Uninterrupted Warfarin vs. Bridge Therapy with Heparin in Acute Coronary Syndrome

Uninterrupted Warfarin vs. Bridge Therapy with Parenteral Anticoagulation in Acute Coronary Syndrome

Take Home Point(s):

For patients taking oral anticoagulant therapy (OAC) and presenting to the emergency department (ED) with acute coronary syndrome (ACS) and have an INR between 2 - 3, controversy exists as to whether to continue OAC or to bridge these patients with heparin, LWMH or bivalrudin.
A small number of recent studies compared uninterrupted warfarin therapy to heparin bridge therapy and found no different in endpoints of major adverse cardiac and cerebrovascular events, but did show a trend towards increased bleeding risk in the bridge therapy group.
Currently, there is no consensus in the available guidelines and until better evidence becomes available, patients with a high risk for thromboemboli, should not have interruption of warfarin to prevent variability in therapeutic anticoagulation that is concerning for increased bleeding.

Summary:

In acute coronary syndrome (ACS), atherosclerotic plaque rupture and subsequent thrombotic occlusion at the rupture site prevents myocardial perfusion, resulting in tissue ischemia. Once plaque rupture has occurred, the potential for reperfusion is maximized by the initiation of anti-platelet and anti-coagulant medications. By interrupting both platelet activation and the coagulation cascade, the goal is to prevent fibrin/platelet clot formation and cross-linking. Traditionally, anti-coagulant therapy has targeted the intrinsic pathway of the coagulation cascade, including unfractionated heparin and low molecular weight heparins.

For patients taking oral anticoagulant therapy (OAC) and presenting to the emergency department with ACS and have an INR between 2 - 3, controversy exists as to whether to continue oral anticoagulation or to bridge these patients with traditional parenteral medications. While OACS block either the extrinsic pathway (i.e. warfarin) or the common pathway (i.e. Xa inhibitors) of the coagulation cascade, the end goal of thrombin inhibition is accomplished and theoretically a reasonable alternative. In vivo, however, no two anti-coagulants are alike and further investigation is warranted for the safety profile of each agent in ACS.

While OACs have commonly been held for a week prior to elective surgery, ACS provides a unique circumstance in which therapy must be initiated or maintained in the face of an imminent procedure without time to allow for INR normalization or OAC washout. Studies on the efficacy and safety of uninterrupted OAC in patients presenting with ACS are limited. Heparin-based regimens in ACS have long been the standard of care. With the exception of the SYNERGY trial, which did exclude patients with an INR >1.5, most of the heparin-based studies for ACS did not delineate whether patients on OACs were included.

A small number of more recent studies compared uninterrupted warfarin therapy to heparin bridge therapy and included endpoints of major adverse cardiac and cerebrovascular events and bleeding complications. They found there to be no statistical difference between the two groups, and if anything, there was a trend towards a higher bleeding risk in the bridge therapy group. While these studies were underpowered and mostly retrospective in nature, they do provide a foundation upon which to direct further study and suggest that uninterrupted warfarin therapy may be beneficial and less costly to both the patient and the health system.

In clinical practice, there is no consensus in the available guidelines. Most advocate for the cessation of warfarin therapy in patients with low risk for thromboemboli and re-initiation after PCI plus or minus a heparin bridge. For patients with a high risk for thromboemboli, however, interruption of warfarin should be avoided to prevent variability in therapeutic anticoagulation. Until high quality evidence becomes available, a balance of risks and benefits must be considered and in the face of new OACs without measurable therapeutic lab values, further investigation is needed to develop encompassing guidelines.

Authors:

Anthony J. Busti, MD, PharmD, FNLA, FAHA
Karolina DeAugustinas, MD

Date Last Reviewed: October 2015

Supporting Guidelines
2014 European Society of Cardiology Working Group on Thrombosis, EHRA, EAPCI, ACCA, HRS, & APHRS: For NSTE-ACS: "In the ACS setting, patients are often given aspirin, clopidogrel, heparin (whether UFH or enoxaparin) or bivalirudin and/or a GP IIb/IIIa inhibitors. Given the risk of ischaemia and bleeding it may be prudent to stop OAC (i.e. whether NOAC or a VKA) therapy, and where a VKA or NOAC is used, administer UFH or bivalirudin only as bailout (but avoiding GP IIb/IIa inhibitors) or if INR ≤2 in a patient on VKA, balancing the acute need for additional antithrombotic therapy with the excess bleeding risk and the 'thrombus burden' (Class IIb, level of evidence C). (a) in low-risk ACS patients with delayed transfer for an invasive strategy at .24 h of admission, it may be prudent to stop OAC therapy and bridge the patient with unfractionated heparin or enoxaparin (class IIb level of evidence C)." For PCI: "In the acute setting, a patient with AF and STEMI may be treated with primary PCI, aspirin, clopidogrel, and heparin (UFH) or bivalirudin, while GP IIb/IIIa inhibitors in bailout situations might be useful in some cases. Given the risk of bleeding with such combination antithrombotic therapies, it may sometimes be prudent to temporarily stop OAC therapy. Regular or even 'routine' use of GP IIb/IIIa inhibitors is discouraged, as are the novel P2Y12 inhibitors (Class IIb, level of evidence B). In the setting of STEMI, radial access for primary PCI is the best option to avoid procedural bleeding depending on operator expertise and preference (Class I, level of evidence A)." Reference: Lip GY et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014;35(45):3155-79. PubMed 2014 ACC/AHA Guidelines for Atrial Fibrillation: Interruption and Bridging Anticoagulation. "Interruption of anticoagulation is often considered for patients with AF who have episodes of bleeding or require surgical or interventional procedures associated with a bleeding risk. There is sparse evidence on which to base specific recommendations on bridging oral anticoagulants among patients with nonvalvular AF with adjusteddose heparin or LMWH.241 .... For patients who are treated with warfarin and who are at low risk of thromboemboli or those who are back in normal sinus rhythm and are undergoing surgical or diagnostic procedures that carry a risk of bleeding, stopping warfarin for up to 1 week and allowing the INR to normalize without substituting UFH is a recognized approach. Warfarin is then resumed after adequate hemostasis has been achieved. For patients at higher risk of thromboembolism (mechanical valves, prior stroke, CHA2DS2-VASc score ≥2), bridging with UFH or LMWH is a common practice, although data for LMWH are limited.22 An increasingly common approach, especially for pacemaker or implantable cardioverter-defibrillator implantation, catheter ablation, coronary angiography, and other vascular interventions, is to perform the procedure without interrupting warfarin. 241,243-247 ... The timing of resumption should take into account the fact that anticoagulation, in contrast to warfarin, is achieved promptly and that reversal agents are not yet available for these agents, which complicates management if bleeding occurs." For PCI: "In patients undergoing percutaneous coronary intervention, dual antiplatelet therapy with aspirin and clopidogrel is indicated to prevent stent thrombosis. The combination of oral anticoagulants and antiplatelet therapy ("triple therapy") is associated with a high annual risk of fatal and nonfatal bleeding episodes.251-254" Guideline Rating: NR Reference: January CT et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. 2014;130(23):e199-267. PubMed 2014 ACC/AHA NSTE-ACS Guidelines: No recommendations related to warfarin bridging or continuation Reference: Amsterdam EA et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014:[Epub ahead of print]. PubMed 2013 AHA STEMI Guidelines No recommendations related to warfarin bridging or continuation Reference:O'Gara PT et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127(4):e362-425. PubMed 2012 ACCP CHEST Guidelines 9^th Edition: No recommendations related to warfarin bridging or continuation Reference: Vandvik PO et al. Primary and secondary prevention of cardiovascular disease. Antithrombotic therapy and prevention of thrombosis, 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012;141(suppl):e637S-e668S. PubMed 2010 AHA ACLS Guidelines for Acute Coronary Syndrome: No recommendations related to warfarin bridging or continuation Reference: O'Connor RE et al. Part 9. Acute Coronary Syndromes: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Circulation 2010;122:S422-S465. PubMed

Supporting Guidelines

2014 European Society of Cardiology Working Group on Thrombosis, EHRA, EAPCI, ACCA, HRS, & APHRS:
For NSTE-ACS:
"In the ACS setting, patients are often given aspirin, clopidogrel, heparin (whether UFH or enoxaparin) or bivalirudin and/or a GP IIb/IIIa inhibitors. Given the risk of ischaemia and bleeding it may be prudent to stop OAC (i.e. whether NOAC or a VKA) therapy, and where a VKA or NOAC is used, administer UFH or bivalirudin only as bailout (but avoiding GP IIb/IIa inhibitors) or if INR ≤2 in a patient on VKA, balancing the acute need for additional antithrombotic therapy with the excess bleeding risk and the 'thrombus burden' (Class IIb, level of evidence C). (a) in low-risk ACS patients with delayed transfer for an invasive strategy at .24 h of admission, it may be prudent to stop OAC therapy and bridge the patient with unfractionated heparin or enoxaparin (class IIb level of evidence C)."

For PCI:
"In the acute setting, a patient with AF and STEMI may be treated with primary PCI, aspirin, clopidogrel, and heparin (UFH) or bivalirudin, while GP IIb/IIIa inhibitors in bailout situations might be useful in some cases. Given the risk of bleeding with such combination antithrombotic therapies, it may sometimes be prudent to temporarily stop OAC therapy. Regular or even 'routine' use of GP IIb/IIIa inhibitors is discouraged, as are the novel P2Y12 inhibitors (Class IIb, level of evidence B). In the setting of STEMI, radial access for primary PCI is the best option to avoid procedural bleeding depending on operator expertise and preference (Class I, level of evidence A)."
- Reference: Lip GY et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014;35(45):3155-79. PubMed
2014 ACC/AHA Guidelines for Atrial Fibrillation:
Interruption and Bridging Anticoagulation.
"Interruption of anticoagulation is often considered for patients with AF who have episodes of bleeding or require surgical or interventional procedures associated with a bleeding risk. There is sparse evidence on which to base specific recommendations on bridging oral anticoagulants among patients with nonvalvular AF with adjusteddose heparin or LMWH.241 .... For patients who are treated with warfarin and who are at low risk of thromboemboli or those who are back in normal sinus rhythm and are undergoing surgical or diagnostic procedures that carry a risk of bleeding, stopping warfarin for up to 1 week and allowing the INR to normalize without substituting UFH is a recognized approach. Warfarin is then resumed after adequate hemostasis has been achieved. For patients at higher risk of thromboembolism (mechanical valves, prior stroke, CHA2DS2-VASc score ≥2), bridging with UFH or LMWH is a common practice, although data for LMWH are limited.22 An increasingly common approach, especially for pacemaker or implantable cardioverter-defibrillator implantation, catheter ablation, coronary angiography, and other vascular interventions, is to perform the procedure without interrupting warfarin. 241,243-247 ... The timing of resumption should take into account the fact that anticoagulation, in contrast to warfarin, is achieved promptly and that reversal agents are not yet available for these agents, which complicates management if bleeding occurs."

For PCI:
"In patients undergoing percutaneous coronary intervention, dual antiplatelet therapy with aspirin and clopidogrel is indicated to prevent stent thrombosis. The combination of oral anticoagulants and antiplatelet therapy ("triple therapy") is associated with a high annual risk of fatal and nonfatal bleeding episodes.251-254"
- Guideline Rating: NR
- Reference: January CT et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. 2014;130(23):e199-267. PubMed
2014 ACC/AHA NSTE-ACS Guidelines:
No recommendations related to warfarin bridging or continuation
- Reference: Amsterdam EA et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014:[Epub ahead of print]. PubMed
2013 AHA STEMI Guidelines
No recommendations related to warfarin bridging or continuation
- Reference:O'Gara PT et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127(4):e362-425. PubMed
2012 ACCP CHEST Guidelines 9^th Edition:
No recommendations related to warfarin bridging or continuation
- Reference: Vandvik PO et al. Primary and secondary prevention of cardiovascular disease. Antithrombotic therapy and prevention of thrombosis, 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012;141(suppl):e637S-e668S. PubMed
2010 AHA ACLS Guidelines for Acute Coronary Syndrome:
No recommendations related to warfarin bridging or continuation
- Reference: O'Connor RE et al. Part 9. Acute Coronary Syndromes: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Circulation 2010;122:S422-S465. PubMed

Landmark or Original Studies

Rubboli A et al. Anti-platelet pre-treatment for atrial fibrillation patients on warfarin referred for coronary angiography/stenting because of non-ST-elevation acute coronary syndrome: an alternative proposal. Int J Cardiol 2015;201:494-496. PubMed

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LOE	2b
Study Design	Single-Center, Retrospective
Sample Size	N = 17
Population	Adult patients with atrial fibrillation (AF) on warfarin undergoing coronary angiography/stenting (CORO/PCI-S) or NSTE-ACS
Inclusion Criteria	Not reported
Exclusion Criteria	Not reported
Intervention	Continue warfarin, initiate clopidogrel (300 or 600 mg loading dose 2 to 6 hrs before procedure), but hold aspirin until time of coronary intervention
Other Treatments	Not reported
Follow-Up	Discharge (5 - 20 days)
Primary Endpoint	Preliminary evidence regarding the safety and efficacy of delayed use of aspirin
Results	Of the 17 overall patients, 14 (82%) were male and mean age was 72.2 ± 8.1 years. The median (± SD) time from admission to CORO/PCI-S was 42 ± 33 h. Ascertained NSTE-ACS was the indication for CORO/PCI-S in 10 (59%) patients. The radial approach was used in 15 cases (88%) and intra-procedural aspirin (in the formulation of lysine acetyl-salicylate) was given intravenously to 7 patients (41%) on whom also PCI-S was performed. The remaining patients were managed conservatively and discharged either on warfarin only because of a normal angiogram in 3 cases (18%) or on warfarin and clopidogrel because of a coronary anatomy judged not suitable for revascularization in 7 (41%). Of the 7 PCI-Ss performed, drug-eluting stents were implanted in 4 (57%). Out of the 7 patients who underwent PCI-S, medium-term triple therapy (TT) was prescribed in 6 (86%), whereas in the remaining (14%) dual therapy of warfarin and clopidogrel was selected. Median (±standard deviation) duration of hospitalization was 5 ± 5 days. Neither adverse cardiac events nor actionable bleeding complications were recorded during hospitalization
Conclusions	Not reported by authors
Locations	Division of Cardiology, Ospedale Maggiore, Bologna, Italy; Laboratory of Interventional Cardiology, Ospedale Maggiore, Bologna, Italy
Comments	This group is providing some preliminary evidence for a strategy of withholding aspirin until the time of coronary intervention while continuing warfarin and starting clopidogrel. There is also no information about the use of additional anticoagulation in addition to continuing warfarin. It is important to note that IV aspirin was used in this setting which is not available in the other parts of the world, including the U.S.

Lahtela H et al. Heparin bridging vs. uninterrupted oral anticoagulation in patients with Atrial Fibrillation undergoing Coronary Artery Stenting. Results from the AFCAS registry. Circ J 2012:76(6):1363-8. PubMed

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LOE	1c
Study Design	Observational, Multicenter, Prospective Registry
Sample Size	N = 451
Population	Adults with atrial fibrillation referred for PCI between December 2006 - February 2010 at 17 centers in 5 European countries
Inclusion Criteria	Not specified
Exclusion Criteria	Unwillingness or inability to give consent
Interventions	N = 290; Uninterrupted warfarin (UAC) use + initiation of heparin/LMWH/bilvarudin N = 161; Bridge therapy (BT) with heparin/LMWH/bilvarudin + stop warfarin for 5 days before PCI
Other Treatments	Glycoprotein IIb/IIIa inhibitors
Follow-up	30 days
Primary Endpoint	Major adverse cardiac (death, MI, revascularization of the target vessel, stent thrombosis) and cerebrovascular events (MACC) and bleeding complications at 30 days
Results	In the BT group, OAC was interrupted for a median of 5 days. Overall bleeding complications tended to be more common in the BT group (18.6% vs. 12.1%, P=0.07), with no significant difference in the rate of major bleeding (2.5% vs. 1.4%) or MACCE (6.2% vs. 3.8%). After adjustment for propensity score, BT was not associated with bleeding complications (odds ratio [OR], 1.38; 95% confidence interval [CI]: 0.77-2.48, P=0.28) or MACCE (OR, 1.16; 95%CI: 0.44-3.05, P=0.76). Periprocedural international normalized ratio was not associated with bleeding or MACCE. The length of hospitalization after PCI was longer in the BT group both in elective and in acute patients (3.2±2.9 vs. 1.9±4.6 days and 7.0±10.4 vs. 5.3±6.3 days, respectively; P<0.05 for both).
Conclusions	"UAC does not increase perioperative complications during coronary stenting and is a simple and cost-effective alternative to conventional heparin bridging."
Location	Department of Medicine, Turku University Hospital, Turku, Finland
Funding	Unrestricted grants from Novartis- Germany and Sanofi-Aventis-Germany; Finnish Foundation for Cardiovascular Research, Helsinki, Finland
ClinicalTrial.gov	NCT00596570
Comments	This is a nonrandomized, unblended, and underpowered to adequately answer the question about safety or efficacy. However, this available of evidence is helpful until better studies are completed. Pre-procedure INRs were a mean of 2.3 in the UAC group vs. 1.8 in the BT group. As such, the BT group was more likely to get the bridge therapy and had longer hospitalization. Without a clear benefit in MACCE, BT did not appear to offer any protective benefits, minor increase in risk for bleeding and resulted in longer hospitalizations.

Karjalainen PP et al. Safety of percutaneous coronary intervention during uninterrupted oral anticoagulant treatment. Eur Heart J 2008;29(8):1001-10. PubMed

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LOE	2c
Study Design	Retrospective Study of a Computerized PCI database in 7 Finnish hospitals between 2002-2006
Sample Size	N = 523
Population	Adults on warfarin referred for PCI
Inclusion Criteria	Not reported
Exclusion Criteria	Not reported
Groups	N = 282; Interrupted anticoagulation (IAC) by warfarin N = 241; Uninterrupted anticoagulation (UAC) by warfarin
Primary Endpoint	Major bleeding, access-site complications, and major adverse cardiac events (death, myocardial infarction, target vessel revascularization, and stent thrombosis) were recorded during hospitalization.
Results	In the IAC group, warfarin was withdrawn for a mean of 3 days prior to PCI (mean INR 1.7). In the UAC group, mean INR value was 2.2. Glycoprotein IIb/IIIa (GP) inhibitors (P < 0.001) and low-molecular-weight heparins (P < 0.001) were more often used in the IAC group. Major bleeding and access-site complications were more common in the IAC group (5.0% vs. 1.2%, P = 0.02 and 11.3% vs. 5.0%, P = 0.01, respectively) than in the UAC group. After adjusting for propensity score, the group difference in access-site complications remained significant [OR (odds ratio) 2.8, 95% CI (confidence interval) 1.3-6.1, P = 0.008], but did not remain significant in major bleeding (OR 3.9, 95% CI 1.0-15.3, P = 0.05). In multivariable analysis, femoral access (OR 9.9, 95% CI 1.3-75.2), use of access-site closure devices (OR 2.1, 95% CI 1.1-4.0), low-molecular-weight heparin (OR 2.7, 95% CI 1.1-6.7) and old age predicted access-site complications, and the use of GP inhibitors (OR 3.0, 95% CI 1.0-9.1) remained as a predictor of major bleeding.
Conclusions	"Our study shows that PCI is a safe procedure during UAC with no excess bleeding complications."
Location	Department of Cardiology, Satakunta Central Hospital, Pori, Finland
Funding	Finnish Foundation for Cardiovascular Research, Helsinki, Finland
Comments	While it is a retrospective study, this data would suggest that not interrupting warfarin therapy to implement additional antithrombotic agents is not only less complicated but is associated with potentially less bleeding risk from using other anticoagulants. This needs to be further analyzed prospectively, but this data also does not show a greater need for revascularization or development of thrombotic events from continuing warfarin.

Jessup DB et al. Elective coronary angiography and percutaneous coronary intervention during uninterrupted warfarin therapy. Catheter Cardiovasc Interv 2003;60(2):180-4. PubMed

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Supporting Studies

Feng L et al. Oral anticoagulation continuation compared with heparin bridging therapy among high risk patients undergoing implantation of cardiac rhythm devices: a meta-analysis. Thromb Haemost 2012;108(6):1124-31. PubMed

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Related Articles & Reviews
TsuLV et al. Safety of new oral anticoagulants with dual antiplatelet therapy in patients with acute coronary syndromes. Ann Pharmacother 2013;47:573-7. PubMed

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Uninterrupted Warfarin vs. Bridge Therapy with Parenteral Anticoagulation in Acute Coronary Syndrome

Supporting Guidelines

Landmark or Original Studies

Supporting Studies

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