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.).

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.

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.

Cerebral Embolic Protection Devices During Transcatheter Aortic Valve Implantation: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Silent ischemic embolic lesions are common after transcatheter aortic valve implantation (TAVI). The use of embolic protection devices (EPD) may reduce the occurrence of these embolic lesions. Thus, a quantitative overview and credibility assessment of the literature was necessary to draw a robust message about EPD. Therefore, the aim of this meta-analysis was to study whether the use of EPD reduces silent ischemic and clinically evident cerebrovascular events associated with TAVI. METHODS: We conducted a comprehensive search to identify studies that evaluated patients undergoing TAVI with or without EPD. Random-effects meta-analyses were performed to estimate the effect of EPD compared with no-EPD during TAVI using aggregate data. RESULTS: Sixteen studies involving 1170 patients (865/305 with/without EPD) fulfilled the inclusion criteria. The EPD delivery success rate was reported in all studies and was achieved in 94.5% of patients. Meta-analyses evaluating EPD versus without EPD strategies could not confirm or exclude any differences in terms of clinically evident stroke (relative risk, 0.70; 95% confidence interval [CI], 0.38-1.29; P=0.26) or 30-day mortality (relative risk, 0.58; 95% CI, 0.20-1.64; P=0.30). There were no significant differences in new-single, multiple, or total number of lesions. The use of EPD was associated with a significantly smaller ischemic volume per lesion (standardized mean difference, -0.52; 95% CI, -0.85 to -0.20; P=0.002) and smaller total volume of lesions (standardized mean difference, -0.23; 95% CI, -0.42 to -0.03; P=0.02). Subgroup analysis by type of valve showed an overall trend toward significant reduction in new lesions per patient using EPD (standardized mean difference, -0.41; 95% CI, -0.82 to 0.00; P=0.05), driven by self-expanding devices. CONCLUSIONS: The use of EPD during TAVI may be associated with smaller volume of silent ischemic lesions and smaller total volume of silent ischemic lesions. However, EPD may not reduce the number of new-single, multiple, or total number of lesions. There was only very low quality of evidence showing no significant differences between patients undergoing TAVI with or without EPD with respect to clinically evident stroke and mortality.

Withholding versus Continuing Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Blockers before Noncardiac Surgery: An Analysis of the Vascular events In noncardiac Surgery patIents cOhort evaluatioN Prospective Cohort.

BACKGROUND: The effect on cardiovascular outcomes of withholding angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in chronic users before noncardiac surgery is unknown. METHODS: In this international prospective cohort study, the authors analyzed data from 14,687 patients (including 4,802 angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users) at least 45 yr old who had in-patient noncardiac surgery from 2007 to 2011. Using multivariable regression models, the authors studied the relationship between withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and a primary composite outcome of all-cause death, stroke, or myocardial injury after noncardiac surgery at 30 days, with intraoperative and postoperative clinically important hypotension as secondary outcomes. RESULTS: Compared to patients who continued their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, the 1,245 (26%) angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users who withheld their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the 24 h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and intraoperative hypotension (adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The risk of postoperative hypotension was similar between the two groups (adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the range of preoperative blood pressures. The practice of withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was only modestly correlated with patient characteristics and the type and timing of surgery. CONCLUSIONS: Withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers before major noncardiac surgery was associated with a lower risk of death and postoperative vascular events. A large randomized trial is needed to confirm this finding. In the interim, clinicians should consider recommending that patients withhold angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 24 h before surgery.

Perioperative Management of Dabigatran: A Prospective Cohort Study.

BACKGROUND: The perioperative management of dabigatran in clinical practice is heterogeneous. We performed this study to evaluate the safety of perioperative management of dabigatran using a specified protocol. METHODS AND RESULTS: Patients treated with dabigatran and planned for an invasive procedure were eligible for inclusion. The timing of the last dose of dabigatran before the procedure was based on the creatinine clearance and procedure-related bleeding risk. Resumption of dabigatran was prespecified according to the complexity of the surgery and consequences of a bleeding complication. Patients were followed up for 30 days for major bleeding (primary outcome), minor bleeding, arterial thromboembolism, and death. We included 541 cases: 324 procedures (60%) with standard risk of bleeding and 217 procedures (40%) with increased risk of bleeding. The last dose of dabigatran was at 24, 48, or 96 hours before surgery according to the protocol in 46%, 37%, and 6%, respectively, of the patients. Resumption was timed according to protocol in 77% with 75 mg as the first dose on the day of procedure in 40% of the patients. Ten patients (1.8%; 95% confidence interval, 0.7-3.0) had major bleeding, and 28 patients (5.2%; 95% confidence interval, 3.3-7.0) had minor bleeding events. The only thromboembolic complication was transient ischemic attack in 1 patient (0.2%; 95% confidence interval, 0-0.5), and there were 4 deaths unrelated to bleeding or thrombosis. Bridging was not used preoperatively but was administered in 9 patients (1.7%) postoperatively. CONCLUSION: Our protocol for perioperative management of dabigatran appears to be effective and feasible.

Aspiration thrombectomy prior to percutaneous coronary intervention in ST-elevation myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: Trials of aspiration thrombectomy (AT) prior to primary percutaneous intervention (PCI) in patients with ST-segment elevation MI (STEMI) have shown apparently inconsistent results and therefore generated uncertainty and controversy. To summarize the effects of AT prior to PCI versus conventional PCI in STEMI patients. METHODS: Searches of MEDLINE, EMBASE and CENTRAL to June 2015 and review of reference lists of previous reviews. We included randomized controlled trials (RCTs) comparing AT prior to PCI with conventional PCI alone. Pairs of reviewers independently screened eligible articles; extracted data; and assessed risk of bias. We used the GRADE approach to rate overall certainty of the evidence. RESULTS: Among 73 potential articles identified, 20 trials including 21,660 patients were eligible; data were complete for 20,866 patients. Moderate-certainty evidence suggested a non statistically significant decrease in overall mortality (risk ratio (RR) 0.89, 95 % confidence interval, 0.78 to 1.01, risk difference (RD) 4/1,000 over 6 months), no impact on recurrent MI (RR 0.94, 95 % CI, 0.79 to 1.12) or major bleeding (RR 1.02, 95 % CI, 0.78 to 1.35), and an increase in stroke (RR 1.56, 95 % CI, 1.09 to 2.24, RD 3/1,000 over 6 months). CONCLUSIONS: Moderate certainty evidence suggests aspiration thrombectomy is associated with a possible small decrease in mortality (4 less deaths/1000 over 6 months) and a small increase in stroke (3 more strokes/1000 over 6 months). Because absolute effects are very small and closely balanced, thrombectomy prior to primary PCI should not be used as a routine strategy.

The epidemiology of venous thromboembolism.

Venous thromboembolism (VTE) is categorized by the U.S. Surgeon General as a major public health problem. VTE is relatively common and associated with reduced survival and substantial health-care costs, and recurs frequently. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and VTE risk factors, including increasing patient age and obesity, hospitalization for surgery or acute illness, nursing-home confinement, active cancer, trauma or fracture, immobility or leg paresis, superficial vein thrombosis, and, in women, pregnancy and puerperium, oral contraception, and hormone therapy. Although independent VTE risk factors and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be relatively constant, or even increasing.

Occurrence and predictors of recurrence after a first episode of acute venous thromboembolism: population-based Worcester Venous Thromboembolism Study.

Venous thromboembolism (VTE) has multiple risk factors and tends to recur. Despite the benefits of anticoagulation, the prevalence of, and case-fatality rate associated with, recurrent VTE remains a concern after an acute episode; it is particularly high during the acute treatment phase. We sought to quantify the magnitude, identify predictors, and develop risk score calculator of recurrence within 3 years after first-time VTE. This was a population-based surveillance study among residents of central Massachusetts (MA), USA, diagnosed with an acute first-time pulmonary embolism and/or lower-extremity deep vein thrombosis from 1999 to 2009 in hospital and ambulatory settings in all 12 central MA hospitals. Medical records were reviewed and validated. The 2989 study patients were followed for 5836 person-years [mean follow-up 23.4 (median 30) months]. Mean age was 64.3 years, 44 % were men, and 94 % were white. The cumulative incidence rate of recurrent VTE within 3 years after an index VTE was 15 % overall, and 25, 13, and 13 % among patients with active cancer, provoked, or unprovoked VTE, respectively. Multivariable regression indicated that active cancer, varicose vein stripping, and inferior vena cava filter placement were independent predictors of recurrence during both 3-month and 3-year follow-up. A risk score calculator was developed based on the 3-month prognostic model. In conclusion, the rate of VTE recurrence over 3 years of follow-up remained high. The risk score calculator may assist clinicians at the index encounter in determining the frequency of clinical surveillance and appropriate outpatient treatment of VTE during the acute treatment phase.

Longer- Versus Shorter-Duration Dual-Antiplatelet Therapy After Drug-Eluting Stent Placement: A Systematic Review and Meta-analysis.

BACKGROUND: The appropriate duration of dual-antiplatelet therapy (DAPT) after drug-eluting stent (DES) placement remains controversial. PURPOSE: To summarize data on clinical outcomes with longer- versus shorter-duration DAPT after DES placement in adults with coronary artery disease. DATA SOURCES: Ovid MEDLINE and EMBASE, 1996 to 27 March 2015, and manual screening of references. STUDY SELECTION: Randomized, controlled trials comparing longer- versus shorter-duration DAPT after DES placement. DATA EXTRACTION: Two reviewers screened potentially eligible articles; extracted data on populations, interventions, and outcomes; assessed risk of bias; and used the Grading of Recommendations Assessment, Development and Evaluation guidelines to rate overall confidence in effect estimates. DATA SYNTHESIS: Among 1010 articles identified, 9 trials including 29,531 patients were eligible; data were complete for 28,808 patients. Moderate-quality evidence showed that longer-duration DAPT decreased risk for myocardial infarction (risk ratio [RR], 0.73 [95% CI, 0.58 to 0.92]) and increased mortality (RR, 1.19 [CI, 1.04 to 1.36]). High-quality evidence showed that DAPT increased risk for major bleeding (RR, 1.63 [CI, 1.34 to 1.99]). LIMITATION: Confidence in estimates were decreased owing to imprecision for most outcomes (particularly myocardial infarction), risk of bias from limited blinding in 7 of 9 studies, indirectness due to variability in use of first- and second-generation stents, and off-protocol use of DAPT in some studies. CONCLUSION: Extended DAPT is associated with approximately 8 fewer myocardial infarctions per 1000 treated patients per year but 6 more major bleeding events than shorter-duration DAPT. Because absolute effects are very small and closely balanced, decisions regarding the duration of DAPT therapy must take into account patients' values and preference. PRIMARY FUNDING SOURCE: None.

D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study.

BACKGROUND: Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment. OBJECTIVE: To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence. DESIGN: Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915). SETTING: 13 university-affiliated clinical centers. PATIENTS: 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy. INTERVENTION: Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month. MEASUREMENTS: Recurrent VTE during an average follow-up of 2.2 years. RESULTS: In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison). LIMITATIONS: Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study. CONCLUSION: The risk for 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 may be low enough to justify stopping therapy in women. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Culprit vessel versus immediate complete revascularization in patients with ST-segment myocardial infarction-a systematic review.

BACKGROUND: Guidelines suggest percutaneous intervention (PCI) of only the culprit artery in patients presenting with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease. However, recent randomized controlled trials (RCTs) suggest benefit to performing PCI of other stenotic vessels at the same time as culprit vessel PCI. METHODS: We conducted a systematic review with complete case meta-analysis and sensitivity analyses. Data sources included MEDLINE, EMBASE, Cochrane Register of Controlled Trials, and CINAHL from 1946 to March 2014; MEDLINE and EMBASE from March 2014 to March 2015; and scanning of literature for new studies until August 2015. All RCTs comparing multivessel versus culprit-only PCI in patients with STEMI were eligible. The primary outcomes of interest were recurrent myocardial infarction (MI), recurrent revascularization, and mortality. We combined data from trials to estimate the pooled risk ratio (RR) and associated 95% CIs using random-effects models. RESULTS: Five RCTs including 1,606 patients of whom 1,568 had complete data proved eligible. Multivessel revascularization was associated with decreased risk of repeat revascularization (RR 0.36, 95% CI 0.27-0.49, risk difference 9.7% over 2 years) and recurrent nonfatal MI (RR 0.58, 95% CI 0.36-0.93, risk difference 1.8% over 2 years), without increase in mortality (RR 0.82, 95% CI 0.53-1.26) or other adverse events. CONCLUSIONS: Pooled data provide moderate-certainty evidence that performance of multivessel PCI will provide an appreciable reduction in nonfatal MI and high-certainty evidence that it will reduce need for repeat revascularization. Patients are likely to place a high value on these benefits.

Cognitive status in patients hospitalized with acute decompensated heart failure.

BACKGROUND: Cognitive impairment is highly prevalent in patients with heart failure and is associated with adverse outcomes. However, whether specific cognitive abilities (eg, memory vs executive function) are impaired in heart failure has not been fully examined. We investigated the prevalence of impairment in 3 cognitive domains in patients hospitalized with acute decompensated heart failure (ADHF) and the associations of impairment with demographic and clinical characteristics. METHODS: The sample included 744 patients hospitalized with ADHF (mean age 72 years, 46% female) at 5 medical centers. Impairment was assessed in 3 cognitive domains (memory, processing speed, executive function) using standardized measures. Demographic and clinical characteristics were obtained from a structured interview and medical record review. RESULTS: A total of 593 (80%) of 744 patients were impaired in at least 1 cognitive domain; 32%, 31%, and 17% of patients were impaired in 1, 2, or all 3 cognitive domains, respectively. Patients impaired in more than 1 cognitive domain were significantly older, had less formal education, and had more noncardiac comorbidities (all P values < .05). In multivariable adjusted analyses, patients with older age and lower education had higher odds of impairment in 2 or more cognitive domains. Depressed patients had twice the odds of being impaired in all 3 cognitive domains (odds ratio 1.98, 95% CI 1.08-3.64). CONCLUSION: Impairments in executive function, processing speed, and memory are common among patients hospitalized for ADHF. Recognition of these prevalent cognitive deficits is critical for the clinical management of these high-risk patients.

Selective D-dimer testing for diagnosis of a first suspected episode of deep venous thrombosis: a randomized trial.

BACKGROUND: D-Dimer testing is sensitive but not specific for diagnosing deep venous thrombosis (DVT). Changing the use of testing and the threshold level for a positive test result on the basis of risk for DVT might improve the tradeoff between sensitivity and specificity and reduce the need for testing. OBJECTIVE: To determine whether using a selective D-dimer testing strategy based on clinical pretest probability (C-PTP) for DVT is safe and reduces diagnostic testing compared with using a single D-dimer threshold for all patients. DESIGN: Randomized, multicenter, controlled trial. Patients were allocated using a central automated system. Ultrasonographers and study adjudicators but not other study personnel were blinded to trial allocation. (ClinicalTrials.gov: NCT00157677) SETTING: 5 Canadian hospitals. PATIENTS: Consecutive symptomatic patients with a first episode of suspected DVT. INTERVENTION: Selective testing (n = 860), defined as D-dimer testing for outpatients with low or moderate C-PTP (DVT excluded at D-dimer levels <1.0 µg/mL [low C-PTP] or <0.5 µg/mL [moderate C-PTP]) and venous ultrasonography without D-dimer testing for outpatients with high C-PTP and inpatients, or uniform testing (n = 863), defined as D-dimer testing for all participants (DVT excluded at D-dimer levels <0.5 µg/mL). MEASUREMENTS: The proportion of patients not diagnosed with DVT during initial testing who had symptomatic venous thromboembolism during 3-month follow-up and the proportion of patients undergoing D-dimer testing and ultrasonography. RESULTS: The incidence of symptomatic venous thromboembolism at 3 months was 0.5% in both study groups (difference, 0.0 percentage point [95% CI, -0.8 to 0.8 percentage points]). Selective testing reduced the proportion of patients who required D-dimer testing by 21.8 percentage points (CI, 19.1 to 24.8 percentage points). It reduced the proportion who required ultrasonography by 7.6 percentage points (CI, 2.9 to 12.2 percentage points) overall and by 21.0 percentage points (CI, 14.2 to 27.6 percentage points) in outpatients with low C-PTP. LIMITATION: Results may not be generalizable to all D-dimer assays or patients with previous DVT, study personnel were not blinded, and the trial was stopped prematurely. CONCLUSION: A selective D-dimer testing strategy seems as safe as and more efficient than having everyone undergo D-dimer testing when diagnosing a first episode of suspected DVT. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Ontario.

Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Use of dexmedetomidine or propofol rather than a benzodiazepine sedation strategy may improve ICU outcomes. We reviewed randomized trials comparing a benzodiazepine and nonbenzodiazepine regimen in mechanically ventilated adult ICU patients to determine if differences exist between these sedation strategies with respect to ICU length of stay, time on the ventilator, delirium prevalence, and short-term mortality. METHODS: We searched CINAHL, MEDLINE, the Cochrane databases, and the American College of Critical Care Medicine's Pain, Agitation, Delirium Management Guidelines' literature database from 1996 to 2013. Citations were screened for randomized trials that enrolled critically ill, mechanically ventilated adults comparing an IV benzodiazepine-based to a nonbenzodiazepine-based sedative regimen and reported duration of ICU length of stay, duration of mechanical ventilation, delirium prevalence, and/or short-term mortality. Trial characteristics and results were abstracted in duplicate and independently, and the Cochrane risk of bias tool was used for quality assessment. We performed random effects model meta-analyses where possible. RESULTS: We included six trials enrolling 1,235 patients: midazolam versus dexmedetomidine (n = 3), lorazepam versus dexmedetomidine (n = 1), midazolam versus propofol (n = 1), and lorazepam versus propofol (n = 1). Compared to a benzodiazepine sedative strategy, a nonbenzodiazepine sedative strategy was associated with a shorter ICU length of stay (n = 6 studies; difference = 1.62 d; 95% CI, 0.68-2.55; I = 0%; p = 0.0007) and duration of mechanical ventilation (n = 4 studies; difference = 1.9 d; 95% CI, 1.70-2.09; I2 = 0%; p < 0.00001) but a similar prevalence of delirium (n = 2; risk ratio = 0.83; 95% CI, 0.61-1.11; I2 = 84%; p = 0.19) and short-term mortality rate (n = 4; risk ratio = 0.98; 95% CI, 0.76-1.27; I2 = 30%; p = 0.88). CONCLUSIONS: Current controlled data suggest that use of a dexmedetomidine- or propofol-based sedation regimen rather than a benzodiazepine-based sedation regimen in critically ill adults may reduce ICU length of stay and duration of mechanical ventilation. Larger controlled studies are needed to further define the impact of nonbenzodiazepine sedative regimens on delirium and short-term mortality.

Safety of withholding anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial compression ultrasound and iliac vein imaging.

BACKGROUND: Compression ultrasonography performed serially over a 7-day period is recommended for the diagnosis of deep vein thrombosis in symptomatic pregnant women, but whether this approach is safe is unknown. We evaluated the safety of withholding anticoagulation from pregnant women with suspected deep vein thrombosis following negative serial compression ultrasonography and iliac vein imaging. METHODS: Consecutive pregnant women who presented with suspected deep vein thrombosis underwent compression ultrasonography and Doppler imaging of the iliac vein of the symptomatic leg(s). Women whose initial test results were negative underwent serial testing on 2 occasions over the next 7 days. Women not diagnosed with deep vein thrombosis were followed for a minimum of 3 months for the development of symptomatic deep vein thrombosis or pulmonary embolism. RESULTS: In total, 221 pregnant women presented with suspected deep vein thrombosis. Deep vein thrombosis was diagnosed in 16 (7.2%) women by initial compression ultrasonography and Doppler studies; none were identified as having deep vein thrombosis on serial testing. One patient with normal serial testing had a pulmonary embolism diagnosed 7 weeks later. The overall prevalence of deep vein thrombosis was 7.7% (17/221); of these, 65% (11/17) of cases were isolated to the iliofemoral veins and 12% (2/17) were isolated iliac deep vein thromboses. The incidence of venous thromboembolism during follow-up was 0.49% (95% confidence interval [CI] 0.09%-2.71%). The sensitivity of serial compression ultrasonography with Doppler imaging was 94.1% (95% CI 69.2%-99.7%), the negative predictive value was 99.5% (95% CI 96.9%-100%), and the negative likelihood ratio was 0.068 (95% CI 0.01-0.39). INTERPRETATION: Serial compression ultrasonography with Doppler imaging of the iliac vein performed over a 7-day period excludes deep-vein thrombosis in symptomatic pregnant women.

Risk-assessment models for predicting venous thromboembolism among hospitalized non-surgical patients: a systematic review.

Venous thromboembolism (VTE) prophylaxis is suboptimal in American hospitals despite long-standing evidence-based recommendations. Data from observational studies indicate a lower uptake of effective prophylaxis in patients hospitalized with medical versus surgical conditions. Reluctance to use prophylaxis in medical patients has been attributed to difficulty in identifying at-risk patients and balancing risks of bleeding against occurrence of VTE. Several risk-assessment models (RAMs) have been proposed to assist physicians in identifying non-surgical patients who need prophylaxis. We conducted a systematic review of published RAMs, based on objective criteria, to determine whether any RAM is validated sufficiently to be employed in clinical practice. We identified 11 RAMs, six derived from primary data and five based on expert opinion. The number, types, and strength of association of VTE risk predictors were highly variable. The variability in methods and outcome measurement precluded pooled estimates of these different models. Published RAMs for VTE lack generalizability and adequate validation. As electronic health records become more ubiquitous, validated dynamic RAMs are needed to assess VTE risk at the point-of-care in real time.

Isolated calf deep vein thrombosis in the community setting: the Worcester Venous Thromboembolism study.

The prevalence of isolated calf deep vein thrombosis (DVT) in the community setting is relatively unexplored. Confusion remains with regards to its management and contemporary natural history. The purpose of this investigation was to describe the number of cases of calf DVT in the community, use of early management strategies, and rates of venous thromboembolism (VTE) recurrence and major bleeding. The medical records of residents of the Worcester (MA) metropolitan area with ICD-9 codes consistent with potential VTE during 4 study years (1999/2001/2003/2005) were validated by trained nurses. Patient demographic/clinical characteristics, treatment practices, and outcomes were evaluated. Isolated calf DVT was diagnosed in 166 (11.1%) of 1,495 patients with lower extremity DVT. Patients with calf DVT were less likely to be discharged on anticoagulants or with an IVC filter than patients with proximal DVT (84.1 vs. 92.3%). The rates of VTE recurrence and pulmonary embolism did not differ significantly between patients with calf DVT and proximal DVT at 6 months (11.0 vs. 8.7%, 2.6 vs. 1.8%, respectively). Patients with calf DVT had higher adjusted risk of early (14-day) VTE recurrence/extension (OR 2.34, 95% CI 1.01-5.44). Patients with calf DVT had lower rates of major bleeding at 6 months compared to patients with proximal DVT (5.2 vs. 9.3%, P = 0.04). Rates of recurrent VTE and major bleeding following calf DVT in the community are much higher than in randomized clinical trials of patients with proximal or calf DVT. Further study of management strategies for isolated calf DVT is needed.

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.