Aims

To identify factors associated with the use of single or dual antiplatelet therapy in patients prescribed warfarin following coronary stenting and to investigate whether single (aspirin or thienopyridine) vs. dual antiplatelet therapy plus warfarin leads to an excess of adverse outcomes.

Methods and results

We analysed data from 800 patients with an acute coronary syndrome who underwent coronary stenting (130 patients received a drug-eluting stent) and were discharged on warfarin and either dual (n = 580) or single (n = 220) antiplatelet therapy. The use of single antiplatelet therapy was more common in Europe than in the USA (34 vs. 17%, P < 0.001). There was no difference in major bleeding in hospital or in 6-month mortality or myocardial infarction. In the single antiplatelet group, the use of either aspirin or thienopyridine (clopidogrel or ticlopidine) in combination with warfarin resulted in similar outcomes.

Conclusion

Use of single vs. dual antiplatelet therapy and warfarin following stenting is common. In this observational study, there was no difference in mortality or myocardial infarction at 6 months; however, larger trials are needed to assert any firm recommendations.

Introduction

Dual antiplatelet therapy with aspirin and a thienopyridine following coronary stenting is superior to aspirin alone in reducing cardiovascular events in both the acute coronary syndrome (ACS) and the elective setting;1,2 however, dual antiplatelet therapy is associated with an increased risk of bleeding.3 Dual antiplatelet therapy tends to be prescribed long term, and the duration of treatment now often extends to 12 months or longer.2 Dual antiplatelet therapy has also been proven to be superior in terms of safety and efficacy when compared with anticoagulation with warfarin following coronary stenting.46

Identifying the optimal regimen for antiplatelet therapy in patients requiring warfarin following coronary stenting is an area that has been understudied. Small, single-centre studies79 and larger observational studies10 and meta-analyses11 have examined the safety of antiplatelet therapy in combination with warfarin. These studies primarily analysed safety rather than efficacy outcomes and do not address the comparison of single vs. dual antiplatelet in combination with warfarin following coronary stenting in patients with a strong indication for warfarin.

Clinical trials in patients with ACS have supported an early invasive approach in those at high risk of a subsequent coronary event.1214 These patients are triaged to coronary angiography, often leading to percutaneous coronary revascularization. They tend to comprise an elderly population with often substantial vascular, valvular, and conduction system disease. Therefore, a significant proportion of these patients also requires warfarin for various co-morbid conditions (e.g. atrial fibrillation, mechanical valve replacement, deep-vein thrombosis/pulmonary embolus, or large anterior myocardial infarcts).

In patients requiring warfarin, standard practice is to combine both antiplatelet and antithrombotic drugs; however, the use of single or dual antiplatelet in combination with warfarin for this population needs further investigation. The choice of single antiplatelet (aspirin vs. thienopyridine) also needs to be examined. In this study, we attempted to identify factors associated with the use of single or dual antiplatelet therapy in patients who required warfarin following coronary stenting in an unselected population presenting with an ACS. We compared the clinical outcomes of each regimen, including those in patients prescribed either aspirin or a thienopyridine (either clopidogrel or ticlopidine) in combination with warfarin.

Methods

Full details of the GRACE methods have been published.1517 GRACE is designed to reflect an unbiased population of patients with ACS, irrespective of geographical region. A total of 113 hospitals located in 14 countries in North and South America, Europe, Australia, and New Zealand have contributed data to this observational study.

Patients entered in the registry had to be at least 18 years old and alive at the time of hospital presentation, be admitted for ACS as a presumptive diagnosis (i.e. have symptoms consistent with acute ischaemia), and should have at least one of the following: electrocardiographic changes consistent with ACS, serial increases in serum biochemical markers of cardiac necrosis, and/or documentation of coronary artery disease. The qualifying ACS must not have been precipitated by significant non-cardiovascular co-morbidity (e.g. trauma or surgery). Approximately 6 months after hospital discharge, patients were followed-up to ascertain the occurrence of selected long-term study outcomes. Where required, study investigators received approval from their local hospital ethics or institutional review board.

The study aimed to enrol an unbiased population and sites were encouraged to recruit the first 10 to 20 consecutive eligible patients each month. Data were collected by trained coordinators using standardized case report forms. Demographic characteristics, medical history, presenting symptoms, duration of pre-hospital delay, biochemical and electrocardiographic findings, treatment practices, and a variety of hospital outcome data were collected. Standardized definitions of all patient-related variables, clinical diagnoses, and hospital complications and outcomes were used.15

We analysed data from 800 patients (entered between April 1999 and September 2006) who underwent coronary stenting following presentation with an ACS and who were subsequently discharged on warfarin and dual antiplatelet therapy or warfarin and single antiplatelet therapy. Baseline demographics, geographical differences, hospital interventions, hospital events, and 6-month outcomes were analysed.

Statistical analysis

Data are expressed as percentages, or as medians and interquartile ranges, as appropriate. Differences between warfarin/single and warfarin/dual antiplatelet groups were evaluated by χ2 or Fisher's exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. Two-sided univariate analyses were performed.

Results

Of the patients in this cohort, 580 (73%) received warfarin and dual antiplatelet therapy and 220 (28%) warfarin and single antiplatelet therapy. The use of single antiplatelet therapy was more frequent outside the USA (35 vs. 17%, P < 0.001; Figure 1). Within the single antiplatelet group, 107 patients received aspirin and 113 a thienopyridine. The use of a thienopyridine (clopidogrel or ticlopidine) in combination with warfarin was most common in Australia/New Zealand when compared with the rest of the world (97 vs. 43%, P < 0.001).

Figure 1

Geographical variation in combination regimen at discharge. Four-way P-value less than 0.001.

Figure 1

Geographical variation in combination regimen at discharge. Four-way P-value less than 0.001.

The baseline characteristics of patients receiving warfarin/dual antiplatelet therapy and warfarin/single antiplatelet therapy are shown in Table 1. Patients receiving single antiplatelet therapy were older and more likely to have a history of prior angina.

Table 1

Patients' demographic and baseline characteristics and clinical presentation according to antiplatelet therapy at discharge

 Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 580) Warfarin/single antiplatelet (n = 220) P-value 
Demographics n (%)    
 Median age, years (IQR) 55–75 (64) 58–77 (66) 0.02 
 Men 432 (74) 129 (70) 0.23 
 Prior angina 227 (39) 105 (48) 0.02 
 Prior myocardial infarction 59 (27) 58 (26) 0.78 
 Prior heart failure 60 (10) 29 (13) 0.26 
 Prior coronary intervention 108 (19) 34 (16) 0.32 
 Prior CABG surgery 86 (15) 27 (12) 0.36 
 Prosthetic valve 20/356 (5.6) 5/124 (4.0) 0.49 
 Smoker (current or former) 336 (58) 116 (53) 0.16 
 Diabetes 130 (23) 49 (23) 0.99 
 Hypertension 331 (57) 129 (59) 0.73 
 Hyperlipidaemia 301 (52) 100 (47) 0.16 
 Atrial fibrillation 130 (22) 52 (24) 0.67 
 Major surgery/trauma 26 (4.5) 13 (5.9) 0.41 
Clinical presentation n (%)    
 Cardiac arrest 15 (2.6) 8 (3.7) 0.41 
 Killip class I 452 (80) 180 (84) 0.34 
 Killip class II–IV 114 (19) 35 (16)  
 STEMI 355 (61) 134 (61) 0.97 
 Non-STEMI 134 (23) 50 (23)  
 Unstable angina 91 (16) 36 (16)  
 Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 580) Warfarin/single antiplatelet (n = 220) P-value 
Demographics n (%)    
 Median age, years (IQR) 55–75 (64) 58–77 (66) 0.02 
 Men 432 (74) 129 (70) 0.23 
 Prior angina 227 (39) 105 (48) 0.02 
 Prior myocardial infarction 59 (27) 58 (26) 0.78 
 Prior heart failure 60 (10) 29 (13) 0.26 
 Prior coronary intervention 108 (19) 34 (16) 0.32 
 Prior CABG surgery 86 (15) 27 (12) 0.36 
 Prosthetic valve 20/356 (5.6) 5/124 (4.0) 0.49 
 Smoker (current or former) 336 (58) 116 (53) 0.16 
 Diabetes 130 (23) 49 (23) 0.99 
 Hypertension 331 (57) 129 (59) 0.73 
 Hyperlipidaemia 301 (52) 100 (47) 0.16 
 Atrial fibrillation 130 (22) 52 (24) 0.67 
 Major surgery/trauma 26 (4.5) 13 (5.9) 0.41 
Clinical presentation n (%)    
 Cardiac arrest 15 (2.6) 8 (3.7) 0.41 
 Killip class I 452 (80) 180 (84) 0.34 
 Killip class II–IV 114 (19) 35 (16)  
 STEMI 355 (61) 134 (61) 0.97 
 Non-STEMI 134 (23) 50 (23)  
 Unstable angina 91 (16) 36 (16)  

CABG, coronary artery bypass grafting; IQR, interquartile range; STEMI, ST-segment elevation myocardial infarction.

A total of 226 (28%) patients were taking warfarin before presentation; 182 had a history of atrial fibrillation. The specific indications for warfarin therapy during admission were not collected on the GRACE case report form. However, of the 574 (72%) patients not on warfarin therapy before hospitalization, the assumed indications for in-hospital initiation of long-term anticoagulation are indicated in Table 2 and included new onset atrial fibrillation, anterior myocardial infarcts, valve surgery, and venous thrombo-embolism. In total, 299 (37%) of the cohort had either a history of atrial fibrillation or developed atrial fibrillation during admission.

Table 2

Assumed indications for warfarin therapy

Indication n (%) Prior warfarin (n = 226) New warfarin therapy (n = 574) 
Atrial fibrillation or flutter 182 (80) 137 (24) 
STEMI 343 (60) 
Prosthetic valve surgery 20 (9) 
Venous thrombo-embolism 20 (9) 12 (2) 
Unidentified 4 (2) 82 (14) 
Indication n (%) Prior warfarin (n = 226) New warfarin therapy (n = 574) 
Atrial fibrillation or flutter 182 (80) 137 (24) 
STEMI 343 (60) 
Prosthetic valve surgery 20 (9) 
Venous thrombo-embolism 20 (9) 12 (2) 
Unidentified 4 (2) 82 (14) 

STEMI, ST-segment elevation myocardial infarction.

Patients discharged on warfarin/single antiplatelet therapy were less likely than those given warfarin/dual therapy to receive unfractionated heparin, glycoprotein IIb/IIIa antagonists, beta-blockers, or statins while in hospital; the use of low-molecular-weight heparin did not differ between groups. They were also less likely to have received a drug-eluting stent, although 28 (22%) of the patients who received a drug-eluting stent were discharged on single antiplatelet therapy (Table 3).

Table 3

Prior medications, and hospital treatment and interventions, according to combination regimen

 Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 580) Warfarin/single antiplatelet (n = 220) P-value 
Prior medications n (%)    
 Aspirin 179 (31) 61 (28) 0.39 
 Warfarin 167 (29) 59 (27) 0.57 
 Thienopyridines 31 (5) 15 (7) 0.44 
Hospital treatment and interventions n (%)    
 Aspirin 574 (99) 198 (90) <0.001 
 Thienopyridines 408 (95) 108 (68) <0.001 
 Unfractionated heparin 433 (75) 136 (62) <0.001 
 LMWH 307 (53) 118 (54) 0.87 
 GP IIb/IIIa inhibitors 356 (61) 108 (49) 0.003 
 Beta-blockers 532 (92) 187 (85) 0.008 
 ACE-inhibitors 479 (83) 174 (79) 0.22 
 Fibrinolytic drug 102 (18) 33 (15) 0.37 
 Pulmonary artery catheter 34 (6) 22 (10) 0.04 
 Drug-eluting stent 102/358 (28) 28/124 (22)a  
 Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 580) Warfarin/single antiplatelet (n = 220) P-value 
Prior medications n (%)    
 Aspirin 179 (31) 61 (28) 0.39 
 Warfarin 167 (29) 59 (27) 0.57 
 Thienopyridines 31 (5) 15 (7) 0.44 
Hospital treatment and interventions n (%)    
 Aspirin 574 (99) 198 (90) <0.001 
 Thienopyridines 408 (95) 108 (68) <0.001 
 Unfractionated heparin 433 (75) 136 (62) <0.001 
 LMWH 307 (53) 118 (54) 0.87 
 GP IIb/IIIa inhibitors 356 (61) 108 (49) 0.003 
 Beta-blockers 532 (92) 187 (85) 0.008 
 ACE-inhibitors 479 (83) 174 (79) 0.22 
 Fibrinolytic drug 102 (18) 33 (15) 0.37 
 Pulmonary artery catheter 34 (6) 22 (10) 0.04 
 Drug-eluting stent 102/358 (28) 28/124 (22)a  

ACE, angiotensin-converting enzyme; GP, glycoprotein; LMWH, low-molecular-weight heparin.

aData on the type of stent (drug-eluting vs. bare-metal stent) were collected from 482 patients.

Patients discharged on warfarin/single antiplatelet therapy were more likely to have experienced atrial fibrillation or congestive heart failure during their admission, but there were no differences in the incidences of myocardial infarction, recurrent ischaemia, cardiogenic shock, or major bleeding (Table 4).

Table 4

Hospital events according to combination regimen

Event n (%) Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 580) Warfarin/single antiplatelet (n = 220) P-value 
Cardiogenic shock 33 (5.7) 17 (7.7) 0.27 
Myocardial infarction > 24 h/re-infarction 48 (8.3) 26 (12) 0.12 
Recurrent ischaemic symptoms 164 (28) 57 (26) 0.49 
Atrial fibrillation/flutter 127 (22) 66 (30) 0.01 
Stroke 6 (1.0) 7 (3.2) 0.05 
Congestive heart failure 128 (22) 65 (30) 0.02 
Major bleeding 34 (5.9) 10 (4.6) 0.46 
Event n (%) Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 580) Warfarin/single antiplatelet (n = 220) P-value 
Cardiogenic shock 33 (5.7) 17 (7.7) 0.27 
Myocardial infarction > 24 h/re-infarction 48 (8.3) 26 (12) 0.12 
Recurrent ischaemic symptoms 164 (28) 57 (26) 0.49 
Atrial fibrillation/flutter 127 (22) 66 (30) 0.01 
Stroke 6 (1.0) 7 (3.2) 0.05 
Congestive heart failure 128 (22) 65 (30) 0.02 
Major bleeding 34 (5.9) 10 (4.6) 0.46 

The use of antiplatelet therapy at 6 months differed significantly between the two groups with those discharged on single antiplatelet being more likely to be on no antiplatelet at 6 months (Table 5).

Table 5

Antiplatelet use at 6-month follow-up (671 of 800 patients had completed medication at 6-month follow-up)

Antiplatelet use n (%) Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 479) Warfarin/single antiplatelet (n = 192) P-value 
Dual antiplatelet at follow-up 116 (24) 24 (12)  
Single antiplatelet at follow-up 235 (49) 94 (49) <0.001 
None at follow-up 128 (27) 74 (39)  
Antiplatelet use n (%) Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 479) Warfarin/single antiplatelet (n = 192) P-value 
Dual antiplatelet at follow-up 116 (24) 24 (12)  
Single antiplatelet at follow-up 235 (49) 94 (49) <0.001 
None at follow-up 128 (27) 74 (39)  

There was no difference in rates of 6-month mortality or myocardial infarction between the groups. The frequency of 6-month stroke was lower in the warfarin/dual antiplatelet group (0.7 vs. 3.4%, P = 0.02), although the number of events was small (Table 6).

Table 6

Six-month outcomes in the overall cohort, in patients with atrial fibrillation, and according to use of aspirin or thienopyridine

 Warfarin/dual antiplatelet Warfarin/single antiplatelet P-value 
Overall cohort n (%)    
 Death 23/453 (5.1) 12/184 (6.5) 0.47 
 Stroke 3/426 (0.7) 6/179 (3.4) 0.02a 
 Unscheduled PCI 45/424 (10.6) 22/176 (12.5) 0.50 
 Myocardial infarction 13/391 (3.3) 7/154 (4.5) 0.49 
Cohort with atrial fibrillation n (%)    
 Death 9/156 (5.8) 7/75 (9.3) 0.32 
 Stroke 0/148 (0) 1/71 (1.4) 0.32 
 Unscheduled PCI 13/148 (8.8) 7/68 (10.3) 0.72 
 Myocardial infarction 3/138 (2.2) 2/61 (3.3) 0.64 
Aspirin vs. thienopyridine n (%) Warfarin/aspirin (n = 107) Warfarin/thienopyridine (n = 113)  
 Death 7/91 (7.7) 5/93 (5.4) 0.52 
 Stroke 4/88 (4.5) 2/91 (2.2) 0.44 
 Myocardial infarction 3/75 (4.0) 4/79 (5.1) 1.00 
 Unscheduled PCI 15/87 (17.2) 7/89 (7.9) 0.06 
 Warfarin/dual antiplatelet Warfarin/single antiplatelet P-value 
Overall cohort n (%)    
 Death 23/453 (5.1) 12/184 (6.5) 0.47 
 Stroke 3/426 (0.7) 6/179 (3.4) 0.02a 
 Unscheduled PCI 45/424 (10.6) 22/176 (12.5) 0.50 
 Myocardial infarction 13/391 (3.3) 7/154 (4.5) 0.49 
Cohort with atrial fibrillation n (%)    
 Death 9/156 (5.8) 7/75 (9.3) 0.32 
 Stroke 0/148 (0) 1/71 (1.4) 0.32 
 Unscheduled PCI 13/148 (8.8) 7/68 (10.3) 0.72 
 Myocardial infarction 3/138 (2.2) 2/61 (3.3) 0.64 
Aspirin vs. thienopyridine n (%) Warfarin/aspirin (n = 107) Warfarin/thienopyridine (n = 113)  
 Death 7/91 (7.7) 5/93 (5.4) 0.52 
 Stroke 4/88 (4.5) 2/91 (2.2) 0.44 
 Myocardial infarction 3/75 (4.0) 4/79 (5.1) 1.00 
 Unscheduled PCI 15/87 (17.2) 7/89 (7.9) 0.06 

PCI, percutaneous coronary intervention.

aFisher's exact test.

Among patients with atrial fibrillation, there were no significant differences in 6-month outcomes between the single and dual antiplatelet groups (Table 6). Of the patients discharged on warfarin/single antiplatelet therapy, 107 (49%) received aspirin and 113 (51%) a thienopyridine. The aspirin/warfarin combination was associated with similar 6-month outcomes to that of thienopyridine/warfarin (Table 6).

Of the 130 patients discharged on warfarin following placement of a drug-eluting stent, antiplatelet therapy was more likely to be continued for 6 months. There were no differences in outcomes between patients discharged on single vs. dual antiplatelet therapy (Table 7).

Table 7

Antiplatelet use at 6-months, and 6-month outcomes, among the cohort who received a drug-eluting stent

 Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 75) Warfarin/single antiplatelet (n = 25) P-value 
Antiplatelet use at follow-up n (%)a    
 Dual antiplatelet 44 (59) 8 (32) 0.02 
 Single antiplatelet 14 (19) 11 (44)  
 No antiplatelet 17 (22) 6 (24)  
Six-month outcomes n (%) (n = 102) (n = 28)  
 Death 5/67 (7.5) 3/25 (12) 0.67 
 Stroke 0/62 (0) 0/21 (0)  
 Unscheduled PCI 14/62 (23) 3/22 (14) 0.54 
 Myocardial infarction 2/63 (3.2) 0/23 (0) 1.0 
 Combination discharge therapy 
 Warfarin/dual antiplatelet (n = 75) Warfarin/single antiplatelet (n = 25) P-value 
Antiplatelet use at follow-up n (%)a    
 Dual antiplatelet 44 (59) 8 (32) 0.02 
 Single antiplatelet 14 (19) 11 (44)  
 No antiplatelet 17 (22) 6 (24)  
Six-month outcomes n (%) (n = 102) (n = 28)  
 Death 5/67 (7.5) 3/25 (12) 0.67 
 Stroke 0/62 (0) 0/21 (0)  
 Unscheduled PCI 14/62 (23) 3/22 (14) 0.54 
 Myocardial infarction 2/63 (3.2) 0/23 (0) 1.0 

PCI, percutaneous coronary intervention.

aInformation on antiplatelet therapy at 6-month follow-up was available in only 100 of the 130 patients.

Discussion

The aim of this study is to review an area of clinical practice that is commonly encountered but grossly understudied. Our real-world data suggest that, in patients with an ACS who are discharged on antiplatelet therapy and warfarin following coronary stenting, the use of single vs. dual antiplatelet therapy leads to similar 6-month efficacy outcomes. A dual antiplatelet regimen of aspirin and a thienopyridine is the optimal treatment strategy following coronary stenting based on superior safety and efficacy when compared with aspirin alone or aspirin in combination with warfarin.5,6 In the Stent Anticoagulation Restenosis Study (STARS),5 three antiplatelet/antithrombotic regimens (aspirin alone, aspirin/ticlopidine, and aspirin/warfarin) were compared in an elective coronary stenting cohort. The Full Anticoagulation vs. Aspirin and Ticlopidine (FANTASTIC) trial6 compared a regimen of dual antiplatelet therapy vs. aspirin/warfarin in both elective and unplanned (to salvage failed angioplasty or optimize the results of balloon angioplasty) cohorts. Both randomized trials demonstrated a significant benefit in terms of safety and efficacy in favour of dual antiplatelet therapy alone. The STARS trial5 indicated that most of the benefits were from reductions in subacute stent thrombosis in the dual antiplatelet group. Both trials occurred during the early bare-metal stent era and involved a cohort of patients primarily undergoing elective procedures.

No large trial has addressed the population of patients with a strong indication for warfarin or presenting with an ACS. Our registry analysis, with the largest sample size in the current literature, reflects real-world practice in a real-world population, investigating a common clinical problem that clinicians face on a daily basis. The fine balance between safety and efficacy in this cohort needs careful consideration. Arab et al.18 performed a systematic review of the literature on the optimal antiplatelet/antithrombotic regimen in those requiring long-term anticoagulation who undergo coronary stenting and found no significant studies or randomized trials addressing this issue.

Our results demonstrate varying practices with significant differences between the USA and other parts of the world such as Europe, Australasia, and Argentina/Brazil. The type of single antiplatelet chosen in combination with warfarin also varied significantly, with Australasia almost exclusively using a thienopyridine in combination with warfarin. The regional variations may reflect differences in healthcare systems as well as economic and social influences.

Our results suggest that, in combination with warfarin, the use of single antiplatelet therapy may be a safe treatment option in selected patients, with similar 6-month efficacy outcomes when compared with dual antiplatelet therapy. There was no difference in major bleeding in-hospital between the groups; however, 6-month bleeding outcomes were not captured. There was a trend towards an increase in events in patients receiving single antiplatelet therapy at 6 months; however, the only significant difference in favour of dual antiplatelet therapy involved stroke at 6 months (0.7 vs. 3.4%, P = 0.02). This result should be interpreted with caution as the event rates were extremely small (3 vs. 6). The type of stroke (ischaemic vs. haemorrhagic) was not identified in this registry.

The use of either aspirin or a thienopyridine as the single antiplatelet in combination with warfarin also proved to be equivalent in terms of efficacy. Thienopyridine use was significantly reduced in patients with a history of major surgery or trauma (1.8 vs. 10.3%, P < 0.01). The incidence of subacute and late stent thrombosis was not collected, but it is a rare event that would be captured in the 6-month myocardial infarction and mortality outcome data. Most patients had ceased dual antiplatelet therapy at 6 months (reflecting a cohort receiving mainly bare-metal stents). There was a significant difference between the two groups, with those discharged on single antiplatelet therapy more likely to be on no antiplatelet at 6 months (39 vs. 27%, P < 0.001) (Table 6). Despite this, there was no excess in events. In the single antiplatelet group, there were only seven myocardial infarcts at 6 months when compared with 13 in the dual antiplatelet group (4.5 vs. 3.3%, P = 0.49) and 12 deaths compared with 23 (6.5 vs. 5.1%, P = 0.47).

The perceived increased risk of late stent thrombosis in those receiving drug-eluting stents has resulted in a recommendation of prolonged dual antiplatelet therapy in these patients.19,20 An alternative strategy of bare-metal stenting in those requiring warfarin may avoid the need for long-term dual antiplatelet therapy. In this registry, which has been accruing data since 1999, only a minority of patients received drug-eluting stents. Among the warfarin/dual antiplatelet group, 102 of 358 (28%) patients received drug-eluting stents when compared with 28 of 124 (22%) in the warfarin/single antiplatelet. Analysis of this small cohort of patients revealed no difference in 6-month outcomes between the two groups (Table 7). However, as this registry is ongoing, we will have the opportunity to describe practice and associated outcomes among these patients in the future.

The optimal antiplatelet strategy for stented patients requiring warfarin is an unresolved clinical question. Practice at present is guided by the clinician's discretion, with no significant evidence to date to validate any one regimen. Although ours is an observational study with a limited number of events, the data suggest the use of single antiplatelet therapy combined with warfarin in patients with an indication for long-term anticoagulation to be an acceptable management option. There remains a pressing need for further investigation into this important area.

Strengths and limitations

GRACE is a large, ongoing, multinational registry. The strength of this study stems from its assessment of a real-world population. It highlights the varying practices from region to region, reflecting both economical and social differences but also the fact that there is no clear evidence or guidelines in this cohort of patients. The GRACE registry is the largest multinational registry to include the spectrum of ACS patients and follows standardized criteria for defining ACS and hospital outcomes allowing an accurate and reliable data set. The limitations of our registry are similar to those of any observational study. The lack of substantial numbers (even though the study is significantly larger than any previous study in this area) also makes it difficult to draw firm conclusions. The study does not capture data on long-term bleeding outcomes, which is important to evaluate the ongoing safety of each regimen.

Acknowledgements

The authors thank the physicians and nurses participating in GRACE. Further information about the project, along with the complete list of participants, can be found at www.outcomes.org/grace. The authors are grateful to Sophie Rushton-Smith, who provided editorial support and was funded by sanofi-aventis. GRACE is supported by an unrestricted educational grant from sanofi-aventis, Paris, France, to the Center for Outcomes Research, University of Massachusetts Medical School, Worcester, MA, USA. Sanofi-aventis had no involvement in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest: The following authors have no conflict of interest: M.C.N., Y.L.L., A.W., J.L., and J.A. The following authors have conflict of interest: G.A., consultant and/or speaker for sanofi-aventis; S.G.G., research grant support and/or consultant and/or speaker for sanofi-aventis and Bristol-Myers Squibb; A.B., consultant and/or speaker for sanofi-aventis; D.C.G., consultant and/or speaker for sanofi-aventis; D.B., consultant and/or speaker for sanofi-aventis; S.R.-S., funded by sanofi-aventis.

References

1
Mehta
SR
Yusuf
S
Peters
RJ
Bertrand
ME
Lewis
BS
Natarajan
MK
Malmberg
K
Rupprecht
H
Zhao
F
Chrolavicius
S
Copland
I
Fox
KA
Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study
Lancet
 
2001
358
527
533
2
Steinhubl
SR
Berger
PB
Mann
JT
III
Fry
ET
DeLago
A
Wilmer
C
Topol
EJ
Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial
JAMA
 
2002
288
2411
2420
3
Yusuf
S
Zhao
F
Mehta
SR
Chrolavicius
S
Tognoni
G
Fox
KK
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation
N Engl J Med
 
2001
345
494
502
4
Schomig
A
Neumann
FJ
Kastrati
A
Schuhlen
H
Blasini
R
Hadamitzky
M
Walter
H
Zitzmann-Roth
EM
Richardt
G
Alt
E
Schmitt
C
Ulm
K
A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents
N Engl J Med
 
1996
334
1084
1089
5
Leon
MB
Baim
DS
Popma
JJ
Gordon
PC
Cutlip
DE
Ho
KK
Giambartolomei
A
Diver
DJ
Lasorda
DM
Williams
DO
Pocock
SJ
Kuntz
RE
A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting
N Engl J Med
 
1998
339
1665
1671
6
Bertrand
ME
Legrand
V
Boland
J
Fleck
E
Bonnier
J
Emmanuelson
H
Vrolix
M
Missault
L
Chierchia
S
Casaccia
M
Niccoli
L
Oto
A
White
C
Webb-Peploe
M
Van Belle
E
McFadden
EP
Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The Full Anticoagulation versus Aspirin and Ticlopidine (FANTASTIC) study
Circulation
 
1998
98
1597
1603
7
Orford
JL
Fasseas
P
Melby
S
Burger
K
Steinhubl
SR
Holmes
DR
Berger
PB
Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation
Am Heart J
 
2004
147
463
467
8
Konstantino
Y
Iakobishvili
Z
Porter
A
Sandach
A
Zahger
D
Hod
H
Hammerman
H
Gottlieb
S
Behar
S
Hasdai
D
Aspirin, warfarin and a thienopyridine for acute coronary syndromes
Cardiology
 
2006
105
80
85
9
Khurram
Z
Chou
E
Minutello
R
Bergman
G
Parikh
M
Naidu
S
Wong
SC
Hong
MK
Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding
J Invasive Cardiol
 
2006
18
162
164
10
Buresly
K
Eisenberg
MJ
Zhang
X
Pilote
L
Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction
Arch Intern Med
 
2005
165
2430
2431
11
Andreotti
F
Testa
L
Biondi-Zoccai
GG
Crea
F
Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients
Eur Heart J
 
2006
27
519
526
12
Fragmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators
Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study
Lancet
 
1999
354
701
707
13
Cannon
CP
Weintraub
WS
Demopoulos
LA
Vicari
R
Frey
MJ
Lakkis
N
Neumann
FJ
Robertson
DH
DeLucca
PT
DiBattiste
PM
Gibson
CM
Braunwald
E
Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban
N Engl J Med
 
2001
344
1879
1887
14
Fox
KA
Poole-Wilson
PA
Henderson
RA
Clayton
TC
Chamberlain
DA
Shaw
TR
Wheatley
DJ
Pocock
SJ
Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina
Lancet
 
2002
360
743
751
15
The GRACE Investigators
Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes
Am Heart J
 
2001
141
190
199
16
Steg
PG
Goldberg
RJ
Gore
JM
Fox
KA
Eagle
KA
Flather
MD
Sadiq
I
Kasper
R
Rushton-Mellor
SK
Anderson
FA
Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE)
Am J Cardiol
 
2002
90
358
363
17
Eagle
KA
Lim
MJ
Dabbous
OH
Pieper
KS
Goldberg
RJ
Van de Werf
F
Goodman
SG
Granger
CB
Steg
PG
Gore
JM
Budaj
A
Avezum
A
Flather
MD
Fox
KA
A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry
J Am Med Assoc
 
2004
291
2727
2733
18
Arab
D
Lewis
B
Cho
L
Steen
L
Joyal
D
Leya
F
Antiplatelet therapy in anticoagulated patients requiring coronary intervention
J Invasive Cardiol
 
2005
17
549
554
19
US Food and Drug Administration(www.fda.gov)—Update to FDA Statement on Coronary Drug-Eluting Stents
4 January 2007
20
Grines
CL
Bonow
RO
Casey
DE
Gardner
TJ
Lockhart
PB
Moliterno
DJ
O'Gara
P
Whitlow
P
Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, With Representation From the American College of Physicians
Circulation
 
2007
Feb
115
813
818

Author notes

Preliminary results of this study were presented as an Abstract at the 2006 Annual Scientific Session of the American College of Cardiology, Atlanta, GA, USA and were published in J Am Coll Cardiol 2006;47:252A.

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