantly better MACE-free prognosis (Fig. 1B) (log-rank test p = 0.02), as well as a lower all-cause mortality (Fig. 1C) (log-rank test p = 0.02). In a Cox regression analysis, nontreatment with coumarins at discharge (p = 0.001) and age (p = 0.017) were independent predictors of MACE (Table 6).
For the secondary safety end point (MAE) that included the occurrence of any MACE, major bleeding complications, and/or stroke at follow-up, this end point was lower among those patients treated with coumarins (26.8% vs. 39.2%; p = 0.014). In a Cox regression analysis, age (p = 0.019) and nontreatment with coumarins at discharge (p = 0.001) were independent predictors of MAE (Table 7). There was no significant increase in the incidence of major hemorrhagic events in the patients treated with coumarins.
Acute coronary syndromes (non–ST-segment elevation in 63.8%, ST-segment elevation in 20.1%) were the main indication for the PCI procedure, but this did not have any influence on either the type of treatment at discharge or the long-term prognosis (Table 4).
Of the whole cohort, 174 patients (40.1%) were treated with at least 1 DES. A higher prevalence of diabetes mellitus was observed in those patients treated with DES (46% vs. 35%: p = 0.03), but no other differences in clinical characteristics were observed. The number of stents implanted in the DES group was higher (2.17 vs. 1.59; p < 0.01), smaller (2.78 mm vs. 2.99 mm; p < 0.01), and longer (39 mm vs. 35 mm; p < 0.01). In a univariate analysis, a lower incidence of MACE was observed in the DES group (29.0% vs. 40.5%; p = 0.032); however, this difference did not persist in a multivariate analysis. Patients treated with DES had a higher rate of stent thrombosis (2.8% vs. 0%; p = 0.034).
To our knowledge, this is the largest dataset of AF patients undergoing PCI/stenting where antithrombotic therapy management strategies have been related to clinical outcomes. We show that our patients with AF undergoing PCI with stenting represent a high-risk population owing to age, comorbidities, and the presence of stroke risk factors, as well as the relatively high incidence of acute coronary syndromes as the indication for PCI. We show a lack of any coordinated strategy for the prevention of thrombotic or thromboembolic events in this AF population, with a high mortality rate and MACE. Importantly, our data confirm the protective effect of the coumarins in patients with AF treated with PCI/stents by decreasing the incidence of MACE. In addition, the beneficial effect of coumarins is confirmed in the multiple regression analysis, where age and nontreatment with coumarins were the only independent predictors of MACE. On the basis of these data, we consider that in those patients with AF treated with PCI/stents who have a low risk of bleeding complications, a triple-therapy regimen should be the elective antithrombotic drug treatment approach.
The present study also illustrates that various antithrombotic drug combinations are used in everyday practice. Such variability is understandable in light of the lack of available guidelines. Indeed, the post-PCI strategy should be tailored to the individual patient and their risk of thromboembolism and stent thrombosis against their risk of bleeding while receiving triple therapy (14). In the small case series by Lip and Karpha (11), for example, 35 patients were reviewed over a 5-year period, but the study did illustrate the wide variability in management strategies between interventional cardiologists.
The combination of coumarins plus aspirin after PCI has previously been shown to be less effective compared to ticlopidine plus aspirin in preventing stent thrombosis (7,15,16). Of note, 1 stroke prevention trial in AF had to be stopped early because of the clear superiority of oral anticoagulation over dual antiplatelet therapy with aspirin plus clopidogrel (17). This may explain why triple therapy has been commonly used in this series, as well as in other case series (18), despite the lack of data from clinical trials. However, such combination therapy increases the risk of bleeding (9,18,19). Our series also highlights the variability in the use of anticoagulant/antiplatelet therapy in patients undergoing PCI with stenting who have AF. Although the combination of aspirin and clopidogrel (40.7%) or triple therapy (50.0%) accounted for the majority of patients, the duration of their use still varied widely among patients. This variability was due essentially to the use of DES, in which sustained therapy with clopidogrel between 6 and 12 months was recommended, as opposed to patients treated with bare-metal stents, in which clopidogrel was maintained for only 1 month.
A recent meta-analysis with estimates of risk and benefit of coumarins plus aspirin after myocardial infarction of ACS reviewed 10 trials involving a total of 5,938 patients and concluded that for patients who are at low or intermediate risk for bleeding, the cardiovascular benefits of coumarins outweigh the bleeding risks (20). The data from Karjalainen et al. (18) support the view that triple therapy is currently the best option for the majority of the patients, although this predisposes to an increased risk of bleeding, which may require stopping anticoagulation and/or antiplatelet therapy. Such therapy cessation exposes these patients to stent thrombosis or stroke/thromboembolism. Other series quantify the use of triple antithrombotic therapy as being associated with a 7% major bleeding risk (19).
In the present series, DES were used in 40.1% of the patients and more frequently in diabetic patients. The type of antithrombotic therapy used in DES patients at discharge was generally similar to that of the patients treated with bare-metal stents, with the exception of the duration of clopidogrel. In a multivariate analysis, there was no significant difference in the incidence of MACE when DES was used. It should also be emphasized that patients treated with DES had a higher rate of stent thrombosis (2.8% vs. 0%; p = 0.034), although this finding should be interpreted with caution given the smaller subgroup here, to evaluate an end point with such a low incidence. However, the implantation of DES should probably be discouraged in anticoagulated AF patients owing to the need for prolonged dual antiplatelet administration (21,22).
This large study is limited by its registry design. This was not a randomized controlled trial, and many confounders/biases are possible, although we have tried to address most in a multivariate analysis. Another limitation is the changes of antithrombotic regiment in these patients during the follow-up period, sometimes in relation to the presence of thrombotic or hemorrhagic complications. Although limited by the experience of 2 European centers, this large series still clearly reveals the complexity, high comorbidity, and high risk of the population with AF that has undergone PCI/stenting, as well as the lack of any coordinated strategy in the prevention of stroke/thromboembolic events among anticoagulated AF patients. Treatment with coumarins at discharge shows a beneficial effect on prognosis by reducing the incidence of death and MACE, and such benefits do not appear to be associated with a substantial increase in major bleeding events. Further large studies are required to assess the bleeding and thrombotic risk with various post-PCI strategies in patients with AF to facilitate the development of guidelines.
The authors gratefully acknowledge Dr. Eloísa Felíu and Dr. José Sánchez-Payá, who provided a revision of the manuscript, and Victor Vicedo, Silvia Gómez, Concepción Fernández, and María Angeles Beltrán for data collection.
- Abbreviations and Acronyms
- acute coronary syndrome
- atrial fibrillation
- drug-eluting stent(s)
- major adverse cardiac events
- major adverse events
- percutaneous coronary intervention
- Received August 20, 2007.
- Revision received October 29, 2007.
- Accepted November 20, 2007.
- American College of Cardiology Foundation
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