Atrial fibrillation (AF) is a common cardiac arrhythmia associated with increased morbidity and mortality.(1,2) Patients with AF are at increased risk of systemic embolism (SE) and stroke, which can cause death, disability, and impaired quality of life.(1) Antithrombotic therapies, such as oral anticoagulant and antiplatelet drugs, can reduce the risk for stroke and systemic thromboembolism and are recommended for most AF patients with risk factors for stroke.(3–7) Antithrombotic therapies are also associated with a risk of bleeding, and their efficacy for stroke prevention should always be balanced against a patient’s risk of hemorrhage.(3–7) Existing guidelines(3–5) recommend antithrombotic therapy based on risk of stroke,(3–5) and most patients with non-valvular AF benefit from some form of antithrombotic therapy with an anticoagulant or antiplatelet drug. However, each oral antithrombotic drug used for stroke prevention in AF has advantages and disadvantages. There are decades of experience with the use of the vitamin K antagonist (VKA) warfarin, as well as compelling evidence of efficacy with regard to stroke prevention.(7–9) However, individualized dose adjustments and laboratory monitoring are required,(10–12) and warfarin remains the most common cause of drug-related emergency hospitalization in the elderly.(13) Because there is less clinical experience with the new oral anticoagulant (NOAC) drugs apixaban, dabigatran, and rivaroxaban outside of randomized controlled trials, it is not yet clear whether the NOACs show increased real-world benefits compared with warfarin. Although less effective at stroke prevention than anticoagulant therapy in most risk categories,(14) antiplatelet agents may still be the best choice for selected patients.(3–5,7,15) Following individual recommendations for dabigatran and rivaroxaban in AF made by the Common Drug Review (CDR),(16,17) the Canadian Agency for Drugs and Technologies in Health (CADTH) previously reviewed the clinical effectiveness and cost-effectiveness of the NOACs compared with warfarin for CDEC to develop recommendations for policy-makers regarding the NOACs and warfarin.(18) At that time, apixaban was not approved for use in Canada, and was therefore not included in the CDEC recommendation; in addition, antiplatelet drugs were not included. The current review was undertaken to extend the previous review to allow CDEC to develop recommendations that include all the NOACs, as well as the antiplatelet drugs acetylsalicylic acid (ASA) and clopidogrel.

BACKGROUND CONTEXT:

The objective of the North American Spine Society (NASS) Evidence-Based Clinical Guideline on antithrombotic therapies in spine surgery was to provide evidence-based recommendations to address key clinical questions surrounding the use of antithrombotic therapies in spine surgery. The guideline is intended to address these questions based on the highest quality clinical literature available on this subject as of February 2008. The goal of the guideline recommendations was to assist in delivering optimum, efficacious treatment with the goal of preventing thromboembolic events.

PURPOSE:

To provide an evidence-based, educational tool to assist spine surgeons in minimizing the risk of deep venous thrombosis (DVT) and pulmonary embolism (PE).

STUDY DESIGN:

Systematic review and evidence-based clinical guideline.

METHODS:

This report is from the Antithrombotic Therapies Work Group of the NASS Evidence-Based Guideline Development Committee. The work group was composed of multidisciplinary spine care specialists, all of whom were trained in the principles of evidence-based analysis. Each member of the group was involved in formatting a series of clinical questions to be addressed by the group. The final questions agreed on by the group are the subject of this report. A literature search addressing each question and using a specific search protocol was performed on English language references found in MEDLINE, EMBASE (Drugs and Pharmacology), and four additional, evidence-based databases. The relevant literature was then independently rated by at least three reviewers using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final grades of recommendation for the answers to each clinical question were arrived at via Web casts among members of the work group using standardized grades of recommendation. When Level I to IV evidence was insufficient to support a recommendation to answer a specific clinical question, expert consensus was arrived at by the work group through the modified nominal group technique and is clearly identified as such in the guideline.

RESULTS:

Fourteen clinical questions were formulated, addressing issues of incidence of DVT and PE in spine surgery and recommendations regarding utilization of mechanical prophylaxis and chemoprophylaxis in spine surgery. The answers to these 14 clinical questions are summarized in this article. The respective recommendations were graded by the strength of the supporting literature that was stratified by levels of evidence.

CONCLUSIONS:

A clinical guideline addressing the use of antithrombotic therapies in spine surgery has been created using the techniques of evidence-based medicine and using the best available evidence as a tool to assist spine surgeons in minimizing the risk of DVT and PE. The entire guideline document, including the evidentiary tables, suggestions for future research, and all references, is available electronically at the NASS Web site (www.spine.org) and will remain updated on a timely schedule.

PURPOSE:

We performed a meta-analysis to ascertain the benefits of antithrombotic therapy for maintaining the patency of vascular grafts following lower extremity bypass operations.

METHODS:

We identified articles using MEDLINE and hand searches of relevant journals for randomized clinical trials that compared the use of antithrombotic therapy with control or placebo therapy. Random-effects (DerSimonian and Laird) analyses were used to determine the risk of graft occlusion following lower extremity bypass operations. We also assessed the odds of secondary outcomes, such as myocardial infarction, cerebrovascular accident, all-cause mortality, and bleeding.

RESULTS:

Sixteen articles met the inclusion criteria of a randomized trial of antithrombotic therapy for the patency of vascular grafts; six were excluded because the analyses involved repeat surgeries or lacked a control group. Of the 10 studies included in the final analysis, seven compared antiplatelet agents with placebo or control, and three compared anticoagulant agents with placebo or control. The 10 studies were homogeneous in spite of differing durations of follow-up. The odds of graft occlusion in the treated group was half that in the placebo or control group. The odds ratio was 0.46 (95% confidence interval [CI]: 0.32 to 0.66) for the 10 studies that reported outcomes at 12 months or longer, 0.50 (95% CI.: 0.29 to 0.87) in the five studies with 12-month rates; and 0.58 (95% CI.: 0.39 to 0.88) at 24 months.

CONCLUSION:

Antithrombotic therapy decreases the risk of graft occlusion after a vascular operation by about 50% at 12 months and is still protective at 24 months after the operation.

Aims: To analyze the risk factors for hemorrhage during endoscopic retrograde cholangiopancreatography and the impact of antithrombotic drugs. Material and methods: Data sources: papers indexed in PubMed have been reviewed, as well as those found during the analysis of the bibliography of meta-analysis and reviews. Selection criteria: the references have been firstly evaluated by review of the abstract. After selecting the most significant articles (mainly randomized trials and well-designed case series) these have been deeply analyzed. Evaluation of the studies and synthesis: criteria by the Oxford Centre for Evidence-Based Medicine have been used for the analysis of the references and elaboration of evidence levels. Results: Seven hundred and sixty-five references were found, 753 in PubMed and the Cochrane Library. Twelve studies were selected during the analysis of other published articles (systematic reviews, meta-analysis and clinical practice guidelines). After analyzing the title or the abstract, 655 studies were excluded. Finally, 83 high quality trials or descriptive studies have been included in the analysis. Conclusion: Seven conclusions regarding the risk factors for bleeding and the impact of antithrombotic drugs have been defined (AU)

BACKGROUND:

There is no consensus on the efficacy of the antithrombotic drugs available for patients with intermittent claudication.

METHODS:

A Medline and manual search was used to identify relevant publications. Uncontrolled or retrospective studies, double reports or trials without clinical outcomes were excluded. Included studies were graded as level 1 (randomised and double- or assessor-blind), level 2 (open randomised), or level 3 (non-randomised comparative). Mortality, cerebro- or cardiovascular events, amputations, arterial occlusions or number of revascularization procedures performed in the lower limbs, pain-free and total walking distance, ankle brachial index and calf blood flow, were the main outcomes considered. When feasible, end of treatment results, either continuous or binary, were combined with appropriate statistical methods.

RESULTS:

Mortality was significantly decreased by ticlopidine compared to placebo (common odds ratio 0.68, 95% C.I., 0.49 - 0.95); clopidogrel decreased vascular events in comparison to aspirin (odds ratio 0.76, 95% C.I., 0.63 - 0.92) in level 1 studies. Arterial occlusions and the number of revascularization procedures performed were statistically significantly decreased by aspirin and ticlopidine, respectively. A small but statistically significant improvement in pain-free walking distance was determined by picotamide, indobufen, low molecular weight heparins, sulodexide and defibrotide, in small studies.

CONCLUSIONS:

Clopidogrel and ticlopidine do reduce clinically important events in patients with intermittent claudication and could be added to the primary medical treatment of these patients. The use of aspirin in these patients cannot be based on direct evidence, but only on analogy with coronary and cerebral atherosclerosis, where it has documented efficacy. Other antithrombotic drugs were not properly evaluated in patients with intermittent claudication.

BACKGROUND:

The important prophylactic role of antithrombotic therapy against stroke in nonrheumatic atrial fibrillation (AF) has been clearly established in recent clinical trials. There have been suggestions, however, that practice has been slow to change in light of the findings of these trials.

AIM:

To review cases of AF at the major teaching hospital in Tasmania, Australia, to determine whether the recommendations from the results of the trials had been translated into local clinical practice.

METHODS:

A retrospective review of the medical records for consecutive patients who had AF documented on ECG between 1 January and 30 June 1997 was performed. An extensive range of demographic and clinical variables were recorded for patients with chronic or paroxysmal nonrheumatic AF. These included antithrombotic and other drug therapy at admission and discharge from hospital care, risk factors for stroke, contraindications to antithrombotic use, and incidents of ischaemic stroke and bleeding complications that occurred during the period from January 1996 up to 3 months after the hospital admission that was studied.

RESULTS:

The 228 patients included in the study had a mean (+/-SD) age of 75.3+/-10.9 years. Sixty-eight per cent had chronic AF and 32% had paroxysmal AF. According to two risk stratification criteria, 91% and 86% of the patients with previously diagnosed chronic or paroxysmal nonrheumatic AF (n=186) had a high risk of developing stroke at the time of admission to hospital care. However, less than one-third of these patients were receiving warfarin (or warfarin plus aspirin), with almost another one-third receiving no antithrombotic agent. Of those who were not taking warfarin, about 60% had no apparent contraindication to warfarin. For those high risk patients who had a possible contraindication to warfarin, only approximately one-third had been prescribed aspirin. Only a slight increase in the use of antithrombotic agents had occurred by the time of discharge from hospital care. The majority of international normalized ratio (INR) values on admission for patients who had been taking warfarin were subtherapeutic. The estimated annual incidence of bleeding complications in patients taking warfarin was 15.0% overall, 5.0% for major bleeds and 3.8% for intracranial haemorrhages.

CONCLUSIONS:

While a number of published trials have demonstrated that antithrombotic agents confer substantial protection against stroke in patients with nonrheumatic AF, the drugs were underused in our setting. There is a need to improve antithrombotic use and to develop a better monitoring system for the provision of safer and more effective antithrombotic therapy.

BACKGROUND:

Left ventricular assist devices (LVADs) have dramatically increased the survival of adults with end-stage systolic heart failure. However, rates of bleeding and thromboembolism remain high.

OBJECTIVES:

We completed a systematic review to evaluate outcomes of adults with LVADs treated with various anticoagulant and antiplatelet strategies.

METHODS:

Databases were searched using the terms "assist device," "thrombosis," and "anticoagulant" or "platelet aggregation inhibitor" with appropriate synonyms, device names and manufacturers.

RESULTS AND CONCLUSIONS:

Of 977 manuscripts, 24 articles met the inclusion criteria of adults with implanted LVADs where clinical outcomes were defined based on anticoagulant and/or antiplatelet regimen. Most studies reported treatment with unfractionated heparin post-operatively which was transitioned to a vitamin K antagonist (VKA). Goal INR varied between 1.5-3.5. Antiplatelet regimens ranged from no treatment to dual therapy. Definition of major bleeding differed between trials and incidence varied between 0% and 58%. The available evidence could not demonstrate a clear benefit of aspirin compared with VKA therapy alone [stroke RR 1.02 (95% CI 0.49-2.1)]. There was a suggestion that treatment with aspirin and dipyridamole decreased the risk of thromboembolism compared to aspirin [RR 0.50 (0.36-0.68)], but the comparison is limited by differences in demographics, devices, and INR goals among studies. Additionally, most studies did not blind to outcomes thus contributing to an increased risk for bias. Clinical equipoise exists as to the most appropriate antithrombotic therapy in LVAD patients. Randomization between regimens within a prospective trial is needed to define the treatment regimen that minimizes both bleeding and thrombotic complications This article is protected by copyright. All rights reserved.

Heart valve prosthesis unquestionably improve quality of life and survival of patients with severe valvular heart disease, but the need for antithrombotic therapy to prevent thromboembolic complications is a major challenge to clinicians and their patients. Of the articles analyzed, most were retrospective series of cases or historical cohorts obtained from the database. The few published randomized trials showed no statistical power to assess the primary outcome of death or thromboembolic event. In this article, we decided to perform a systematic literature review, in an attempt to answer the following question: what is the best antithrombotic strategy in the first three months after bioprosthetic heart valve implantation (mitral and aortic)? After two reviewers applying the extraction criteria, we found 1968 references, selecting 31 references (excluding papers truncated, which combined bioprosthesis with mechanical prosthesis, or without follow-up). Based on this literature review, there was a low level of evidence for any antithrombotic therapeutic strategy evaluated. It´s therefore interesting to use aspirin 75 to 100 mg / day as antithrombotic strategy after bioprosthesis replacement in the aortic position, regardless of etiology, for patients without other risk factors such as atrial fibrillation or previous thromboembolic event. In the mitral position, the risk of embolism, although low, is more relevant than in the aortic position, according to published series and retrospective cohorts comprised mostly of elderly non-rheumatic patients.

BACKGROUND:

Antithrombotic agents, including antiplatelet agents, anticoagulants and thrombolysis agents, have been widely used in the management of immunoglobulin A (IgA) nephropathy in Chinese and Japanese populations. To systematically evaluate the effects of antithrombotic agents for IgA nephropathy.

METHODS:

Data sources consisted of MEDLINE, EMBASE, the Cochrane Library, Chinese Biomedical Literature Database (CBM), Chinese Science and Technology Periodicals Databases (CNKI) and Japana Centra Revuo Medicina (http://www.jamas.gr.jp) up to April 5, 2011. The quality of the studies was evaluated from the intention to treat analysis and allocation concealment, as well as by the Jadad method. Meta-analyses were performed on the outcomes of proteinuria and renal function.

RESULTS:

Six articles met the predetermined inclusion criteria. Antithrombotic agents showed statistically significant effects on proteinuria (p<0.0001) but not on the protection of renal function (p=0.07). The pooled risk ratio for proteinuria was 0.53, [95% confidence intervals (CI): 0.41-0.68; I(2)=0%] and for renal function it was 0.42 (95% CI 0.17-1.06; I(2)=72%). Subgroup analysis showed that dipyridamole was beneficial for proteinuria (p=0.0003) but had no significant effects on protecting renal function. Urokinase had statistically significant effects both on the reduction of proteinuria (p=0.0005) and protecting renal function (p<0.00001) when compared with the control group.

CONCLUSION:

Antithrombotic agents had statistically significant effects on the reduction of proteinuria but not on the protection of renal function in patients with IgAN. Urokinase had statistically significant effects both on the reduction of proteinuria and on protecting renal function. Urokinase was shown to be a promising medication and should be investigated further.

BACKGROUND:

Although the efficacy of postoperative antithrombotics in free flap survival is well demonstrated through animal studies, debate remains in the clinical literature. This review estimates the benefits and risks of each antithrombotic drug and evaluates whether antithrombotics can produce better outcomes than nonantithrombotic treatment.

METHODS:

English-language articles evaluating the efficacy of antithrombotics in free flap surgery through comparisons with control groups were analyzed. The outcome measures were total flap failure, pedicle thrombosis, and hematoma formation.

RESULTS:

Twelve articles representing 4984 cases were analyzed. None of the antithrombotics showed significant benefits for flap survival. Heparin reduced the risk of flap loss by 35 percent, but the difference was not significant (relative risk, 0.65; 95 percent CI, 0.25 to 1.69). Dextran and aspirin showed little protective effects on pedicle thrombosis and flap failure. All antithrombotics showed increased risks of hematoma, and aspirin raised the risk of hematoma significantly (relative risk, 1.91; 95 percent CI, 1.05 to 3.47). In an analysis combining six studies comparing outcomes between the antithrombotic group and the nonantithrombotic group, antithrombotic administration did not reduce the risk of total flap loss (relative risk, 0.99; 95 percent CI, 0.72 to 1.35) or thrombosis (relative risk, 1.00; 95 percent CI, 0.74 to 1.36) but significantly increased the risk of hematoma (relative risk, 1.78; 95 percent CI, 1.20 to 2.63).

CONCLUSIONS:

There is little evidence suggesting that the use of antithrombotics reduces the risk of thrombosis and total flap failure. Although randomized controlled studies would be required, the risks of routine administration of antithrombotics may outweigh the benefits.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.