Per Olav Vandvik

VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy. METHODS The methods of this guideline follow 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 in this supplement. RESULTS We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin (Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfill the laboratory criteria for antiphospholipid antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B). CONCLUSIONS Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies in this population.

Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS The methods of this guideline follow those described in 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 in this supplement. RESULTS Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Probiotics for the Prevention of Clostridium difficile–Associated Diarrhea: A Systematic Review and Meta-analysis

66% (pooled relative risk, 0.34 [95% CI, 0.24 to 0.49]; I 2 0%). In a population with a 5% incidence of antibiotic-associated CDAD (median control group risk), probiotic prophylaxis would prevent 33 episodes (CI, 25 to 38 episodes) per 1000 persons. Of probiotictreated patients, 9.3% experienced adverse events, compared with 12.6% of control patients (relative risk, 0.82 [CI, 0.65 to 1.05]; I 2 17%). Limitations: In 13 trials, data on CDAD were missing for 5% to 45% of patients. The results were robust to worst-plausible assumptions regarding event rates in studies with missing outcome data. Conclusion: Moderate-quality evidence suggests that probiotic prophylaxis results in a large reduction in CDAD without an increase in clinically important adverse events.

Primary and Secondary Prevention of Cardiovascular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND This guideline focuses on long-term administration of antithrombotic drugs designed for primary and secondary prevention of cardiovascular disease, including two new antiplatelet therapies. METHODS The methods of this guideline follow those described in 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 in this supplement. RESULTS We present 23 recommendations for pertinent clinical questions. For primary prevention of cardiovascular disease, we suggest low-dose aspirin (75-100 mg/d) in patients aged > 50 years over no aspirin therapy (Grade 2B). For patients with established coronary artery disease, defined as patients 1-year post-acute coronary syndrome, with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, we recommend long-term low-dose aspirin or clopidogrel (75 mg/d) (Grade 1A). For patients with acute coronary syndromes who undergo percutaneous coronary intervention (PCI) with stent placement, we recommend for the first year dual antiplatelet therapy with low-dose aspirin in combination with ticagrelor 90 mg bid, clopidogrel 75 mg/d, or prasugrel 10 mg/d over single antiplatelet therapy (Grade 1B). For patients undergoing elective PCI with stent placement, we recommend aspirin (75-325 mg/d) and clopidogrel for a minimum duration of 1 month (bare-metal stents) or 3 to 6 months (drug-eluting stents) (Grade 1A). We suggest continuing low-dose aspirin plus clopidogrel for 12 months for all stents (Grade 2C). Thereafter, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B). CONCLUSIONS Recommendations continue to favor single antiplatelet therapy for patients with established coronary artery disease. For patients with acute coronary syndromes or undergoing elective PCI with stent placement, dual antiplatelet therapy for up to 1 year is warranted.

Patient Values and Preferences in Decision Making for Antithrombotic Therapy: A Systematic Review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Development of clinical practice guidelines involves making trade-offs between desirable and undesirable consequences of alternative management strategies. Although the relative value of health states to patients should provide the basis for these trade-offs, few guidelines have systematically summarized the relevant evidence. We conducted a systematic review relating to values and preferences of patients considering antithrombotic therapy. METHODS We included studies examining patient preferences for alternative approaches to antithrombotic prophylaxis and studies that examined, in the context of antithrombotic prophylaxis or treatment, how patients value alternative health states and experiences with treatment. We conducted a systematic search and compiled structured summaries of the results. Steps in the process that involved judgment were conducted in duplicate. RESULTS We identified 48 eligible studies. Sixteen dealt with atrial fibrillation, five with VTE, four with stroke or myocardial infarction prophylaxis, six with thrombolysis in acute stroke or myocardial infarction, and 17 with burden of antithrombotic treatment. CONCLUSION Patient values and preferences regarding thromboprophylaxis treatment appear to be highly variable. Participant responses may depend on their prior experience with the treatments or health outcomes considered as well as on the methods used for preference elicitation. It should be standard for clinical practice guidelines to conduct systematic reviews of patient values and preferences in the specific content area.

Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

OBJECTIVES This article provides recommendations on the use of antithrombotic therapy in patients with stroke or transient ischemic attack (TIA). METHODS We generated treatment recommendations (Grade 1) and suggestions (Grade 2) based on high (A), moderate (B), and low (C) quality evidence. RESULTS In patients with acute ischemic stroke, we recommend IV recombinant tissue plasminogen activator (r-tPA) if treatment can be initiated within 3 h (Grade 1A) or 4.5 h (Grade 2C) of symptom onset; we suggest intraarterial r-tPA in patients ineligible for IV tPA if treatment can be initiated within 6 h (Grade 2C); we suggest against the use of mechanical thrombectomy (Grade 2C) although carefully selected patients may choose this intervention; and we recommend early aspirin therapy at a dose of 160 to 325 mg (Grade 1A). In patients with acute stroke and restricted mobility, we suggest the use of prophylactic-dose heparin or intermittent pneumatic compression devices (Grade 2B) and suggest against the use of elastic compression stockings (Grade 2B). In patients with a history of noncardioembolic ischemic stroke or TIA, we recommend long-term treatment with aspirin (75-100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended release dipyridamole (25 mg/200 mg bid), or cilostazol (100 mg bid) over no antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), the combination of clopidogrel plus aspirin (Grade 1B), or triflusal (Grade 2B). Of the recommended antiplatelet regimens, we suggest clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or cilostazol (Grade 2C). In patients with a history of stroke or TIA and atrial fibrillation we recommend oral anticoagulation over no antithrombotic therapy, aspirin, and combination therapy with aspirin and clopidogrel (Grade 1B). CONCLUSIONS These recommendations can help clinicians make evidence-based treatment decisions with their patients who have had strokes.

Credibility of claims of subgroup effects in randomised controlled trials: systematic review

Objective To investigate the credibility of authors’ claims of subgroup effects using a representative sample of recently published randomised controlled trials. Design Systematic review. Data source Core clinical journals, as defined by the National Library of Medicine, in Medline. Study selection Randomised controlled trials published in 2007. Using prespecified criteria, teams of trained reviewers independently judged whether authors claimed subgroup effects and the strength of their claims. Reviewers assessed each of these claims against 10 predefined criteria, developed through a search of existing criteria and a consensus process. Results Of 207 randomised controlled trials reporting subgroup analyses, 64 (31%) made claims for the primary outcome. Of those, 20 were strong claims and 28 claims of a likely effect. Authors included subgroup variables measured at baseline in 60 (94%) trials, used subgroup variable as a stratification factor at randomisation in 13 (20%), clearly prespecified their hypotheses in 26 (41%), correctly prespecified direction in 4 (6%), tested a small number of hypotheses in 28 (44%), carried out a test of interaction that proved statistically significant in 6 (9%), documented replication of a subgroup effect with previous related studies in 21 (33%), identified consistency of a subgroup effect across related outcomes in 19 (30%), and provided a compelling indirect evidence for the effect in 14 (22%). In the 19 trials making more than one claim, only one (5%) checked the independence of the interaction. Of the 64 claims, 54 (84%) met four or fewer of the 10 criteria. For strong claims, more than 50% failed each of the individual criteria, and only three (15%) met more than five criteria. Conclusion Authors often claim subgroup effects in their trial report. However, the credibility of subgroup effects, even when claims are strong, is usually low. Users of the information should treat claims that fail to meet most criteria with scepticism. Trial researchers should report the conduct of subgroup analyses and provide sufficient evidence when claiming a subgroup effect or suggesting a possible effect.

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

BACKGROUND To develop the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines (AT9), the American College of Chest Physicians (ACCP) assembled a panel of clinical experts, information scientists, decision scientists, and systematic review and guideline methodologists. METHODS Clinical areas were designated as articles, and a methodologist without important intellectual or financial conflicts of interest led a panel for each article. Only panel members without significant conflicts of interest participated in making recommendations. Panelists specified the population, intervention and alternative, and outcomes for each clinical question and defined criteria for eligible studies. Panelists and an independent evidence-based practice center executed systematic searches for relevant studies and evaluated the evidence, and where resources and evidence permitted, they created standardized tables that present the quality of the evidence and key results in a transparent fashion. RESULTS One or more recommendations relate to each specific clinical question, and each recommendation is clearly linked to the underlying body of evidence. Judgments regarding the quality of evidence and strength of recommendations were based on approaches developed by the Grades of Recommendations, Assessment, Development, and Evaluation Working Group. Panel members constructed scenarios describing relevant health states and rated the disutility associated with these states based on an additional systematic review of evidence regarding patient values and preferences for antithrombotic therapy. These ratings guided value and preference decisions underlying the recommendations. Each topic panel identified questions in which resource allocation issues were particularly important and, for these issues, experts in economic analysis provided additional searches and guidance. CONCLUSIONS AT9 methodology reflects the current science of evidence-based clinical practice guideline development, with reliance on high-quality systematic reviews, a standardized process for quality assessment of individual studies and the body of evidence, an explicit process for translating the evidence into recommendations, disclosure of financial as well as intellectual conflicts of interest followed by management of disclosed conflicts, and extensive peer review.

Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies

Objective To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus. Design Systematic review and meta-analysis. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. Eligibility criteria Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs. Data collection and analysis Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis. Results 60 studies (n=353 639), consisting of 55 randomised controlled trials (n=33 350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320 289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13). Conclusions The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk.

Antithrombotic Therapy in Peripheral Artery Disease

BACKGROUND This guideline focuses on antithrombotic drug therapies for primary and secondary prevention of cardiovascular disease as well as for the relief of lower-extremity symptoms and critical ischemia in persons with peripheral arterial disease (PAD). METHODS The methods of this guideline follow those described in 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 in this supplement. RESULTS The most important of our 20 recommendations are as follows. In patients aged ≥ 50 years with asymptomatic PAD or asymptomatic carotid stenosis, we suggest aspirin (75-100 mg/d) over no therapy (Grade 2B) for the primary prevention of cardiovascular events. For secondary prevention of cardiovascular disease in patients with symptomatic PAD (including patients before and after peripheral arterial bypass surgery or percutaneous transluminal angioplasty), we recommend long-term aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 1A). We recommend against the use of warfarin plus aspirin in patients with symptomatic PAD (Grade 1B). For patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting, we suggest single rather than dual antiplatelet therapy (Grade 2C). For patients with refractory claudication despite exercise therapy and smoking cessation, we suggest addition of cilostazol (100 mg bid) to aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 2C). In patients with critical limb ischemia and rest pain unable to undergo revascularization, we suggest the use of prostanoids (Grade 2C). In patients with acute limb ischemia due to acute thrombosis or embolism, we recommend surgery over peripheral arterial thrombolysis (Grade 1B). CONCLUSIONS Recommendations continue to favor single antiplatelet therapy for primary and secondary prevention of cardiovascular events in most patients with asymptomatic PAD, symptomatic PAD, and asymptomatic carotid stenosis. Additional therapies for relief of limb symptoms should be considered only after exercise therapy, smoking cessation, and evaluation for peripheral artery revascularization.