- Email: [email protected]
Safety of Diagnostic Coronary Angiography During Uninterrupted Therapeutic Warfarin Treatment
Safety of Diagnostic Coronary Angiography During Uninterrupted Therapeutic Warfarin Treatment Antti-Pekka Annala, MDa, Pasi P. Karjalainen, MD, PhDa, Pekka Porela, MD, PhDb, Kai Nyman, MDc, Antti Ylitalo, MD, PhDa, and K.E. Juhani Airaksinen, MD, PhDb,* Long-term warfarin therapy is assumed to increase bleeding and access site complications after coronary angiography and it is often recommended to postpone invasive procedures to reach international normalized ratio (INR) levels <1.8. To assess the safety and feasibility of diagnostic coronary angiography during uninterrupted warfarin therapy, we retrospectively analyzed all consecutive patients (n ⴝ 258) on warfarin therapy referred for diagnostic coronary angiography in 2 centers with long experience in uninterrupted warfarin therapy during coronary angiography and in 1 center with a policy of preprocedural warfarin pause. An age- and gender-matched control group (n ⴝ 258) with similar disease presentation (unstable or stable symptoms) was collected from each center. Radial access was used in 56% of patients in the warfarin group and in 60% of controls (p ⴝ 0.21). There was no difference in access site and bleeding complications (1.9% vs 1.6%) or major adverse cardiovascular and cerebrovascular events (0.4% vs 0.8%) between the warfarin group and their controls. Warfarin was interrupted in 80 patients (31%), and bridging therapy was used in 24 of these patients (30%). INR levels were higher in the uninterrupted warfarin group (2.3 vs 1.9, p <0.001), but the incidence of access site complications was not higher (1.7%) than in patients (n ⴝ 80) with a warfarin pause (2.5%) or in patients with pause and bridging therapy (8.3%). Need for blood transfusions (n ⴝ 2) occurred only in patients with bridging therapy. Access site complications were more common in the 22 patients with supratherapeutic anticoagulation (INR >3) than in patients with therapeutic periprocedural INR (9.1% vs 1.5%, p <0.05). In conclusion, a simple strategy of performing coronary angiography during uninterrupted therapeutic warfarin anticoagulation is a tempting alternative to bridging therapy and is likely to lead to considerable cost savings. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:386 –390)
The management of patients with long-term warfarin therapy referred for coronary angiography may be problematic. The standard recommendation for these patients is to discontinue warfarin before coronary angiography because uninterrupted warfarin therapy is assumed to increase bleeding and access site complications. A periprocedural international normalized ratio (INR) level ⬍1.8 is most often recommended.1,2 Unfractionated or low-molecular-weight heparins are often administered as a bridging therapy during the invasive procedure until INR has been restored to therapeutic levels.3 Bridging therapy with heparins may prolong hospitalization and increase the risk of thromboembolism associated with subtherapeutic anticoagulation.4 – 6 Not surprisingly, the safety of bridging therapy has been recently questioned.7 There are only a few cohort studies on different management strategies of this patient group during coronary angiography, and they are based on small and heterogenous a
Department of Cardiology, Satakunta Central Hospital, Pori, bDepartment of Medicine, Turku University Hospital, Turku, and cDepartment of Medicine, Jyväskylä Central Hospital, Jyväskylä, Finland. Manuscript received February 7, 2008; revised manuscript received and accepted April 2, 2008. This study was supported by grants from the Finnish Foundation for Cardiovascular Research, Helsinki, Finland. *Corresponding author: Tel: 358-2-313-1005; fax: 358-2-313-2030. E-mail address: [email protected] (K.E.J. Airaksinen). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.04.003
patient populations. In the present study, we evaluated the safety of coronary angiography in patients with long-term warfarin therapy in 2 Finnish hospitals with long experience in performing cardiac procedures during uninterrupted therapeutic warfarin therapy and in 1 hospital with a main strategy to interrupt warfarin therapy and add bridging therapy in patients at increased risk of thromboembolism. Our aim was to assess the safety of a simple and time-saving strategy to perform coronary angiography during therapeutic warfarin therapy with no bridging therapy or interruption of warfarin. Methods The present study is based on computerized databases in 3 hospitals and is part of a research program in progress to assess thrombotic and bleeding complications of cardiac procedures in western Finland.8,9 We analyzed retrospectively all consecutive patients on long-term warfarin therapy (n ⫽ 258) referred for coronary angiography from 2003 through 2005. In addition, we collected an age- (⫾5 years) and gender-matched control group with similar indication (acute/elective) for coronary angiography in each hospital during the same study period. Matching was perfect except for 2 cases with a gender mismatch and 12 cases with an indication mismatch. Coronary angiography was performed according to standard techniques using a radial or femoral www.AJConline.org
4 (2%)
1.0
1 (0.4%) 1 (0.4%)
2 (1%) 1 (0.4%)
1.0 1.0
1 (0.4%) 2 (1%)
1 (0.4%) 0
1.0 0.50
approach.2 Immediate sheath (5Fr to 6Fr) removal was the policy in all 3 hospitals. Medical records of all valid patients were reviewed to evaluate rates of access site complications, major bleeding, and major adverse cardiovascular and cerebrovascular events (MACCEs) during hospitalization. We also gathered data on length of hospitalization and patient baseline characteristics including indications for warfarin therapy and
Compression device Femoral Elective Atrial fibrillation No
* Low-molecular-weight heparin was started before angiography as bridging therapy. Unfractionated heparin bolus 2,500 IU was administered during angiography.
5 (2%)
†
Patients with access site complications Pseudoaneurysm Access site bleeding delaying discharge Need for corrective surgery Transfusion of blood products
Complication
Warfarin Group Control Group p (n ⫽ 258) (n ⫽ 258) Value
Table 3 Access site and bleeding complications in the warfarin group
Table 2 Access site and bleeding complications in patients with warfarin treatment and in the control group
INR
Warfarin Pause
* Angio-Seal (St. Jude Medical, St. Paul, Minnesota).
1.7
NS
Femoral dissection, surgical closure
48 (19%)
77/M
49 (19%)
5
NS NS
Manual compression
156 (60%) 49 (19%)
Radial
144 (56%) 63 (24%)
Unstable angina
NS
Aspirin, clopidogrel, low-molecular-weight heparin None
6 (2%)
Deep vein thrombosis
2 (1%)
Yes
⬍0.01
2.8
8 (3%)
73/M
0
4
⬍0.001 ⬍0.001 ⬍0.001
Compression device
227 (88%) 68 (26%) 76 (29%)
Femoral
55 (21%) 17 (7%) 41 (16%)
Atrial fibrillation
NS
No
21 (8%)
3.3
16 (6%)
71/M
NS
3
19 (7%)
Femoral Femoral
25 (10%)
Elective Non–ST-elevation myocardial infarction, pulmonary edema Elective
NS 0.01
None Aspirin, low-molecular-weight heparin,* unfractionated heparin† None
200 (78%) 18 (7%)
Atrial fibrillation Mechanical heart valve
212 (82%) 5 (2%)
No Yes
NS
2.1 4.2
21 (8%)
Pseudoaneurysm Groin hematoma, transfusion of blood, died Prolonged hospitalization due to groin hematoma Decrease in hemoglobin, transfusion of blood
29 (11%)
59/F 67/M
NS NS ⬍0.001 ⬍0.001 NS NS
387
1 2
72 (28%) 157 (61%) 32 (12%) 12 (5%) 74 (29%) 22 (9%)
Access Site
59 (23%) 146 (57%) 93 (36%) 40 (16%) 69 (27%) 23 (9%)
Indication for Angiography
NS NS NS ⬍0.001
Other Antithrombotic Treatments
176 (68%) 66 ⫾ 10 58 (22%) 177 (67%)
Indication for Warfarin
177 (69%) 66 ⫾ 10 53 (21%) 129 (50%)
Age/Sex
Men Age (yrs) Diabetes mellitus Treatment for hypercholesterolemia Current or ex-smoker Hypertension Heart failure Stroke Myocardial infarction Percutaneous coronary intervention Coronary bypass grafting Indication for angiography Stable angina pectoris ST-elevation myocardial infarction Non–ST-elevation myocardial infarction Unstable angina pectoris Antithrombotic medications Aspirin Clopidogrel Low-molecular-weight heparin Glycoprotein IIb/IIIa inhibitor Previous thrombolysis Vascular access Radial access Closure device for femoral approach* Compression device for femoral approach
p Value
Patient No.
Warfarin Group Control Group (n ⫽ 258) (n ⫽ 258)
Vascular Hemostasis
Table 1 Baseline and procedural characteristics in patients with warfarin treatment and their controls
Compression device Closure device
Coronary Artery Disease/Coronary Angiography During Warfarin Anticoagulation
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periprocedural antithrombotic therapy. The CHADS2 score quantifying the annual stroke risk for patients who have nonvalvular atrial fibrillation was also recorded.10 Vascular access site complications included pseudoaneurysm, arteriovenous fistula, retroperitoneal hemorrhage, need for corrective surgery, need for transfusions, and prolonged hospitalization due to hematoma. Major bleeding was defined as a decrease in blood hemoglobin level of ⬎4.0 g/dl, need for transfusion of ⱖ2 U of blood, need for corrective surgery, occurrence of an intracranial or retroperitoneal hemorrhage, or any combination of these events. A MACCE was defined as the occurrence of death, myocardial infarction, and/or stroke during hospitalization. Myocardial infarction was diagnosed if any increase in a myocardial injury marker level (troponin I or T) was detected with the symptoms suggestive of acute myocardial ischemia. For the diagnosis of myocardial reinfarction a new increase ⬎50% of baseline injury marker level was demanded. All outcome events were recorded during the index hospitalization. Continuous variables are presented as mean ⫾ SD and study groups were compared by Student’s unpaired t test. Categorical variables are presented as counts and percentages and were compared by chi-square or Fisher’s exact test. Multivariable logistic regression analyses were performed to identify independent predictors for access site and bleeding complications in the warfarin group. Variables considered for the model included age, gender, disease type (acute vs stable), access site, INR level, use of low-molecular-weight heparin bridging, and warfarin pause. Adequacy of the model was ascertained using the Hosmer-Lemeshow goodness-of-fitness test. Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). A 2-sided p value ⬍0.05 was required for statistical significance. All data were analyzed with SPSS 15.0 for Windows (SPSS, Inc., Chicago, Illinois). This study complied with the Declaration of Helsinki. The study protocol was approved by the ethics committees of the co-ordinating center, Satakunta Central Hospital, and the participating hospitals. Results A total of 258 patients with an indication of long-term warfarin therapy underwent coronary angiography during the study period. Baseline clinical characteristics of the study population and indications for coronary angiography are presented in Table 1. Aspirin, clopidogrel, and lowmolecular-weight heparins were more often used in the control group. Femoral access was used in 44% of patients in the warfarin group and in 40% of controls with no difference in the use of closure devices. Atrial fibrillation was the most common (73%) indication for warfarin treatment followed by previous stroke (7%) and mechanical heart valve (6%). The mean CHADS2 score of patients with atrial fibrillation was 1.55. No significant difference was observed in the incidence of access site complications between the warfarin and control groups (1.9% vs 1.6%, p ⫽ 1.0; Table 2). Major bleeding complications occurred in 3 patients (1.1%) in the warfarin group and in 1 control patient (0.4%; Tables 2 and 3). One patient in the warfarin group and 2 patients in the
control group developed MACCEs during hospitalization, but none of the events were related to coronary angiography. In the warfarin group, MACCEs occurred in the patient presenting with acute myocardial infarction complicated by pulmonary edema (Table 3, patient 2). The patient died 10 days after angiography due to progressive renal and heart failure. In the control group, 1 patient died after coronary artery bypass grafting 6 days after uneventful coronary angiography. The other death occurred in a patient with acute ST-elevation myocardial infarction complicated by cardiogenic shock. No strokes or other thromboembolic events occurred in either group. Coronary angiography was performed during uninterrupted warfarin treatment in 178 patients (69%) and only 17 of them also received a periprocedural low-molecularweight heparin bolus and 5 patients unfractionated heparin bolus mainly due to subtherapeutic periprocedural INR values and/or unstable angina. Coronary angiography was performed after a warfarin pause (mean 2.3 days, range 1 to 30, before angiography) in 80 patients (31%). Bridging therapy with therapeutic low-molecular-weight heparin dosing was used only in 24 patients (30%) during the warfarin pause, but a bolus of unfractionated heparin was given to 73 patients (91%) during the procedure. INR levels were higher in patients with uninterrupted warfarin therapy (2.3 vs 1.9, p ⬍0.001), but the incidence of access site complications was not higher (1.7%) than in patients (n ⫽ 56) with a warfarin pause without bridging (0%) or in patients (n ⫽ 24) with bridging therapy (8.3%). The 2 major bleeding events necessitating blood transfusions occurred during bridging therapy (Table 3). In the warfarin group, the incidence of access site complications was increased in the 22 patients with supratherapeutic (INR ⬎3) compared with patients with therapeutic (INR 2-3) or subtherapautic (INR ⬍2) periprocedural anticoagulation (9.1% vs 1.5% vs 1.0%, respectively, p ⬍0.05). In multivariable analysis, supratherapeutic INR remained the only significant predictor for access site and bleeding complications (OR 5.1, 95% CI 1.1 to 23.8, p ⬍0.05) in the warfarin group. Femoral approach predicted access site complications in the entire study population (OR 11.8, 95% CI 1.5 to 94.9, p ⬍0.01), but not significantly (p ⫽ 0.11) in the warfarin group. Discussion Our results suggest that uninterrupted therapeutic warfarin treatment does not predispose a patient to excessive bleeding or access site complications during coronary angiography. However, supratherapeutic INR levels seem to be associated with access site complications. Of note, the 2 major bleeding events leading to blood transfusions occurred in patients with concomitant low-molecular-weight heparin therapy. It is estimated that 5% of patients undergoing coronary angiography are on long-term warfarin therapy because of underlying long-term medical conditions such as atrial fibrillation or mechanical heart valve.11 In this patient group, it is common consensus to postpone invasive procedures to reach INR levels ⬍1.8.1,2 Bridging therapy is recommended for patients considered to be at increased risk of thromboembolism. Recently, the safety of bridging therapy has been
Coronary Artery Disease/Coronary Angiography During Warfarin Anticoagulation
questioned in patients undergoing noncardiac surgery or pulmonary vein ablation.7,12 In these 2 studies, bridging therapy was associated with an increased incidence of bleeding events. MacDonald et al13 reported that 4.2% of 119 patients developed access site complications with enoxaparin bridging during cardiac catheterization. In the present series, low-molecular-weight heparins were seldom used and the incidence of bleeding complications in those patients was high (8.3%). Wide fluctuations in INR values are known to be common and long-lasting after interruption of warfarin, often necessitating prolonged bridging therapy.14 Moreover, reinitiation of warfarin may cause a transient prothrombotic state due to protein C and S suppression.14 The incidence of major bleeding was higher in those patients who crossed over from 1 anticoagulant to the other in the Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial,15 which is of potential relevance in this context. Performing coronary angiography without interrupting warfarin avoids the thrombotic risks associated with periods of subtherapeutic anticoagulation if the interruption is not fully covered by heparins. The fear for unopposed fatal bleeding has been the major argument against uninterrupted warfarin therapy policy during cardiac procedures. Indeed, increased risk of bleeding is unavoidable with all modes of anticoagulation and is closely related to the intensity of anticoagulation. In case of major bleeding, the anticoagulant effect of warfarin can be rapidly overcome by concentrates of blood clotting factors II, VII, IX, and X. The anticoagulant effect can be decreased also by low doses of vitamin K1, but patients treated with large doses of vitamin K1 can become resistant to warfarin for up to 1 week, because vitamin K1 accumulates in the liver. It is often forgotten that low-molecular-weight heparins and especially fondaparinux, which are often used for bridging therapy, also lack a specific antidote, if anticoagulation needs to be rapidly neutralized. Another potential strategy is a temporary adjustment of warfarin dosing to reach a periprocedural INR range of 1.5 to 2.0. This strategy has been shown to be safe and effective in the prevention of thromboembolism after noncardiac surgery16 and according to our present findings may be a reasonable option for patients with a high bleeding risk also during coronary angiography. Because of the lack of large-scale randomized trials, the antithrombotic strategy during coronary angiography is based on consensus. In a prospective study by HildickSmith et al,17 coronary angiography was performed for 66 fully anticoagulated patients using a radial approach, and only 1 minor postprocedural hemorrhage occurred. Jessup et al18 showed in a small series of 23 patients that cardiac catheterization may be feasible in the setting of uninterrupted warfarin therapy, because no bleeding or thrombotic complications occurred despite use of the femoral route. In the only controlled study, El-Jack et al19 randomized 61 patients to undergo coronary angiography during therapeutic warfarin treatment or after warfarin withdrawal (ⱖ48 hours). There were no major bleedings and a low incidence of small hematomas with either strategy, although all procedures were performed using the femoral approach. Of importance, it took a median of 9 days for the INR to return to the therapeutic level. Thus, the current literature is sub-
389
stantially limited in its ability to help choose an optimal treatment strategy in this patient subset. The low incidence (⬃1.5%) of clinical access site complications in our series supports the view that performing coronary angiography during uninterrupted therapeutic warfarin treatment is a reasonable option in clinical practice. Our study has all the inherent limitations of retrospective studies including individual risk-based decision making. The strength of our analysis is that we could identify and include all consecutive warfarin-treated patients from the records and avoid potential selection bias of prospective studies. In addition to differences in the perioperative use of antithrombotic medications, other differences in management strategies and patient selection may have modified our results. The threshold for an access site bleeding that caused prolonged hospitalization may have varied among institutions. Although our study is the largest and most comprehensive thus far, the sample may not be sufficient to cover all small, but clinically significant, differences between treatment groups. 1. Popma JJ, Bittl JA. Coronary angiography and intravascular ultrasonography. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: Textbook of Cardiovascular Medicine, 6th Ed. Philadelphia: WB Saunders, 2001:387– 421. 2. Grossman W. Historical perspective and present practice of cardiac catheterisation. In: Baim D, ed. Grossman’s Cardiac Catheterization, angiography and intervention, 6th Ed. Philadelphia: Lippincott Williams & Wilkins, 2000:1– 8. 3. Ansell J, Hirch J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126(suppl):201S–233S. 4. Kearon D, Hirch J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997;336:1506 –1511. 5. Spandorfer JM, Lynch S, Weitz HH, Fertel S, Merli GJ. Use of enoxaparin for the chronically anticoagulated patient before and after procedures. Am J Cardiol 1999;84:478 – 480. 6. Lev-Ran O, Kramer A, Gurevitch J, Shapira I, Mohr R. Low-molecular-weight heparin for prosthetic heart valves: treatment failure. Ann Thorac Surg 2000;69:264 –265. 7. Wazni OM, Beheiry S, Fahmy T, Barrett C, Hao S, Patel D, Di Biase L, Martin DO, Kanj M, Arruda M, et al. Atrial fibrillation ablation in patients with therapeutic international normalized ratio: comparison of strategies of anticoagulation management in the periprocedural period. Circulation 2007;116:2531–2534. 8. Karjalainen PP, Porela P, Ylitalo A, Vikman S, Nyman K, Vaittinen M-A, Airaksinen TJ, Niemela M, Vahlberg T, Airaksinen KE. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 2007;28:726 –732. 9. Korkeila P, Saraste M, Nyman K, Koistinen J, Lund J, Airaksinen KEJ. Transesophageal echocardiography in the diagnosis of thrombosis associated with permanent transvenous pacemaker electrodes. Pacing Clin Electrophysiol 2006;29:1245–1250. 10. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the national registry of atrial fibrillation. JAMA 2001;285:2864 –2870. 11. Helft G, Gilard M, Le Feuvre C, Zaman AG. Drug insight: antithrombotic therapy after percutaneous coronary intervention in patients with an indication for anticoagulation. Nat Clin Pract Cardiovasc Med 2006;3:673– 680. 12. Garcia DA, Regan S, Henault LE, Upadhyay A, Baker J, Othman M, Hylek EM. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med 2008;168:63– 69. 13. MacDonald LA, Meyers S, Bennett CL, Fintel D, Grosshans N, Syegco R, Davidson CJ. Post-cardiac catheterization access site complications and low-molecular-weight heparin following cardiac catheterization. J Invasive Cardiol 2003;15:60 – 62.
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14. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119(suppl):8S–21S. 15. White HD, Kleiman NS, Mahaffey KW, Lokhnygina Y, Pieper KS, Chiswell K, Cohen M, Harrington RA, Chew DP, Petersen JL, et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non–ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the superior yield of the new strategy of enoxaparin, revascularization and glycoprotein IIb/IIIa inhibitors (SYNERGY) trial. Am Heart J 2006;152:1042–1050. 16. Larson BJG, Zumberg MS, Kitchens CS. A feasibility study of continuing dose-reduced warfarin for invasive procedures in patients with high thromboembolic risk. Chest 2005;127:922–927.
17. Hildick-Smith DJR, Walsh JT, Lowe MD, Petch MC. Coronary angiography in the fully anticoagulated patient: The transradial route is successful and safe. Catheter Cardiovasc Interv 2003;58: 8 –10. 18. Jessup DB, Coletti AT, Muhlestein JB, Barry WH, Shean FC, Whisenant BK. Elective coronary angiography and percutaneous coronary intervention during uninterrupted warfarin therapy. Catheter Cardiovasc Interv 2003;60:180 –184. 19. El-Jack SS, Ruygrok PN, Webster MW, Stewart JT, Bass NM, Armstrong GP, Ormiston JA, Pornratanarangsi S. Effectiveness of manual pressure hemostasis following transfemoral coronary angiography in patients on therapeutic warfarin anticoagulation. Am J Cardiol 2006; 97:485– 488.
The management of patients with long-term warfarin therapy referred for coronary angiography may be problematic. The standard recommendation for these patients is to discontinue warfarin before coronary angiography because uninterrupted warfarin therapy is assumed to increase bleeding and access site complications. A periprocedural international normalized ratio (INR) level ⬍1.8 is most often recommended.1,2 Unfractionated or low-molecular-weight heparins are often administered as a bridging therapy during the invasive procedure until INR has been restored to therapeutic levels.3 Bridging therapy with heparins may prolong hospitalization and increase the risk of thromboembolism associated with subtherapeutic anticoagulation.4 – 6 Not surprisingly, the safety of bridging therapy has been recently questioned.7 There are only a few cohort studies on different management strategies of this patient group during coronary angiography, and they are based on small and heterogenous a
Department of Cardiology, Satakunta Central Hospital, Pori, bDepartment of Medicine, Turku University Hospital, Turku, and cDepartment of Medicine, Jyväskylä Central Hospital, Jyväskylä, Finland. Manuscript received February 7, 2008; revised manuscript received and accepted April 2, 2008. This study was supported by grants from the Finnish Foundation for Cardiovascular Research, Helsinki, Finland. *Corresponding author: Tel: 358-2-313-1005; fax: 358-2-313-2030. E-mail address: [email protected] (K.E.J. Airaksinen). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.04.003
patient populations. In the present study, we evaluated the safety of coronary angiography in patients with long-term warfarin therapy in 2 Finnish hospitals with long experience in performing cardiac procedures during uninterrupted therapeutic warfarin therapy and in 1 hospital with a main strategy to interrupt warfarin therapy and add bridging therapy in patients at increased risk of thromboembolism. Our aim was to assess the safety of a simple and time-saving strategy to perform coronary angiography during therapeutic warfarin therapy with no bridging therapy or interruption of warfarin. Methods The present study is based on computerized databases in 3 hospitals and is part of a research program in progress to assess thrombotic and bleeding complications of cardiac procedures in western Finland.8,9 We analyzed retrospectively all consecutive patients on long-term warfarin therapy (n ⫽ 258) referred for coronary angiography from 2003 through 2005. In addition, we collected an age- (⫾5 years) and gender-matched control group with similar indication (acute/elective) for coronary angiography in each hospital during the same study period. Matching was perfect except for 2 cases with a gender mismatch and 12 cases with an indication mismatch. Coronary angiography was performed according to standard techniques using a radial or femoral www.AJConline.org
4 (2%)
1.0
1 (0.4%) 1 (0.4%)
2 (1%) 1 (0.4%)
1.0 1.0
1 (0.4%) 2 (1%)
1 (0.4%) 0
1.0 0.50
approach.2 Immediate sheath (5Fr to 6Fr) removal was the policy in all 3 hospitals. Medical records of all valid patients were reviewed to evaluate rates of access site complications, major bleeding, and major adverse cardiovascular and cerebrovascular events (MACCEs) during hospitalization. We also gathered data on length of hospitalization and patient baseline characteristics including indications for warfarin therapy and
Compression device Femoral Elective Atrial fibrillation No
* Low-molecular-weight heparin was started before angiography as bridging therapy. Unfractionated heparin bolus 2,500 IU was administered during angiography.
5 (2%)
†
Patients with access site complications Pseudoaneurysm Access site bleeding delaying discharge Need for corrective surgery Transfusion of blood products
Complication
Warfarin Group Control Group p (n ⫽ 258) (n ⫽ 258) Value
Table 3 Access site and bleeding complications in the warfarin group
Table 2 Access site and bleeding complications in patients with warfarin treatment and in the control group
INR
Warfarin Pause
* Angio-Seal (St. Jude Medical, St. Paul, Minnesota).
1.7
NS
Femoral dissection, surgical closure
48 (19%)
77/M
49 (19%)
5
NS NS
Manual compression
156 (60%) 49 (19%)
Radial
144 (56%) 63 (24%)
Unstable angina
NS
Aspirin, clopidogrel, low-molecular-weight heparin None
6 (2%)
Deep vein thrombosis
2 (1%)
Yes
⬍0.01
2.8
8 (3%)
73/M
0
4
⬍0.001 ⬍0.001 ⬍0.001
Compression device
227 (88%) 68 (26%) 76 (29%)
Femoral
55 (21%) 17 (7%) 41 (16%)
Atrial fibrillation
NS
No
21 (8%)
3.3
16 (6%)
71/M
NS
3
19 (7%)
Femoral Femoral
25 (10%)
Elective Non–ST-elevation myocardial infarction, pulmonary edema Elective
NS 0.01
None Aspirin, low-molecular-weight heparin,* unfractionated heparin† None
200 (78%) 18 (7%)
Atrial fibrillation Mechanical heart valve
212 (82%) 5 (2%)
No Yes
NS
2.1 4.2
21 (8%)
Pseudoaneurysm Groin hematoma, transfusion of blood, died Prolonged hospitalization due to groin hematoma Decrease in hemoglobin, transfusion of blood
29 (11%)
59/F 67/M
NS NS ⬍0.001 ⬍0.001 NS NS
387
1 2
72 (28%) 157 (61%) 32 (12%) 12 (5%) 74 (29%) 22 (9%)
Access Site
59 (23%) 146 (57%) 93 (36%) 40 (16%) 69 (27%) 23 (9%)
Indication for Angiography
NS NS NS ⬍0.001
Other Antithrombotic Treatments
176 (68%) 66 ⫾ 10 58 (22%) 177 (67%)
Indication for Warfarin
177 (69%) 66 ⫾ 10 53 (21%) 129 (50%)
Age/Sex
Men Age (yrs) Diabetes mellitus Treatment for hypercholesterolemia Current or ex-smoker Hypertension Heart failure Stroke Myocardial infarction Percutaneous coronary intervention Coronary bypass grafting Indication for angiography Stable angina pectoris ST-elevation myocardial infarction Non–ST-elevation myocardial infarction Unstable angina pectoris Antithrombotic medications Aspirin Clopidogrel Low-molecular-weight heparin Glycoprotein IIb/IIIa inhibitor Previous thrombolysis Vascular access Radial access Closure device for femoral approach* Compression device for femoral approach
p Value
Patient No.
Warfarin Group Control Group (n ⫽ 258) (n ⫽ 258)
Vascular Hemostasis
Table 1 Baseline and procedural characteristics in patients with warfarin treatment and their controls
Compression device Closure device
Coronary Artery Disease/Coronary Angiography During Warfarin Anticoagulation
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periprocedural antithrombotic therapy. The CHADS2 score quantifying the annual stroke risk for patients who have nonvalvular atrial fibrillation was also recorded.10 Vascular access site complications included pseudoaneurysm, arteriovenous fistula, retroperitoneal hemorrhage, need for corrective surgery, need for transfusions, and prolonged hospitalization due to hematoma. Major bleeding was defined as a decrease in blood hemoglobin level of ⬎4.0 g/dl, need for transfusion of ⱖ2 U of blood, need for corrective surgery, occurrence of an intracranial or retroperitoneal hemorrhage, or any combination of these events. A MACCE was defined as the occurrence of death, myocardial infarction, and/or stroke during hospitalization. Myocardial infarction was diagnosed if any increase in a myocardial injury marker level (troponin I or T) was detected with the symptoms suggestive of acute myocardial ischemia. For the diagnosis of myocardial reinfarction a new increase ⬎50% of baseline injury marker level was demanded. All outcome events were recorded during the index hospitalization. Continuous variables are presented as mean ⫾ SD and study groups were compared by Student’s unpaired t test. Categorical variables are presented as counts and percentages and were compared by chi-square or Fisher’s exact test. Multivariable logistic regression analyses were performed to identify independent predictors for access site and bleeding complications in the warfarin group. Variables considered for the model included age, gender, disease type (acute vs stable), access site, INR level, use of low-molecular-weight heparin bridging, and warfarin pause. Adequacy of the model was ascertained using the Hosmer-Lemeshow goodness-of-fitness test. Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). A 2-sided p value ⬍0.05 was required for statistical significance. All data were analyzed with SPSS 15.0 for Windows (SPSS, Inc., Chicago, Illinois). This study complied with the Declaration of Helsinki. The study protocol was approved by the ethics committees of the co-ordinating center, Satakunta Central Hospital, and the participating hospitals. Results A total of 258 patients with an indication of long-term warfarin therapy underwent coronary angiography during the study period. Baseline clinical characteristics of the study population and indications for coronary angiography are presented in Table 1. Aspirin, clopidogrel, and lowmolecular-weight heparins were more often used in the control group. Femoral access was used in 44% of patients in the warfarin group and in 40% of controls with no difference in the use of closure devices. Atrial fibrillation was the most common (73%) indication for warfarin treatment followed by previous stroke (7%) and mechanical heart valve (6%). The mean CHADS2 score of patients with atrial fibrillation was 1.55. No significant difference was observed in the incidence of access site complications between the warfarin and control groups (1.9% vs 1.6%, p ⫽ 1.0; Table 2). Major bleeding complications occurred in 3 patients (1.1%) in the warfarin group and in 1 control patient (0.4%; Tables 2 and 3). One patient in the warfarin group and 2 patients in the
control group developed MACCEs during hospitalization, but none of the events were related to coronary angiography. In the warfarin group, MACCEs occurred in the patient presenting with acute myocardial infarction complicated by pulmonary edema (Table 3, patient 2). The patient died 10 days after angiography due to progressive renal and heart failure. In the control group, 1 patient died after coronary artery bypass grafting 6 days after uneventful coronary angiography. The other death occurred in a patient with acute ST-elevation myocardial infarction complicated by cardiogenic shock. No strokes or other thromboembolic events occurred in either group. Coronary angiography was performed during uninterrupted warfarin treatment in 178 patients (69%) and only 17 of them also received a periprocedural low-molecularweight heparin bolus and 5 patients unfractionated heparin bolus mainly due to subtherapeutic periprocedural INR values and/or unstable angina. Coronary angiography was performed after a warfarin pause (mean 2.3 days, range 1 to 30, before angiography) in 80 patients (31%). Bridging therapy with therapeutic low-molecular-weight heparin dosing was used only in 24 patients (30%) during the warfarin pause, but a bolus of unfractionated heparin was given to 73 patients (91%) during the procedure. INR levels were higher in patients with uninterrupted warfarin therapy (2.3 vs 1.9, p ⬍0.001), but the incidence of access site complications was not higher (1.7%) than in patients (n ⫽ 56) with a warfarin pause without bridging (0%) or in patients (n ⫽ 24) with bridging therapy (8.3%). The 2 major bleeding events necessitating blood transfusions occurred during bridging therapy (Table 3). In the warfarin group, the incidence of access site complications was increased in the 22 patients with supratherapeutic (INR ⬎3) compared with patients with therapeutic (INR 2-3) or subtherapautic (INR ⬍2) periprocedural anticoagulation (9.1% vs 1.5% vs 1.0%, respectively, p ⬍0.05). In multivariable analysis, supratherapeutic INR remained the only significant predictor for access site and bleeding complications (OR 5.1, 95% CI 1.1 to 23.8, p ⬍0.05) in the warfarin group. Femoral approach predicted access site complications in the entire study population (OR 11.8, 95% CI 1.5 to 94.9, p ⬍0.01), but not significantly (p ⫽ 0.11) in the warfarin group. Discussion Our results suggest that uninterrupted therapeutic warfarin treatment does not predispose a patient to excessive bleeding or access site complications during coronary angiography. However, supratherapeutic INR levels seem to be associated with access site complications. Of note, the 2 major bleeding events leading to blood transfusions occurred in patients with concomitant low-molecular-weight heparin therapy. It is estimated that 5% of patients undergoing coronary angiography are on long-term warfarin therapy because of underlying long-term medical conditions such as atrial fibrillation or mechanical heart valve.11 In this patient group, it is common consensus to postpone invasive procedures to reach INR levels ⬍1.8.1,2 Bridging therapy is recommended for patients considered to be at increased risk of thromboembolism. Recently, the safety of bridging therapy has been
Coronary Artery Disease/Coronary Angiography During Warfarin Anticoagulation
questioned in patients undergoing noncardiac surgery or pulmonary vein ablation.7,12 In these 2 studies, bridging therapy was associated with an increased incidence of bleeding events. MacDonald et al13 reported that 4.2% of 119 patients developed access site complications with enoxaparin bridging during cardiac catheterization. In the present series, low-molecular-weight heparins were seldom used and the incidence of bleeding complications in those patients was high (8.3%). Wide fluctuations in INR values are known to be common and long-lasting after interruption of warfarin, often necessitating prolonged bridging therapy.14 Moreover, reinitiation of warfarin may cause a transient prothrombotic state due to protein C and S suppression.14 The incidence of major bleeding was higher in those patients who crossed over from 1 anticoagulant to the other in the Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial,15 which is of potential relevance in this context. Performing coronary angiography without interrupting warfarin avoids the thrombotic risks associated with periods of subtherapeutic anticoagulation if the interruption is not fully covered by heparins. The fear for unopposed fatal bleeding has been the major argument against uninterrupted warfarin therapy policy during cardiac procedures. Indeed, increased risk of bleeding is unavoidable with all modes of anticoagulation and is closely related to the intensity of anticoagulation. In case of major bleeding, the anticoagulant effect of warfarin can be rapidly overcome by concentrates of blood clotting factors II, VII, IX, and X. The anticoagulant effect can be decreased also by low doses of vitamin K1, but patients treated with large doses of vitamin K1 can become resistant to warfarin for up to 1 week, because vitamin K1 accumulates in the liver. It is often forgotten that low-molecular-weight heparins and especially fondaparinux, which are often used for bridging therapy, also lack a specific antidote, if anticoagulation needs to be rapidly neutralized. Another potential strategy is a temporary adjustment of warfarin dosing to reach a periprocedural INR range of 1.5 to 2.0. This strategy has been shown to be safe and effective in the prevention of thromboembolism after noncardiac surgery16 and according to our present findings may be a reasonable option for patients with a high bleeding risk also during coronary angiography. Because of the lack of large-scale randomized trials, the antithrombotic strategy during coronary angiography is based on consensus. In a prospective study by HildickSmith et al,17 coronary angiography was performed for 66 fully anticoagulated patients using a radial approach, and only 1 minor postprocedural hemorrhage occurred. Jessup et al18 showed in a small series of 23 patients that cardiac catheterization may be feasible in the setting of uninterrupted warfarin therapy, because no bleeding or thrombotic complications occurred despite use of the femoral route. In the only controlled study, El-Jack et al19 randomized 61 patients to undergo coronary angiography during therapeutic warfarin treatment or after warfarin withdrawal (ⱖ48 hours). There were no major bleedings and a low incidence of small hematomas with either strategy, although all procedures were performed using the femoral approach. Of importance, it took a median of 9 days for the INR to return to the therapeutic level. Thus, the current literature is sub-
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stantially limited in its ability to help choose an optimal treatment strategy in this patient subset. The low incidence (⬃1.5%) of clinical access site complications in our series supports the view that performing coronary angiography during uninterrupted therapeutic warfarin treatment is a reasonable option in clinical practice. Our study has all the inherent limitations of retrospective studies including individual risk-based decision making. The strength of our analysis is that we could identify and include all consecutive warfarin-treated patients from the records and avoid potential selection bias of prospective studies. In addition to differences in the perioperative use of antithrombotic medications, other differences in management strategies and patient selection may have modified our results. The threshold for an access site bleeding that caused prolonged hospitalization may have varied among institutions. Although our study is the largest and most comprehensive thus far, the sample may not be sufficient to cover all small, but clinically significant, differences between treatment groups. 1. Popma JJ, Bittl JA. Coronary angiography and intravascular ultrasonography. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: Textbook of Cardiovascular Medicine, 6th Ed. Philadelphia: WB Saunders, 2001:387– 421. 2. Grossman W. Historical perspective and present practice of cardiac catheterisation. In: Baim D, ed. Grossman’s Cardiac Catheterization, angiography and intervention, 6th Ed. Philadelphia: Lippincott Williams & Wilkins, 2000:1– 8. 3. Ansell J, Hirch J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126(suppl):201S–233S. 4. Kearon D, Hirch J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997;336:1506 –1511. 5. Spandorfer JM, Lynch S, Weitz HH, Fertel S, Merli GJ. Use of enoxaparin for the chronically anticoagulated patient before and after procedures. Am J Cardiol 1999;84:478 – 480. 6. Lev-Ran O, Kramer A, Gurevitch J, Shapira I, Mohr R. Low-molecular-weight heparin for prosthetic heart valves: treatment failure. Ann Thorac Surg 2000;69:264 –265. 7. Wazni OM, Beheiry S, Fahmy T, Barrett C, Hao S, Patel D, Di Biase L, Martin DO, Kanj M, Arruda M, et al. Atrial fibrillation ablation in patients with therapeutic international normalized ratio: comparison of strategies of anticoagulation management in the periprocedural period. Circulation 2007;116:2531–2534. 8. Karjalainen PP, Porela P, Ylitalo A, Vikman S, Nyman K, Vaittinen M-A, Airaksinen TJ, Niemela M, Vahlberg T, Airaksinen KE. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 2007;28:726 –732. 9. Korkeila P, Saraste M, Nyman K, Koistinen J, Lund J, Airaksinen KEJ. Transesophageal echocardiography in the diagnosis of thrombosis associated with permanent transvenous pacemaker electrodes. Pacing Clin Electrophysiol 2006;29:1245–1250. 10. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the national registry of atrial fibrillation. JAMA 2001;285:2864 –2870. 11. Helft G, Gilard M, Le Feuvre C, Zaman AG. Drug insight: antithrombotic therapy after percutaneous coronary intervention in patients with an indication for anticoagulation. Nat Clin Pract Cardiovasc Med 2006;3:673– 680. 12. Garcia DA, Regan S, Henault LE, Upadhyay A, Baker J, Othman M, Hylek EM. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med 2008;168:63– 69. 13. MacDonald LA, Meyers S, Bennett CL, Fintel D, Grosshans N, Syegco R, Davidson CJ. Post-cardiac catheterization access site complications and low-molecular-weight heparin following cardiac catheterization. J Invasive Cardiol 2003;15:60 – 62.
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14. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119(suppl):8S–21S. 15. White HD, Kleiman NS, Mahaffey KW, Lokhnygina Y, Pieper KS, Chiswell K, Cohen M, Harrington RA, Chew DP, Petersen JL, et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non–ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the superior yield of the new strategy of enoxaparin, revascularization and glycoprotein IIb/IIIa inhibitors (SYNERGY) trial. Am Heart J 2006;152:1042–1050. 16. Larson BJG, Zumberg MS, Kitchens CS. A feasibility study of continuing dose-reduced warfarin for invasive procedures in patients with high thromboembolic risk. Chest 2005;127:922–927.
17. Hildick-Smith DJR, Walsh JT, Lowe MD, Petch MC. Coronary angiography in the fully anticoagulated patient: The transradial route is successful and safe. Catheter Cardiovasc Interv 2003;58: 8 –10. 18. Jessup DB, Coletti AT, Muhlestein JB, Barry WH, Shean FC, Whisenant BK. Elective coronary angiography and percutaneous coronary intervention during uninterrupted warfarin therapy. Catheter Cardiovasc Interv 2003;60:180 –184. 19. El-Jack SS, Ruygrok PN, Webster MW, Stewart JT, Bass NM, Armstrong GP, Ormiston JA, Pornratanarangsi S. Effectiveness of manual pressure hemostasis following transfemoral coronary angiography in patients on therapeutic warfarin anticoagulation. Am J Cardiol 2006; 97:485– 488.