Antithrombotic therapy in patients treated with oral anticoagulation undergoing coronary artery stenting. An expert consensus document with focus on atrial fibrillation

Abstract

Dual antiplatelet treatment with aspirin and clopidogrel is recommended after coronary stenting (PCI-S). There is scant evidence defining optimal post-PCI-S antithrombotic therapy in patients with atrial fibrillation (AF) in whom oral anticoagulation (OAC) is mandated. To evaluate the safety and efficacy of the antithrombotic strategies for this population, we conducted a systematic review of the available evidence in patients treated with OAC undergoing PCI-S. AF was the most frequent indication for OAC. Post-PCI-S management was highly variable, and triple therapy with warfarin, aspirin, and clopidogrel was the most frequent and effective combination. Warfarin plus aspirin alone was not sufficiently effective in the early period after PCI-S and should not be prescribed. While acknowledging that the optimal antithrombotic treatment for patients with AF at medium or high thromboembolic risk undergoing PCI-S is currently undefined, triple therapy of warfarin, aspirin, and clopidogrel is currently recommended, although associated with an increased risk of major bleeding. Restrictive use of drug-eluting stent is also recommended, due to the need for prolonged multiple-drug antithrombotic therapy which may increase the bleeding risk. Whether the combination of warfarin and clopidogrel (without aspirin) will preserve efficacy and produce less bleeding is an important issue still needing to be addressed.

• Antiplatelet drugs
• aspirin
• atrial fibrillation
• clopidogrel
• percutaneous coronary intervention
• stent
• warfarin

Introduction

Long-term oral anticoagulation (OAC) with vitamin K antagonists is recommended for patients with atrial fibrillation (AF) at intermediate or high risk for thromboembolism 1. In the event that these patients are submitted to percutaneous coronary intervention with stent implantation (PCI-S), whether in the context of an acute coronary syndrome or not, their management becomes challenging because of the concurrent indication for antiplatelet therapy. Since aspirin alone 1 or in combination with clopidogrel 2 provides inferior protection against stroke in patients with AF, substitution of OAC with antiplatelet treatment appears insufficient. The issue, therefore, is whether or not aspirin and/or clopidogrel should be combined with OAC in patients with AF who are referred for PCI-S.

Key messages

• In patients with atrial fibrillation at intermediate or high thromboembolic risk undergoing coronary artery stenting, triple therapy with warfarin, aspirin, and clopidogrel is recommended, although an increased risk of major hemorrhagic complications may ensue.

• Combination treatment of oral anticoagulation and aspirin is not sufficiently effective and therefore should not be prescribed.

• Insufficient evidence supports at present the combined use of warfarin and clopidogrel (without aspirin), although favorable preliminary data, warranting further investigation, have been reported.

In the most recent American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for the management of patients with atrial fibrillation 1, triple therapy of warfarin (International Normalized Ratio (INR) range 2.0–3.0), low-dose aspirin (≤100 mg/day), and clopidogrel (75 mg/day) is briefly recommended early after PCI-S. A maintenance regimen of warfarin (INR 2.0–3.0) and clopidogrel (75 mg/day) should then follow for 9–12 months, after which warfarin monotherapy (INR 2.0–3.0) should be continued indefinitely 1. Whereas the effectiveness of moderate intensity (INR 2.0–3.0) warfarin monotherapy for the long-term treatment of patients with AF suffering from ischemic heart disease has been demonstrated 3, 4, triple therapy of warfarin, aspirin, and clopidogrel, or the combination of warfarin plus a single antiplatelet agent has not been thoroughly evaluated. Accordingly, treatment recommendations are currently graded IIb (that is, expected benefits ≥ risks), with a C level of evidence (that is, arising from an expert consensus) 1.

Since the publication of the American College of Cardiology/American Heart Association/European Society of Cardiology guidelines on atrial fibrillation, several studies reporting on patients treated with OAC undergoing PCI-S have been made available. In this article, we aim to provide a systematic review of the currently available data, in order to derive practical suggestions for the antithrombotic management of this specific patient subset.

Abbreviations

Table

AF	atrial fibrillation
INR	international normalized ratio
OAC	oral anticoagulation
PCI-S	percutaneous coronary intervention with stent implantation

Search strategy

Published studies on antithrombotic therapy use in patients treated with OAC undergoing PCI-S were sought by computerized searches on MEDLINE. Bibliographies of all retrieved articles were reviewed for other relevant articles. Finally, the supplements of major journals were hand-searched to identify relevant abstracts that had not been published as peer-reviewed articles. Where necessary, study authors were contacted to obtain further data.

Overview of the literature

To date, 13 full reports on the antithrombotic treatment of patients treated with OAC undergoing PCI-S have been published 5–17. One of these articles 6 represents a preliminary report of a subsequent study 13, leaving only 12 studies involving independent cohorts 5, 7–17 (Table I).

Table I.  Design and outcome evaluation in the published studies reporting on patients treated with oral anticoagulation and undergoing coronary artery stenting.

Author	Design of the study	Outcomes evaluated	Outcome comparisons	Time of outcome evaluation
Orford JL et al. 5	retrospective, single-center	bleeding, MACE	none	30 days
Mattichak SJ et al. 7	retrospective, single-center	bleeding, stroke, MACE	versus contemporary pts on dual antiplatelet	6 and 12 months
Khurram Z et al. 8	retrospective, single-center	bleeding	versus contemporary pts on dual antiplatelet	12 months
Porter A et al. 9	retrospective, single-center	bleeding	none	30 days
Lip GYH & Karpha M 10	retrospective, single-center	bleeding	within population	30 days
Karjalainen PP et al. 11	retrospective, multi-center	bleeding, stroke, MACE	versus contemporary pts on dual antiplatelet, and within population	in-hospital/12 months
DeEugenio D et al. 12	retrospective, single-center	bleeding	versus contemporary pts on dual antiplatelet	6 months
Rubboli A et al. 13	retrospective, single-center	bleeding, thromboembolism, MACE	within population	30 days
Nguyen MC et al. 14	prospective (post-hoc analysis), multi-center (GRACE registry)	MACE, stroke (bleeding, MI, shock, heart failure, stroke)	within population	6 months (in-hospital)
Wang TY et al. 15	prospective (post-hoc analysis), multi-center (CRUSADE registry)	bleeding, transfusion, MI, heart failure	within population	in-hospital
Ruiz-Nodar JM et al. 16	retrospective, two-center	bleeding, thromboembolism MACE	within population	∼ 20 months
Rogacka R et al. 17	retrospective, two-center	bleeding, MACE, cerebrovascular events, stent thrombosis	none	∼ 21 months

MACE = major adverse cardiac events (death, myocardial infarction, repeat revascularization); MI = myocardial infarction; pts = patients.

Nearly all of the studies are small, retrospective, and single-center, except for a few where patients either were included in several centers or enrolled in large-scale, multi-center registries, such as GRACE 14 and CRUSADE 15 (Table I). None of the study was conducted prospectively, except for the GRACE 14 and CRUSADE 15 registries, where the analysis of the population on OAC was carried out post hoc (Table I). The safety outcome of bleeding was evaluated in all of the studies, whereas efficacy outcomes, such as thromboembolism/stroke, stent thrombosis, and adverse cardiac events were variably investigated (Table I). Outcome comparisons were carried out either against contemporary cohorts of patients without indication for OAC who were submitted to PCI-S and treated with dual antiplatelet treatment, or within the same study cohort of patients on OAC (Table I). In some studies, no safety or efficacy comparison was made (Table I). The time points for the outcome evaluation were variable, ranging from the in-hospital stay to over a year (Table I). In only three reports did clinical follow-up include both the periods on and off the multiple-drug regimen prescribed after PCI-S 9–11.

The overall number of patients on OAC who underwent PCI-S in the published studies is limited to 3413, with an average age of about 70 years (Table II). In nearly all the studies, AF was the most frequent indication for OAC, but only two publications were focused solely on AF patients 10, 16. In another study, separate analyses of both the overall cohort and patients with AF were carried out 14. Indications for PCI-S variably included either stable or unstable coronary syndromes, with one study enrolling only patients with ST-elevation myocardial infarction 7 (Table II). Also highly variable was the use of drug-eluting stents, ranging from 2% to 77% (Table II). Whereas six studies aimed at evaluating the safety and efficacy of triple therapy, and therefore only patients on this regimen were enrolled 5, 7–9, 12, 17, in the others the prescribed regimens were variable, with triple therapy of warfarin, aspirin, and clopidogrel being overall the most frequently used (Table II).

Table II.  Epidemiological and procedural characteristics in the published studies on patients treated with oral anticoagulation undergoing coronary artery stenting.

				Indication for PCI-S				Antithrombotic therapy at discharge
Author	N° of pts	Age (yrs) ^a	Prevalence of AF	STEMI	NSTE ACS	Elective	Implantation of DES	TT	DAT	OAC + ASA	OAC + clopidogrel
Orford JL et al. 5	66	74	39%	14%	75%	NR	NR	100%	–	–	–
Mattichak SJ et al. 7	40	67	43%	100%	–	–	NR	100%	–	–	–
Khurram Z et al. 8	107	69	80%	NR	NR	NR	50%	100%	–	–	–
Porter A et al. 9	180	65	37%	46%	37%	17%	NR	100%	–	–	–
Lip GYH & Karpha M 10	35	71	100%	31%	63%	6%	14%	17%	71%	6%
Karjalainen PP et al. 11	239	70	70%	9%	44%	NR	42%	48%	16%	15%	21%
DeEugenio D et al. 12	97	70	60%	NR	NR	NR	25%	100%	–	–	–
Rubboli A et al. 13	49	69	60%	31%	29%	40%	2%	41%	45%	14%	–
Nguyen MC et al. 14	800	65	37%	61%	39%	–	25%	73%	–	13%	14%
Wang TY et al. 15	1247	76	NR	NR	NR	NR	77%	60%	31%	3%	3%
Ruiz-Nodar JM et al. 16	426	72	100%	20%	64%	16%	40%	50%	41%	2%	4%
Rogacka R et al. 17	127	70	59%	3%	23%	47%	56%	100%	–	–	–

^a mean/median.

AF = atrial fibrillation; ASA = aspirin; DAT = dual antiplatelet therapy of aspirin and clopidogrel; DES = drug eluting stent; GP = glycoprotein; NR = not reported; NSTE ACS = non-ST-elevation acute coronary syndrome; OAC = oral anticoagulation; PCI-S = percutaneous coronary intervention with stent; STEMI = ST-elevation myocardial infarction; TT = triple therapy of warfarin, aspirin, and clopidogrel; pts = patients.

Triple therapy was associated with a variable incidence of major bleeding, which ranged from 0% to 21% (Table III). In one report, major bleeding was fatal in half of cases 17. Overall, duration of treatment limited to about 30 days was associated with fewer hemorrhagic complications (4.6% pooled incidence of major bleeding) than more prolonged administration of 6–12 months or more (10.3% pooled incidence of major bleeding) (Table III). Most bleeding events were gastrointestinal and not infrequently associated with supratherapeutic INR levels. Contributory factors include advanced age, preexisting lesions of the gastrointestinal tract, or trauma 5, 7, 13. Periprocedural administration of additional antithrombotic drugs, such as heparin or glycoprotein IIb/IIIa inhibitors (which were used in 20% to 71% of patients) 5, 9–14, 16, also seems to increase the short-term hemorrhagic risk after stenting 9, 11. In three studies, where the safety of triple therapy was compared with that of dual antiplatelet therapy (the ‘gold standard’ after PCI-S), the relative risk of combined major/minor bleeding was consistently and significantly about 5-fold higher at 1, 6, and 9 months 8, 12, 13. Since a minority of patients was treated with the combination of OAC and a single antiplatelet agent (either aspirin or clopidogrel) (Table II) and corresponding individual data are seldom reported, a reliable evaluation of the relative safety of these regimens could not be carried out.

Table III.  Incidence of major bleedings in patients receiving triple therapy of warfarin, aspirin, and clopidogrel after coronary artery stent implantation.

Author	At 30 days	At 6 months	At ≥12 months
Orford JL et al. 5	2/66 pts (3.1%)	NR	NR
Mattichak SJ et al. 7	NR	5/40 pts (12.5%)	8/40 pts (21%)
Khurram Z et al. 8	NR	NR	7/107 pts (6.6%)
Porter A et al. 9	2/180 pts (1.1%)	NR	NR
Lip GYH & Karpha M 10	0/6 pts (0%)	NR	NR
Karjalainen PP et al. 11	NR	NR	7/106 pts (6.6%)
DeEugenio D et al. 12	NR	14/97 pts (14%)	NR
Rubboli A et al. 13	3/20 pts (15%)	NR	NR
Nguyen MC et al. 14	NR (34/580 pts; 5.9%) ^a	NR	NR
Wang TY et al. 15	NR	NR	NR
Ruiz-Nodar JM et al. 16	NR	NR	NR (36/242 pts; 14.9%) ^b
Rogacka R et al. 17	NR	NR	6/127 pts (4.7%)
Total	7/272 pts (2.6%)	19/137 pts (13.9%)	28/380 pts (7.4%)
	(39/852 pts; 4.6%, including ref. (14))		(64/622 pts; 10.3%, including ref. (16))

^aOccurring in-hospital.

^bOccurring in all anticoagulated patients: triple therapy, oral anticoagulant plus single antiplatelet agent, and oral anticoagulant monotherapy.

NR = not reported; pts = patients.

Occurrence of stroke was rarely reported in the various studies, although triple therapy was generally more effective than both dual antiplatelet treatment and the combination of OAC and a single antiplatelet agent 11, 14, 16. Because of the large difference in stroke rates (2.8% versus 8.8%), the study by Karjalainen et al. 11 supports the use of triple therapy and argues against dual antiplatelet combination. For such an indication, triple therapy of warfarin, aspirin, and a thienopyridine may be even more effective than the combination of warfarin and a single antiplatelet agent, as suggested, albeit not conclusively proven, by the study by Nguyen et al. (0.7% versus 3.4%) 14.

Stent thrombosis was also rare, being the lowest with triple therapy, as compared to dual antiplatelet treatment and the combination of warfarin and aspirin 11, 13, 16. As long as a triple therapy regimen was ongoing, thromboembolic events were infrequent 11, whereas a much higher incidence of this complication was reported in patients while on treatment with the combination of warfarin and aspirin (0.8% versus 15.2%) 11. Indeed, among the patients examined by Rubboli et al. 13, the only thrombotic event (i.e. subacute stent thrombosis) was observed with the combination of warfarin and aspirin 13. A suboptimal efficacy of the warfarin plus aspirin regimen was observed for prevention of myocardial infarction (8.5% versus 18.2%) 11. Also, a trend toward worse outcomes both in the overall cohort and the subset with AF receiving warfarin and a single antiplatelet agent was observed by Nguyen et al. 14. However, the small number of adverse events and the lack of information about the time of and the ongoing treatment at the complication should be taken into account when considering these results.

At present, minimal data are available on the combination of warfarin and clopidogrel, although in the small subgroup of patients receiving this treatment in the study by Karjalainen et al. 11 the efficacy appeared to be good. The combination of warfarin and a thienopyridine, both in the overall cohort and in the AF subset, appeared comparably effective to triple therapy also in the study by Nguyen et al. 14, but no statistically significant differences in efficacy were observed in comparison to the warfarin/aspirin regimen.

Adverse cardiac events appear to be generally more frequent in patients on OAC 11, 14. As observed in previous reports, however 18, 19, this finding may simply reflect a higher prevalence of high-risk features (such as diabetes, previous myocardial infarction, stroke, or heart failure) at baseline.

Considerations for clinical practice

Since AF was the predominant indication for OAC in the studied populations undergoing PCI-S 5, 7–17 (Table I), we believe that some considerations for clinical practice arising from these studies may reasonably be extrapolated to this specific subset. However, we recognize that the patient profile (i.e. age, comorbidities, concomitant therapies, etc.) may be quite different between a patient on OAC for AF as compared to one with a mechanical heart valve or venous thromboembolism.

Whereas a short course (i.e. 1 month) of dual antiplatelet treatment may substitute OAC after PCI-S in patients with AF at low thromboembolic risk (CHADS₂ score < 2: risk < 2%–3% per year) (Table IV), the addition to OAC of one or two antiplatelet agents appears necessary in patients with intermediate or high risk features for thromboembolism (CHADS₂ score ≥2: risk > 4% per year) 1, 20, 21 (Table IV).

Table IV.  Stroke risk according to CHADS₂ score (1).

Score	Annual risk (%)
0	1.9
1	2.8
2	4.0
3	5.9
4	8.5
5	12.5
6	18.2

CHADS₂ risk score: 1 point each for congestive heart failure, hypertension, age ≥75 years, Diabetes; 2 points for prior stroke.

Triple therapy of warfarin, aspirin, and clopidogrel is the most widely employed and is the most effective regimen for prevention of both stent thrombosis and systemic thromboembolism 11, 13, 14, 16, 17. Therefore, in the early period after PCI-S, during which reendothelization takes place, we recommend triple therapy with warfarin, aspirin, and clopidogrel to prevent stent thrombosis. Since this period may last from a few weeks to several months, depending on whether a bare-metal or a drug-eluting stent is implanted, and prolonged triple therapy is associated with an increasing risk of hemorrhage, an estimation of the individual risk of bleeding prior to starting PCI-S is warranted 22 (Table V). To minimize the bleeding risk, moderate intensity OAC (INR 2.0–3.0) and low-dose aspirin (≤100 mg/day), along with the standard dose of 75 mg/day or clopidogrel, should be used, and the shortest possible duration of treatment prescribed. Thus, restrictive use of drug-eluting stents is recommended, since at least 3 and 6 months (and ideally 12 months), depending on whether a sirolimus-eluting or a paclitaxel-eluting stent is implanted, of clopidogrel administration is recommended 23. Careful and frequent (even weekly in some patients) monitoring of INR is also advised, in order to keep it strictly within and possibly on the lower side of the therapeutic range. Since most bleeding with triple therapy occurs in the gastrointestinal tract 5, 7–9, 11–13, measures directed at protection of the gastric mucosa seem reasonable, but a possible interaction between certain proton-pump inhibitors and clopidogrel might reduce the antiplatelet effect 24. Finally, to reduce early hemorrhagic complications at the arterial access site, radial approach and uninterrupted anticoagulation (i.e. keeping INR value >2) instead of heparin bridging may be an option 25, 26.

Table V.  Bleeding risk according to outpatient bleeding risk index (22).

Score	Annual risk (%)
0	3
1–2	8–12
3–4	30–48

Outpatient bleeding risk index score: 1 point each for age ≥65 years, prior stroke, history of bleeding; and 1 point for any of the following: hematocrit <30%, serum creatinine >1.5 mg/dL, or diabetes.

When the bleeding risk is very high, such as for a patient with an outpatient bleeding risk score >2 22 (Table V), only bare-metal stents should be implanted and triple therapy limited to only 2 weeks 23. An alternative option to be considered is the combination of OAC plus aspirin (and proton-pump inhibitors) in association with either plain old balloon angioplasty or the implantation of a carbon-coated stent. Recent experience with such ‘less-thrombogenic’ stents supports the safety and efficacy of aspirin monotherapy for 30 days 27. Whilst waiting for confirmatory data, the combination of warfarin plus aspirin alone should not be used when bare-metal stents are implanted, owing to suboptimal efficacy compared with dual antiplatelet therapy in preventing adverse cardiac events, as reported both in the historical trials comparing such a regimen with dual antiplatelet treatment 28, and in the studies by Karjalainen et al. 11 and Rubboli et al. 13.

Upon completion of the triple therapy course, antithrombotic treatment is still needed to prevent recurrences of coronary events and/or late stent thrombosis. According to the most recent guidelines on percutaneous coronary intervention 23, ST-elevation myocardial infarction 29, and unstable angina/non-ST-elevation myocardial infarction 30, prolonged administration of up to 12 months or clopidogrel (along with aspirin) is indicated for both purposes. However, in patients with AF at intermediate or high thromboembolic risk, in whom OAC is warranted, such strategy appears associated with a prohibitively high risk of bleeding.

A reasonable approach to reduce such risk is represented by the combination of OAC and a single antiplatelet agent. For the latter, there is uncertainty over whether aspirin or clopidogrel is best. Indeed, aspirin is directly gastrotoxic 31, although clopidogrel may possibly be less so. In the clinical setting, there is a similar safety profile of clopidogrel as compared to the combination of aspirin and a proton pump inhibitor, at least for the prevention of recurrent ulcer bleeding (and not PCI-S complications) 32. The addition of aspirin to anticoagulated AF subjects (whether warfarin or the direct thrombin inhibitor ximelagatran) did not reduce strokes or myocardial infarction, but substantially increased bleeding events 33, 34. In post-myocardial infarction patients, the effects of aspirin are early (with the main reduction in deaths seen in the first 35 days), with little further benefit or loss during subsequent years 35, and other trials did not suggest a significant additive effect from aspirin plus OAC compared to OAC alone 36. Nonetheless, PCI-S was hardly used in these older studies 35, 36. Based on post-hoc analyses of prospective trials comparing clopidogrel versus aspirin, clopidogrel may be marginally better than aspirin in ‘high-risk’ subgroups with vascular disease 37. In our present review of (mainly registry) studies of patients treated with OAC undergoing PCI-S, there were no substantial differences in efficacy of aspirin and clopidogrel when combined with OAC 14. Thus, we recommend the combination of OAC and clopidogrel after the initial triple therapy period, but given the lack of prospective data, the combination of OAC, aspirin, and proton-pump inhibitors may be considered as an alternative in this setting.

The chronic (i.e. long-term after the first year) antithrombotic treatment we recommend in stable patients with AF treated with OAC who have had PCI-S with or without an acute coronary syndrome consists of moderate intensity (INR 2.0–3.0) OAC monotherapy, with no need for adding antiplatelet agents 3, 37, 38.

A summary of our recommendations is presented in Table VI.

Table VI.  Recommended antithrombotic strategies following coronary artery stenting in patients with atrial fibrillation at intermediate or high thromboembolic risk (in whom oral anticoagulation therapy is required).

Hemorrhagic risk	Clinical setting	Stent implanted	Recommendations
Low or intermediate	Elective	Bare-metal	1 month: triple therapy of warfarin (INR 2.0–3.0) + aspirin ≤100 mg/day + clopidogrel 75 mg/day + PPI
			lifelong: warfarin (INR 2.0–3.0) alone
	Elective	Drug-eluting	3 (-olimus group) to 6 (paclitaxel) months: triple therapy of warfarin (INR 2.0–3.0) + aspirin ≤100 mg/day + clopidogrel 75 mg/day + PPI
			up to 12th month: combination of warfarin (INR 2.0–3.0) + clopidogrel 75 mg/day ^a
			lifelong: warfarin (INR 2.0–3.0) alone
	ACS	Bare-metal/drug-eluting	6 months: triple therapy of warfarin (INR 2.0–3.0) + aspirin ≤100 mg/day + clopidogrel 75 mg/day + PPI
			up to 12th month: combination of warfarin (INR 2.0–3.0) + clopidogrel 75 mg/day ^a
			lifelong: warfarin (INR 2.0–3.0) alone
High	Elective	Bare-metal ^b,c	2 to 4 weeks: triple therapy of warfarin (INR 2.0–3.0) + aspirin ≤100 mg/day + clopidogrel 75 mg/day + PPI
			lifelong: warfarin (INR 2.0–3.0) alone
	ACS	Bare-metal ^b,d	2 to 4 weeks: triple therapy of warfarin (INR 2.0–3.0) + aspirin ≤100 mg/day + clopidogrel 75 mg/day + PPI
			up to 12th month: combination of warfarin (INR 2.0–3.0) + clopidogrel 75 mg/day ^a
			lifelong: warfarin (INR 2.0–3.0) alone

^aCombination of warfarin (INR 2.0–3.0) + aspirin ≤100 mg/day + PPI may be considered as an alternative.

^bDrug-eluting stents must not be implanted.

^cImplantation of a carbon-coated stent associated with the combination of warfarin (INR 2.0–3.0) + aspirin ≤100 mg/day + PPI for 1 month, followed by warfarin (INR 2.0–3.0) lifelong, should be considered.

^dImplantation of a carbon-coated stent associated with the combination of warfarin (INR 2.0–3.0) + aspirin ≤100 mg/day + PPI for up to 6 months, followed by warfarin (INR 2.0–3.0) lifelong, should be considered.

ACS = acute coronary syndrome; INR = international normalized ratio; PPI = proton pump inhibitors.

Future directions

Since current recommendations derive from limited evidence obtained mostly from small, single-center, and retrospectively analyzed cohorts, large-scale registries and prospective clinical studies appear warranted to determine the optimal antithrombotic management of patients with AF at intermediate or high thromboembolic risk undergoing PCI-S, who are estimated to account for about 5%–7% of the overall population referred for PCI-S 13, 15, 38. A prospective, multi-center registry named AFCAS (Management of patients with Atrial Fibrillation undergoing Coronary Artery Stenting), aiming at prospectively evaluating the antithrombotic strategies currently adopted in this patient subset, and at investigating the potential benefit or harm of VKA and/or antiplatelet treatments, has been recently launched in several European countries. The primary end point is the combined occurrence of major hemorrhagic and thrombotic/thromboembolic complications at 12 months follow-up. The results of this study (expected in late 2008) will hopefully contribute to shed light on this common but understudied issue.

There may be also possibilities for alternative antiplatelet drugs, given that combined therapy with the antiplatelet drug triflusal (a cyclooxygenase inhibitor) plus moderate-intensity anticoagulation therapy significantly decreased adverse events (vascular death and non-fatal stroke or systemic embolism) compared with anticoagulation alone and proved to be safe from the bleeding aspect in AF patients 38. No data, however, are available for triflusal in patients submitted to PCI-S. It is also possible that new non-vitamin K oral anticoagulation agents (i.e. direct thrombin inhibitors or factor Xa inhibitors) could be tested in randomized clinical trials to address the lack of prospective trial data on the optimal management of patients treated with OAC undergoing PCI-S.

Finally, newly developed stents capable of capturing circulating endothelial progenitor cells, and therefore promoting rapid reendothelization 39, will possibly prove valuable for these patients.

Conclusions

The optimal antithrombotic treatment for patients with AF at medium or high thromboembolic risk who undergo PCI-S is currently undefined. Based on scant available data, triple therapy consisting of the combination of warfarin, aspirin, and clopidogrel appears to offer the best protection against thromboembolic and myocardial ischemic events, at the price of an increased risk of major hemorrhagic complications. The combination of OAC and aspirin appears less effective, and therefore should not be prescribed in the early period post-PCI-S. Whether the combination of warfarin and clopidogrel will preserve efficacy and produce less bleeding is an important unanswered question, but initial data support its use for several months after the early period of triple therapy for the prevention of recurrences of coronary events.

Acknowledgements

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.