The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant Who Need an Elective Surgery or Procedure: Design and Rationale.

Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol. Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group. Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.

Bridge Therapy Outcomes in Patients With Mechanical Heart Valves.

BACKGROUND: Bridge therapy is associated with an increased risk of major bleeding in patients with atrial fibrillation and venous thromboembolism (TE) without a corresponding reduction in TE. The benefits of bridge therapy in patients with mechanical heart valve (MHV) prostheses interrupting warfarin for invasive procedures are not well described. METHODS AND RESULTS: A retrospective cohort study was conducted at an integrated health-care delivery system. Anticoagulated patients with MHV interrupting warfarin for invasive diagnostic or surgical procedures between January 1, 2006, and March 31, 2012, were identified. Patients were categorized according to exposure to bridge therapy during the periprocedural period and TE risk (low, medium, and high). Outcomes validated via manual chart review included clinically relevant bleeding, TE, and all-cause mortality in the 30 days following the procedure. There were 547 procedures in 355 patients meeting inclusion criteria. Mean cohort age was 65.2 years, and 38% were female. Bridge therapy was utilized in 466 (85.2%) procedures (95.2%, 77.3%, and 65.8% of high, medium, and low TE risk category procedures, respectively). The 30-day rate of clinically relevant bleeding was numerically higher in bridged (5.8%; 95% confidence interval [CI], 3.9%-8.3%) versus not bridged procedures (1.2%; 95% CI, <0.1%-6.7%; P = .102). No TEs or deaths were identified. CONCLUSION: The use of bridge therapy is common among patients with MHV and may be associated with increased bleeding risk. Further research is needed to determine whether bridge therapy reduces TE in patients with MHV interrupting warfarin for invasive procedures.

Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures.

IMPORTANCE: The risk of bleeding and recurrent venous thromboembolism (VTE) among patients receiving long-term warfarin sodium therapy for secondary VTE prevention who require temporary interruption of anticoagulant therapy for surgery or invasive diagnostic procedures has not been adequately described. OBJECTIVE: To describe the rates of clinically relevant bleeding and recurrent VTE among patients in whom warfarin therapy is interrupted for invasive procedures and compare these rates among patients who did and did not receive bridge therapy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at Kaiser Permanente Colorado, an integrated health care delivery system. Patients in whom warfarin therapy was interrupted for invasive diagnostic or surgical procedures between January 1, 2006, and March 31, 2012, were identified via queries of administrative data sets. A total of 1812 procedures in 1178 patients met inclusion criteria. Data on outcomes and exposures were collected between June 1, 2005, and April 30, 2012. EXPOSURES: Use of bridge therapy vs no bridge therapy during warfarin interruption. MAIN OUTCOMES AND MEASURES: Thirty-day clinically relevant bleeding, recurrent VTE, and all-cause mortality. Outcomes were verified via manual review of medical records. RESULTS: Among the 1178 patients, the mean (SD) age was 66.1 (12.7) years, 830 procedures (45.8%) were in men, and the most common indication for warfarin therapy was deep vein thrombosis (56.3%). Most patients were considered to be at low risk for VTE recurrence at the time of warfarin interruption (1431 procedures [79.0%]) according to the consensus guidelines of the American College of Chest Physicians. Clinically relevant bleeding within 30 days after the procedure in the bridge therapy and non-bridge therapy groups occurred in 15 patients (2.7%) and 2 patients (0.2%), respectively (hazard ratio, 17.2; 95% CI, 3.9-75.1). There was no significant difference in the rate of recurrent VTE between the bridge and non-bridge therapy groups (0 vs 3; P = .56). No deaths occurred in either group. CONCLUSIONS AND RELEVANCE: Bridge therapy was associated with an increased risk of bleeding during warfarin therapy interruption for invasive procedures in patients receiving treatment for a history of VTE and is likely unnecessary for most of these patients. Further research is needed to identify patient- and procedure-related characteristics associated with a high risk of perioperative VTE recurrence during warfarin therapy interruption.

Approach to the new oral anticoagulants in family practice: part 1: comparing the options.

OBJECTIVE: To compare key features of the new oral anticoagulants (NOACs)-dabigatran, rivaroxaban, and apixaban-and to address questions that arise when comparing the NOACs. SOURCES OF INFORMATION: PubMed was searched for recent (January 2008 to week 32 of 2013) clinical studies relating to NOAC use for stroke prevention in atrial fibrillation (AF) and for the treatment of acute venous thromboembolism (VTE). MAIN MESSAGE: All NOACs are at least as effective as warfarin for stroke prevention in patients with nonvalvular AF, and are at least as safe in terms of bleeding risk according to 3 large trials. Meta-analyses of these trials have shown that, compared with warfarin therapy, NOACs reduced total mortality, cardiovascular mortality, and intracranial bleeding, and there was a trend toward less overall bleeding. Practical advantages of NOACs over warfarin include fixed once- or twice-daily oral dosing without the need for coagulation monitoring, and few known or defined drug or food interactions. Potential drawbacks of NOACs include a risk of bleeding that might be increased in patients older than 75 years, increased major gastrointestinal bleeding with high-dose dabigatran, increased dyspepsia with dabigatran, the lack of a routine laboratory test to reliably measure anticoagulant effect, and the lack of an antidote for reversal. No direct comparisons of NOACs have been made in randomized controlled trials, and the choice of NOAC is influenced by individual patient characteristics, including risk of stroke or VTE, risk of bleeding, and comorbidity (eg, renal dysfunction). CONCLUSION: The NOACs represent important alternatives in the management of patients with AF and VTE, especially for patients who have difficulty accessing regular coagulation monitoring. The companion to this article addresses common "what if" questions that arise in the long-term clinical follow-up and management of patients receiving NOACs.

Approach to the new oral anticoagulants in family practice: part 2: addressing frequently asked questions.

OBJECTIVE: To address common "what if" questions that arise relating to the long-term clinical follow-up and management of patients receiving the new oral anticoagulants (NOACs). SOURCES OF INFORMATION: For this narrative review, we searched the PubMed database for recent (January 2008 to week 32 of 2013) clinical studies relating to NOAC use for stroke prevention in atrial fibrillation and for the treatment of acute venous thromboembolism. We used this evidence base to address prespecified questions relating to NOAC use in primary care settings. MAIN MESSAGE: Dabigatran and rivaroxaban should be taken with meals to decrease dyspepsia and increase absorption, respectively. There are no dietary restrictions with any of the NOACs, beyond moderating alcohol intake, and rivaroxaban and apixaban can be crushed if required. The use of acid suppressive therapies does not appear to affect the efficacy of the NOACs. As with warfarin, patients taking NOACs should avoid long-term use of nonsteroidal anti-inflammatory and antiplatelet drugs. For patients requiring surgery, generally NOACs should be stopped 2 to 5 days before the procedure, depending on bleeding risk, and the NOAC should usually be resumed at least 24 hours after surgery. Preoperative coagulation testing is generally unnecessary. In patients who develop bleeding, minor bleeding typically does not require laboratory testing or discontinuation of NOACs; with major bleeding, the focus should be on local measures to control the bleeding and supportive care, and coagulation testing should be performed. There are currently no antidotes to reverse NOACs. The NOACs should not be used in patients with valvular heart disease, prosthetic heart valves, cancer-associated deep vein thrombosis, or superficial thrombophlebitis. CONCLUSION: Management of "what if" scenarios for patients taking NOACs have been proposed, but additional study is needed to address these issues, especially periprocedural management and bleeding.

Perioperative management of patients who are receiving a novel oral anticoagulant.

The use of novel oral anticoagulants (NOACs) is increasing since these drugs are at least as efficacious and safe as vitamin K antagonists (VKAs) for the management of patients with non-valvular atrial fibrillation and venous thromboembolism. Compared with VKAs, NOACs have a faster onset and offset of action, a predictable and consistent pharmacokinetic profile, fewer drug interactions, and ease of use since anticoagulant monitoring is not required. Current perioperative management will be affected by these characteristics, with the potential to obviate the need for heparin bridging. This review aims to summarize the current evidence of perioperative thromboembolic and bleeding risk during anticoagulant interruption, which is derived predominantly from patients receiving VKA therapy, and early studies involving NOACs which mainly focus on patients who are receiving dabigatran. The role of heparin bridging is discussed. We also provide a practical approach for the perioperative management of patients who are receiving NOAC therapy.

Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: This guideline addresses the management of patients who are receiving anticoagulant or antiplatelet therapy and require an elective surgery or procedure. METHODS: The methods herein follow those discussed in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement. RESULTS: In patients requiring vitamin K antagonist (VKA) interruption before surgery, we recommend stopping VKAs 5 days before surgery instead of a shorter time before surgery (Grade 1B). In patients with a mechanical heart valve, atrial fibrillation, or VTE at high risk for thromboembolism, we suggest bridging anticoagulation instead of no bridging during VKA interruption (Grade 2C); in patients at low risk, we suggest no bridging instead of bridging (Grade 2C). In patients who require a dental procedure, we suggest continuing VKAs with an oral prohemostatic agent or stopping VKAs 2 to 3 days before the procedure instead of alternative strategies (Grade 2C). In moderate- to high-risk patients who are receiving acetylsalicylic acid (ASA) and require noncardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C). In patients with a coronary stent who require surgery, we recommend deferring surgery > 6 weeks after bare-metal stent placement and > 6 months after drug-eluting stent placement instead of undertaking surgery within these time periods (Grade 1C); in patients requiring surgery within 6 weeks of bare-metal stent placement or within 6 months of drug-eluting stent placement, we suggest continuing antiplatelet therapy perioperatively instead of stopping therapy 7 to 10 days before surgery (Grade 2C). CONCLUSIONS: Perioperative antithrombotic management is based on risk assessment for thromboembolism and bleeding, and recommended approaches aim to simplify patient management and minimize adverse clinical outcomes.

Combination warfarin-ASA therapy: which patients should receive it, which patients should not, and why?

Combination warfarin-ASA therapy is currently used in approximately 800,000 patients in North America as long-term treatment for the primary and secondary prevention of atherothrombotic and thromboembolic diseases. Despite a potentially complementary action of anticoagulant and antiplatelet drugs, the use of combination warfarin-ASA therapy is not based on compelling evidence of a net therapeutic benefit, with the exception of patients with a mechanical heart valve. On the other hand, there is more compelling and consistent evidence that combination warfarin-ASA therapy confers a 1.5- to 2.0-fold increased risk for serious bleeding compared with use of warfarin alone. In everyday practice, clinicians should combine the best available evidence with clinical judgment, considering that in most clinical scenarios, clinical practice guideline may not provide clear recommendations for patients who should, and should not, receive combination warfarin-ASA therapy. The objectives of this review are to describe which patients are receiving combined warfarin-aspirin therapy, to summarize the evidence for the therapeutic benefit and harm of combined warfarin-ASA therapy, and to suggest practical guidelines as to which patients should, and should not, receive such treatment.

Combined warfarin-aspirin therapy: what is the evidence for benefit and harm and which patients should (and should not) receive it?

Combined warfarin-aspirin therapy is currently used in about 1 million patients in North America for the long-term primary and secondary prevention of atherothrombotic and thromboembolic diseases. Despite a potentially complementary action of anticoagulant and antiplatelet drugs on different components of the thrombotic pathway, their combined use, typically with warfarin and aspirin, is not based in many cases on compelling evidence of a net therapeutic benefit. In the real-world management of patients, clinicians should combine the best available evidence with clinical judgment, considering also that, in most clinical scenarios, clinical practice guidelines may not provide strong or prescriptive recommendations for patients who should (and should not) receive combined aspirin-warfarin therapy. The objectives of this review are to describe the characteristics of patients who are receiving combined warfarin-aspirin therapy, to summarize the evidence for the therapeutic benefit and harm of combined warfarin-aspirin, and to provide practical guidelines as to which patients should (or should not) receive such treatment.

The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This article discusses the perioperative management of antithrombotic therapy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). The primary objectives of this article are the following: (1) to address the perioperative management of patients who are receiving vitamin K antagonists (VKAs) or antiplatelet drugs, such as aspirin and clopidogrel, and require an elective surgical or other invasive procedures; and (2) to address the perioperative use of bridging anticoagulation, typically with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). A secondary objective is to address the perioperative management of such patients who require urgent surgery. The recommendations in this article incorporate the grading system that is discussed in this supplement (Guyatt G et al, CHEST 2008; 133:123S-131S). Briefly, Grade 1 recommendations are considered strong and indicate that the benefits do (or do not) outweigh risks, burden, and costs, whereas Grade 2 recommendations are referred to as suggestions and imply that individual patient values may lead to different management choices. The key recommendations in this article include the following: in patients with a mechanical heart valve or atrial fibrillation or venous thromboembolism (VTE) at high risk for thromboembolism, we recommend bridging anticoagulation with therapeutic-dose subcutaneous (SC) LMWH or IV UFH over no bridging during temporary interruption of VKA therapy (Grade 1C); in patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, or low-dose SC LMWH over no bridging during temporary interruption of VKA therapy (Grade 2C); in patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest low-dose SC LMWH or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH (Grade 2C). In patients with a bare metal coronary stent who require surgery within 6 weeks of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C); in patients with a drug-eluting coronary stent who require surgery within 12 months of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C). In patients who are undergoing minor dental procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure and co-administering an oral prohemostatic agent (Grade 1B); in patients who are undergoing minor dermatologic procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C); in patients who are undergoing cataract removal and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C).

Has the incidence of deep vein thrombosis in patients undergoing total hip/knee arthroplasty changed over time? A systematic review of randomized controlled trials.

BACKGROUND: There is a perception in the orthopaedic and thromboembolism community that the incidence of deep vein thrombosis (DVT) has decreased in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA). OBJECTIVES: To assess the incidence of DVT with warfarin thromboprophylaxis over time in patients undergoing elective TKA or THA. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched to October 2006, supplemented by a manual search of reference lists. Two reviewers independently extracted data on study characteristics, quality and the frequency of total, symptomatic and proximal DVT. RESULTS: Fourteen studies (4,423 patients) were included. Total and proximal DVT after TKA declined over time (r=-0.75, p=0.031; r=-0.86, p=0.007 respectively). Total and proximal DVT after THA did not change. The risk of developing DVT after TKA was significantly higher than after THA (OR 1.85, 95% CI 1.6-2.14; p<0.0001). The risk of developing symptomatic DVT after THA was significantly higher than after TKA (OR 2.18, 95% CI 1.11-4.27; p=0.012). CONCLUSIONS: The incidence of DVT in patients undergoing elective TKA appears to have declined in patients receiving warfarin thromboprophylaxis.

Systematic overview of warfarin and its drug and food interactions.

BACKGROUND: Warfarin is a highly efficacious oral anticoagulant, but its use is limited by a well-founded fear of bleeding. Drug and food interactions are frequently cited as causes of adverse events with warfarin. We provide an updated systematic overview of the quality, clinical effect, and importance of these reported interactions. DATA SOURCES: MEDLINE, TOXLINE, IPA, and EMBASE databases from October 1993 to March 2004. Database searches combined the keyword warfarin with drug interactions, herbal medicines, Chinese herbal drugs, and food-drug interactions. STUDY SELECTION: Eligible articles contained original reports of warfarin drug or food interactions in human subjects. Non-English articles were included if sufficient information could be abstracted. DATA EXTRACTION: Reports were rated independently by 2 investigators for interaction direction, clinical severity, and quality of evidence. Quality of evidence was based on previously validated causation criteria and study design. DATA SYNTHESIS: Of 642 citations retrieved, 181 eligible articles contained original reports on 120 drugs or foods. Inter-rater agreement was excellent, with weighted kappa values of 0.84 to 1.00. Of all reports, 72% described a potentiation of warfarin's effect and 84% were of poor quality, 86% of which were single case reports. The 31 incidents of clinically significant bleeding were all single case reports. Newly reported interactions included celecoxib, rofecoxib, and herbal substances, such as green tea and danshen. CONCLUSIONS: The number of drugs reported to interact with warfarin continues to expand. While most reports are of poor quality and present potentially misleading conclusions, the consistency of reports of interactions with azole antibiotics, macrolides, quinolones, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, selective serotonin reuptake inhibitors, omeprazole, lipid-lowering agents, amiodarone, and fluorouracil, suggests that coadministration with warfarin should be avoided or closely monitored. More systematic study of warfarin drug interactions in patients is urgently needed.

The management of hypertension in the overweight and obese patient: is weight reduction sufficient?

The management of hypertension in the overweight and obese patient is a frequently encountered but under investigated clinical problem. The conventional management of such patients involves weight reduction with dietary therapy or a combined approach with dietary and anti-obesity drug therapy. However, long-term weight reduction, which is necessary to sustain blood pressure (BP) control, is not feasible in over 80% of patients. Anti-obesity therapy with orlistat has inconsistent effects on BP and may benefit only patients who have uncontrolled or non-medicated hypertension. Anti-obesity therapy with sibutramine may be associated with a modest worsening of BP control. Consequently, antihypertensive drug therapy is often required to supplement a weight reduction programme, and also in patients with severe hypertension or hypertension-associated end-organ damage. Treatment with a thiazide diuretic should be considered as first-line antihypertensive drug therapy in overweight and obese patients. ACE inhibitors or non-dihydropyridine calcium channel antagonists are reasonable alternatives where clinically indicated, or they can be used in combination with a thiazide diuretic if treatment with the diuretic alone is insufficient. If such treatment is inadequate for BP control, the addition or substitution of an alpha- or beta-adrenoceptor antagonist may be considered, although the latter can be associated with weight gain. Concurrent disease is an important determinant of first-line and supplementary antihypertensive drug therapy. Additional studies are needed to determine the long-term (>1 year) efficacy and safety of antihypertensive and anti-obesity management strategies in the overweight and obese hypertensive patient.