PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations.

CLINICAL QUESTION: In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug? CURRENT PRACTICE: Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients' values and preferences, absolute benefits and harms and potential treatment burdens. RECOMMENDATIONS: The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins. HOW THIS GUIDELINE WAS CREATED: An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation. THE EVIDENCE: A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/. UNDERSTANDING THE RECOMMENDATIONS: The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient's risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors.

Risk-assessment models for VTE and bleeding in hospitalized medical patients: an overview of systematic reviews.

Multiple risk-assessment models (RAMs) for venous thromboembolism (VTE) in hospitalized medical patients have been developed. To inform the 2018 American Society of Hematology (ASH) guidelines on VTE, we conducted an overview of systematic reviews to identify and summarize evidence related to RAMs for VTE and bleeding in medical inpatients. We searched Epistemonikos, the Cochrane Database, Medline, and Embase from 2005 through June 2017 and then updated the search in January 2020 to identify systematic reviews that included RAMs for VTE and bleeding in medical inpatients. We conducted study selection, data abstraction and quality assessment (using the Risk of Bias in Systematic Reviews [ROBIS] tool) independently and in duplicate. We described the characteristics of the reviews and their included studies, and compared the identified RAMs using narrative synthesis. Of 15 348 citations, we included 2 systematic reviews, of which 1 had low risk of bias. The reviews included 19 unique studies reporting on 15 RAMs. Seven of the RAMs were derived using individual patient data in which risk factors were included based on their predictive ability in a regression analysis. The other 8 RAMs were empirically developed using consensus approaches, risk factors identified from a literature review, and clinical expertise. The RAMs that have been externally validated include the Caprini, Geneva, IMPROVE, Kucher, and Padua RAMs. The Padua, Geneva, and Kucher RAMs have been evaluated in impact studies that reported an increase in appropriate VTE prophylaxis rates. Our findings informed the ASH guidelines. They also aim to guide health care practitioners in their decision-making processes regarding appropriate individual prophylactic management.

Risk models for VTE and bleeding in medical inpatients: systematic identification and expert assessment.

Risk assessment models (RAMs) for venous thromboembolism (VTE) and bleeding in hospitalized medical patients inform appropriate use of thromboprophylaxis. Our aim was to use a novel approach for selecting risk factors for VTE and bleeding to be included in RAMs. First, we used the results of a systematic review of all candidate factors. Second, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence for the identified factors. Third, we using a structured approach to select factors to develop the RAMs, by building on clinical and methodological expertise. The expert panel made judgments on whether to include, potentially include, or exclude risk factors, according to domains of the GRADE approach and the Delphi method. The VTE RAM included age >60 years, previous VTE, acute infections, immobility, acute paresis, active malignancy, critical illness, and known thrombophilia. The bleeding RAM included age ≥65 years, renal failure, thrombocytopenia, active gastroduodenal ulcers, hepatic disease, recent bleeding, and critical illness. We identified acute infection as a factor that was not considered in widely used RAMs. Also, we identified factors that require further research to confirm or refute their importance in a VTE RAM (eg, D-dimer). We excluded autoimmune disease which is included in the IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) bleeding RAM. Our results also suggest that sex, malignancy, and use of central venous catheters (factors in the IMPROVE bleeding RAM) require further research. In conclusion, our study presents a novel approach to systematically identifying and assessing risk factors to be included or further explored during RAM development.

DOACs vs LMWHs in hospitalized medical patients: a systematic review and meta-analysis that informed 2018 ASH guidelines.

Venous thromboembolism (VTE) is a relatively frequent complication in hospitalized patients, especially in those with risk factors. The benefit of using direct oral anticoagulants (DOACs) for prevention is controversial. This systematic review was performed as part of the American Society of Hematology (ASH) guidelines on VTE, developed in partnership with McMaster University. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Epistemonikos were used as data sources from date of inception to November 2019. We included randomized trials in patients hospitalized for an acute medical disease, evaluating any DOACs vs other pharmacological prophylaxis, and included 3 trials with low risk of bias. We analyzed the effects of DOACs vs low-molecular-weight heparins (LMWHs) at 2 different time points: at the end of the short-term treatment phase (both drugs given for the same period of time) and at the end of the extended prophylaxis period (extended DOACs vs a shorter course of LMWHs). We observed that the use of DOACs did not reduce the risk of pulmonary embolism or symptomatic deep venous thrombosis (DVT) in comparison with LMWHs. However, the risk of major bleeding was slightly increased. Additionally, we observed that the benefit of DOACs previously reported was largely based on the reduction of asymptomatic DVT and was not apparent when only symptomatic events were considered. The use of DOACs in hospitalized medical patients slightly increases the risk of major bleeding with no appreciable benefit over LMWHs.

Prognostic factors for VTE and bleeding in hospitalized medical patients: a systematic review and meta-analysis.

There may be many predictors of venous thromboembolism (VTE) and bleeding in hospitalized medical patients, but until now, systematic reviews and assessments of the certainty of the evidence have not been published. We conducted a systematic review to identify prognostic factors for VTE and bleeding in hospitalized medical patients and searched Medline and EMBASE from inception through May 2018. We considered studies that identified potential prognostic factors for VTE and bleeding in hospitalized adult medical patients. Reviewers extracted data in duplicate and independently and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. Of 69 410 citations, we included 17 studies in our analysis: 14 that reported on VTE, and 3 that reported on bleeding. For VTE, moderate-certainty evidence showed a probable association with older age; elevated C-reactive protein (CRP), D-dimer, and fibrinogen levels; tachycardia; thrombocytosis; leukocytosis; fever; leg edema; lower Barthel Index (BI) score; immobility; paresis; previous history of VTE; thrombophilia; malignancy; critical illness; and infections. For bleeding, moderate-certainty evidence showed a probable association with older age, sex, anemia, obesity, low hemoglobin, gastroduodenal ulcers, rehospitalization, critical illness, thrombocytopenia, blood dyscrasias, hepatic disease, renal failure, antithrombotic medication, and presence of a central venous catheter. Elevated CRP, a lower BI, a history of malignancy, and elevated heart rate are not included in most VTE risk assessment models. This study informs risk prediction in the management of hospitalized medical patients for VTE and bleeding; it also informs guidelines for VTE prevention and future research.

Supplying Pharmacist Home Visit and Anticoagulation Professional Consultation During Transition of Care for Patients With Venous Thromboembolism.

OBJECTIVE: The aim of the study was to assess the feasibility, satisfaction, and effectiveness of a care transition intervention with pharmacist home visit and subsequent anticoagulation expert consultation for patients with new episode of venous thromboembolism within a not-for-profit health care network. METHODS: We randomized patients to the intervention or control. During the home visit, a clinical pharmacist assessed medication management proficiency, asked open-ended questions to discuss knowledge gaps, and distributed illustrated medication instructions. Subsequent consultation with anticoagulation expert further filled knowledge gaps. At 30 days, we assessed satisfaction with the intervention and also measured the quality of care transition, knowledge of anticoagulation and venous thromboembolism, and anticoagulant beliefs (level of agreement that anticoagulant is beneficial, is worrisome, and is confusing/difficult to take). RESULTS: The mean ± SD time required to conduct home visits was 52.4 ± 20.5 minutes and most patients agreed that the intervention was helpful. In general, patients reported a high-quality care transition including having been advised of safety issues related to medications. Despite that, the mean percentage of knowledge items answered correctly among patients was low (51.5 versus 50.7 for intervention and controls, respectively). We did not find any significant difference between intervention and control patients for care transition quality, knowledge, or anticoagulant beliefs. CONCLUSIONS: We executed a multicomponent intervention that was feasible and rated highly. Nevertheless, the intervention did not improve care transition quality, knowledge, or beliefs. Future research should examine whether alternate strategies potentially including some but not all components of our intervention would be more impactful.

Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability.

BACKGROUND: Retrospective analyses suggest that pulmonary embolism is ruled out by a d-dimer level of less than 1000 ng per milliliter in patients with a low clinical pretest probability (C-PTP) and by a d-dimer level of less than 500 ng per milliliter in patients with a moderate C-PTP. METHODS: We performed a prospective study in which pulmonary embolism was considered to be ruled out without further testing in outpatients with a low C-PTP and a d-dimer level of less than 1000 ng per milliliter or with a moderate C-PTP and a d-dimer level of less than 500 ng per milliliter. All other patients underwent chest imaging (usually computed tomographic pulmonary angiography). If pulmonary embolism was not diagnosed, patients did not receive anticoagulant therapy. All patients were followed for 3 months to detect venous thromboembolism. RESULTS: A total of 2017 patients were enrolled and evaluated, of whom 7.4% had pulmonary embolism on initial diagnostic testing. Of the 1325 patients who had a low C-PTP (1285 patients) or moderate C-PTP (40 patients) and a negative d-dimer test (i.e., <1000 or <500 ng per milliliter, respectively), none had venous thromboembolism during follow-up (95% confidence interval [CI], 0.00 to 0.29%). These included 315 patients who had a low C-PTP and a d-dimer level of 500 to 999 ng per milliliter (95% CI, 0.00 to 1.20%). Of all 1863 patients who did not receive a diagnosis of pulmonary embolism initially and did not receive anticoagulant therapy, 1 patient (0.05%; 95% CI, 0.01 to 0.30) had venous thromboembolism. Our diagnostic strategy resulted in the use of chest imaging in 34.3% of patients, whereas a strategy in which pulmonary embolism is considered to be ruled out with a low C-PTP and a d-dimer level of less than 500 ng per milliliter would result in the use of chest imaging in 51.9% (difference, -17.6 percentage points; 95% CI, -19.2 to -15.9). CONCLUSIONS: A combination of a low C-PTP and a d-dimer level of less than 1000 ng per milliliter identified a group of patients at low risk for pulmonary embolism during follow-up. (Funded by the Canadian Institutes of Health Research and others; PEGeD ClinicalTrials.gov number, NCT02483442.).

Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant.

IMPORTANCE: Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. OBJECTIVE: To investigate the safety of a standardized perioperative DOAC management strategy. DESIGN, SETTING, AND PARTICIPANTS: The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. INTERVENTIONS: A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low-bleeding-risk procedure and 2 to 3 days after a high-bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. MAIN OUTCOMES AND MEASURES: Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (<50 ng/mL) at the time of the procedure. RESULTS: The 3007 patients with AF (mean [SD] age of 72.5 [9.39] years; 1988 men [66.1%]) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high-bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of arterial thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high-bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort. CONCLUSIONS AND RELEVANCE: In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and arterial thromboembolism.

Long-term risk of recurrence in patients with a first unprovoked venous thromboembolism managed according to d-dimer results; A cohort study.

Essentials Long-term recurrence risk after a first unprovoked VTE with negative d-dimer levels is uncertain. Anticoagulation was stopped if d-dimer was negative, and was continued if d-dimer was positive. Five years after stopping anticoagulants, recurrent VTE was 30% in men and 17% in women. Negative d-dimers do not justify stopping anticoagulants in most men but appear to in most women. BACKGROUND: The long-term risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative d-dimer results is uncertain. OBJECTIVES: To determine this risk, including in subgroups based on sex. PATIENTS AND METHODS: ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if d-dimer was negative on therapy and 1 month after stopping therapy. Other patients remained on anticoagulant therapy. We previously reported findings after a mean of 2.2 years. The current report includes 3 years of additional follow-up in 293 of these patients. RESULTS: During a median follow-up of 5.0 years, recurrent VTE after stopping therapy in response to negative d-dimer testing was 5.1% (95% confidence interval [CI], 3.6-6.5) per patient-year overall, 7.5% (95% CI, 5.5-10.0) in men, 3.8% (95% CI, 2.0-6.6) in women with VTE not associated with estrogens, and 0.4% (95% CI, 0.0-2.3) in women with VTE associated with estrogens (P < 0.001 for three-group comparison). Risk of recurrence at 5 years was 21.5% (95% CI, 16.4-26.5) overall, 29.7% (95% CI, 22.1-37.3) in men, 17.0% (95% CI, 8.1-25.9) in non-estrogen women, and 2.3% (95% CI, 0.0-6.8) in estrogen women. CONCLUSION: The long-term risk of recurrence in patients with a first unprovoked VTE who have negative d-dimer results is not low enough to justify stopping anticoagulant therapy in men, but appears to be low enough in women for many to choose stopping therapy (ClinicalTrials.gov; NCT00720915).

Pulse pressure in acute coronary syndromes: Comparative prognostic significance with systolic blood pressure.

BACKGROUND: Pulse pressure is a readily available vital sign that has been shown to independently predict outcomes in several cardiovascular disease states. We investigated the prognostic significance of pulse pressure (PP) and systolic blood pressure (SBP) among patients with acute coronary syndromes (ACS). METHODS: A total of 14,514 patients with ACS in the prospective, multicentre Global Registry of Acute Coronary Events (GRACE), expanded GRACE (GRACE-2) and Canadian Registry of Acute Coronary Events (CANRACE) were stratified by initial PP on presentation. Patient characteristics and in-hospital outcomes were compared by PP quartiles and the independent prognostic significance of PP for in-hospital mortality was quantified. We compared the discriminative ability (c-statistic) of models incorporating either PP or SBP. RESULTS: Patients with higher PPs were older, more frequently female and had higher prevalence rates of conventional cardiovascular risk factors (all p < 0.01). Lower PP was associated with ST-segment elevation myocardial infarction presentation, higher GRACE risk scores and higher rates of adverse in-hospital outcomes (p < 0.001). PP was strongly correlated with SBP (Pearson's correlation coefficient = 0.79, p < 0.001). After adjustment for other GRACE risk model predictors, lower PP was independently associated with in-hospital mortality (first vs. fourth quartile [reference]: adjusted odds ratio 2.57, 95% confidence interval 1.80-3.67). The c-statistic was slightly higher for the multivariable model incorporating SBP as compared to the model with PP (0.868 vs. 0.864, respectively, p = 0.028) for in-hospital mortality. CONCLUSION: Higher presenting PP is associated with increased age and more prevalent cardiovascular risk factors, whereas patients with lower PP present with worse clinical characteristics and in-hospital outcomes. Lower PP is an independent adverse prognosticator in ACS. However, PP did not improve the discriminatory performance of the GRACE risk score compared with SBP.

American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients.

BACKGROUND: Venous thromboembolism (VTE) is the third most common vascular disease. Medical inpatients, long-term care residents, persons with minor injuries, and long-distance travelers are at increased risk. OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and others in decisions about preventing VTE in these groups. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and adult patients. The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 19 recommendations for acutely ill and critically ill medical inpatients, people in long-term care facilities, outpatients with minor injuries, and long-distance travelers. CONCLUSIONS: Strong recommendations included provision of pharmacological VTE prophylaxis in acutely or critically ill inpatients at acceptable bleeding risk, use of mechanical prophylaxis when bleeding risk is unacceptable, against the use of direct oral anticoagulants during hospitalization, and against extending pharmacological prophylaxis after hospital discharge. Conditional recommendations included not to use VTE prophylaxis routinely in long-term care patients or outpatients with minor VTE risk factors. The panel conditionally recommended use of graduated compression stockings or low-molecular-weight heparin in long-distance travelers only if they are at high risk for VTE.

Efficacy and safety of direct oral anticoagulants approved for cardiovascular indications: Systematic review and meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) have emerged as promising alternatives to vitamin K antagonists (VKAs) for patients with non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Few meta-analyses have included all DOACs that have received FDA approval for these cardiovascular indications, and their overall comparisons against VKAs have shortcomings in data and methods. We provide an updated overall assessment of the efficacy and safety of those DOACs at dosages currently approved for NVAF or VTE, in comparison with VKAs. METHODS: We used data from Phase 3 randomized trials that compared an FDA-approved DOAC with VKA for primary prevention of stroke in patients with NVAF or for treatment of acute VTE. RESULTS: Among trial participants with NVAF, DOAC recipients had a lower risk of stroke or systemic embolism [Pooled Odds Ratio (OR) 0.76, 95% Confidence Interval (CI) (0.68-0.84)], any stroke (0.80, 0.73-0.88), systemic embolism (0.56, 0.34-0.93), and total mortality (0.89, 0.84-0.95). Safety outcomes also showed a lower risk of fatal, major, and intracranial bleeding but higher risk for gastrointestinal bleeding (GIB). Patients with acute VTE randomized to DOACs had comparable risk of recurrent VTE and death (OR 0.88, 95% CI 0.75-1.03), recurrent DVT (0.83, 0.66-1.05), recurrent non-fatal PE (0.97, 0.75-1.25), and total mortality (0.94, 0.79-1.12). Safety outcomes for DOACs showed a lower risk of major, fatal, and intracranial bleeding, but similar risk of GIB. CONCLUSIONS: Patients receiving DOACs for NVAF had predominantly superior efficacy and safety. Patients who were treated with DOACs for acute VTE had non-inferior efficacy, but an overall superior safety profile.

Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism.

It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-ß2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915.

Addition of Ezetimibe to statins for patients at high cardiovascular risk: Systematic review of patient-important outcomes.

Ezetimibe is widely used in combination with statins to reduce low-density lipoprotein. We sought to examine the impact of ezetimibe when added to statins on patient-important outcomes. Medline, EMBASE, CINAHL, and CENTRAL were searched through July, 2016. Randomized controlled trials (RCTs) of ezetimibe combined with statins versus statins alone that followed patients for at least 6 months and reported on at least one of all-cause mortality, cardiovascular deaths, non-fatal myocardial infarctions (MI), and non-fatal strokes were included. Pairs of reviewers extracted study data and assessed risk of bias independently and in duplicate. Quality of evidence was assessed using the GRADE approach. We conducted a narrative review with complementary subgroup and sensitivity analyses. IMPROVE-IT study enrolled 93% of all patients enrolled in the 8 included trials. Our analysis of the IMPROVE-IT study results showed that in patients at high risk of cardiovascular events, ezetimibe added to statins was associated with i) a likely reduction in non-fatal MI (17 fewer/1000 treated over 6 years, moderate certainty in evidence); ii) a possible reduction in non-fatal stroke (6 fewer/1000 treated over 6 years, low certainty); iii) no impact on myopathy (moderate certainty); iv) potentially no impact on all-cause mortality and cardiovascular death (both moderate certainty); and v) possibly no impact on cancer (low certainty). Addition of ezetimibe to moderate-dose statins is likely to result in 17 fewer MIs and possibly 6 fewer strokes/1000 treated over 6 years but is unlikely to reduce all-cause mortality or cardiovascular death. Patients who place a high value on a small absolute reduction in MI and are not adverse to use of an additional medication over a long duration may opt for ezetimibe in addition to statin therapy. Our analysis revealed no increased specific harms associated with addition of ezetimibe to statins.

Implantable cardiac defibrillator and mortality in non-ischaemic cardiomyopathy: an updated meta-analysis.

OBJECTIVES: The benefit of implantable cardiac defibrillator (ICD) in symptomatic patients with systolic dysfunction and non-ischaemic cardiomyopathy remains controversial. We conducted a systematic review and meta-analysis to determine the effect of ICD in patients with non-ischaemic cardiomyopathy on (1) all-cause mortality, (2) cardiovascular mortality and (3) sudden cardiac death. METHODS: We searched citations in meta-analyses published until 2012, and in MEDLINE, Embase, PubMed and Cochrane databases from 2012 to October 2016. We included randomised controlled trials (RCTs) evaluating the effect of ICD therapy on all-cause and cardiovascular mortality and sudden cardiac death in patients with non-ischaemic cardiomyopathy. Independent reviewers evaluated study eligibility, abstracted data and assessed risk of bias in duplicate. We used random-effect models to meta-analyse relative risks (RR) and hazard ratios (HR) across studies, the Grades of Recommendation, Assessment, Development, and Evaluation system to quantify absolute effects and quality of evidence, and I2 to evaluate heterogeneity. RESULTS: We identified six RCTs including 1715 patients experiencing 421 deaths. ICD therapy was associated with reduced overall mortality (HR 0.78, 95% CI 0.66 to 0.92, I2 = 0%, risk difference 4.7%, high quality), cardiovascular mortality (RR 0.77, 95% CI 0.60 to 0.98, I2 = 39%, risk difference 3.3%, high quality) and sudden cardiac death (RR 0.45, 95% CI 0.29 to 0.70, I2 = 0%, risk difference 4.1%, high quality). The benefit of ICD was not influenced by the use of amiodarone in the comparison group, the duration of follow-up, by use of β-blockers and ACE inhibitors/angiotensin receptor blocker or cardiac resynchronisation therapy. CONCLUSION: Primary prevention ICD therapy reduces all-cause and cardiovascular mortality and sudden cardiac death in patients with non-ischaemic cardiomyopathy.

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.