Recent Research

VTE risk after joint replacement, antipsychotics and MI, and more.


Factor Xa inhibitors lower DVT risk in hip, knee replacement

For patients undergoing total hip or knee replacement, lower doses of oral direct factor Xa inhibitors reduce the risk of symptomatic deep venous thrombosis (DVT) compared to low-molecular-weight heparin (LMWH), a review found.

Current guidelines recommend routine postprocedural thromboprophylaxis with vitamin K antagonists, LMWH or synthetic pentasaccharides (fondaparinux) for hip and knee replacements. The latter two require daily subcutaneous injection, while vitamin K antagonists require laboratory monitoring. Researchers searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials in patients undergoing hip or knee replacement. All trials evaluated oral factor Xa inhibitors compared to any pharmacologic or nonpharmacologic thromboprophylactic intervention. Reported outcomes were mortality at the end of prophylaxis or during follow-up, symptomatic DVT, nonfatal pulmonary embolism (PE), major bleeding, intracranial bleeding, and bleeding leading to reoperation. After exclusions, there were 22 trials in the analysis, all of which compared factor Xa inhibitors to LMWH.

The review found that factor Xa inhibitors can prevent three to four instances of symptomatic DVT per 1,000 treated patients but may increase major bleeding by two events per 1,000 patients. High doses of oral factor Xa inhibitors increased bleeding versus LMWH, but low doses didn't. The absolute effect of the two treatments didn't differ in terms of all-cause mortality or nonfatal PE. Results were published in the May 15 Annals of Internal Medicine.

Limitations include that most trials didn't report outcomes data for a significant proportion of patients, and in one-third of trials, the follow-up period was 14 days or less. The review results do indicate that oral factor Xa inhibitors are a “convenient alternative” to LMWH and fondaparinux, the researchers wrote. “Clinicians and patients must make trade-offs between the convenience of use and small absolute reduction in thrombosis with lower-dose factor Xa inhibitors and the increased costs of the newer agents and the possibility that other adverse effects may emerge over the long term,” they wrote.

Longer venous thromboprophylaxis after total hip replacement decreases events

Venous thromboprophylaxis for 21 days or more after total hip replacement lowers risk for venous thromboembolism (VTE), pulmonary embolism (PE) and deep venous thrombosis (DVT) while increasing the risk for minor bleeding, according to a recent study.

Researchers performed a systematic review of randomized, controlled trials that compared prolonged versus standard-duration thromboprophylaxis (≥21 days vs. 7 to 10 days) after orthopedic surgery (total hip or knee replacement and hip fracture surgery) and reported on thromboembolic or bleeding outcomes. Eight trials involving 2,917 participants were deemed eligible for inclusion; three trials were of good quality and five were of fair quality. Six of the eight trials examined the use of warfarin, enoxaparin and dalteparin in patients undergoing total hip replacement. The mean patient age was 63 to 79 years, and 38% to 74% of patients were women. The study results were published in the May 15 Annals of Internal Medicine.

Overall, high-strength evidence indicated that patients who received prolonged rather than standard-duration therapy after total hip replacement had fewer PEs (5 trials; odds ratio [OR], 0.14; absolute risk reduction [ARR], 0.8%), asymptomatic DVTs (4 trials; relative risk [RR], 0.48; ARR, 5.8%), symptomatic DVTs (4 trials; OR, 0.36; ARR, 1.5%), and proximal DVTs (6 trials; RR, 0.29; ARR, 7.1%). Moderate-strength evidence indicated that those who received prolonged therapy had fewer symptomatic, objectively confirmed VTE episodes (4 trials; RR, 0.38; ARR, 5.7%), nonfatal PEs (4 trials, OR, 0.13; ARR, 0.7%), and DVTs (7 trials; RR, 0.37; ARR, 12.1%). According to high-strength evidence, patients who received prolonged therapy had more minor bleeding events (OR, 2.44; absolute risk increase, 6.3%). One trial suggested that patients who had hip fracture surgery and received prolonged prophylaxis had more episodes of bleeding at the surgical site (OR, 7.55), but the evidence was deemed insufficient.

The authors acknowledged that they found limited good-quality data on knee replacement and hip fracture surgery, that most of the included trials involved relatively few events, and that they did not evaluate costs, among other limitations. However, they concluded that prolonged thromboprophylaxis increases risk for minor bleeding after total hip replacement but decreases risk for VTE, PE and DVT. Future studies, they wrote, should be larger and should evaluate newer anticoagulants as well as total knee replacement and surgery for hip fracture.

Antipsychotics associated with MI in patients treated for dementia

Antipsychotics are associated with a modestly increased risk for myocardial infarction (MI) in older patients also taking cholinesterase inhibitors for dementia, according to a recent study.

Researchers in Quebec used data from a prescription claims database to perform a retrospective cohort study of patients 66 years of age and older who began treatment with cholinesterase inhibitors between Jan. 1, 2000, and Dec. 31, 2009. Patients in the cohort who began using antipsychotics during the study period were matched with a random sample of patients who were not taking antipsychotics. The goal of the study was to determine the association of MI with use of antipsychotics in patients with treated dementia. Results appeared in the April 23 Archives of Internal Medicine.

Among 37,138 patients with treated dementia, 10,969 (29.5%) began taking antipsychotics during the study period. These patients were matched with 10,969 patients who were not taking antipsychotics. Within one year, an MI occurred in 1.3% of those who were taking antipsychotics and 1.2% of those who were not. Compared with patients not taking antipsychotics, the hazard ratios for MI risk were 2.19 (95% CI, 1.11 to 4.32), 1.62 (95% CI, 0.99 to 2.65), 1.36 (95% CI, 0.89 to 2.08), and 1.15 (95% CI, 0.89 to 1.47), respectively, for the first 30 days, first 60 days, first 90 days, and first 365 days. In the case series study, which involved 804 MIs in patients starting antipsychotics, incidence rate ratios for 1 to 30 days, 31 to 60 days, and 61 to 90 days were 1.78 (95% CI, 1.26 to 2.52), 1.67 (95% CI, 1.09 to 2.56), and 1.37 (95% CI, 0.82 to 2.28), respectively.

The authors noted that the start date for antipsychotic therapy may not have been assessed correctly in all patients, among other limitations. However, they concluded that antipsychotics are associated with a modest increase in risk for MI among patients taking cholinesterase inhibitors for dementia, and this risk is highest in the first month after antipsychotics are started.

An accompanying invited commentary stressed that previous research on this topic is inconsistent and that no biological mechanism can currently explain a relationship between antipsychotics and MI risk.

“Important lessons about the pathogenesis of cardiovascular disease may underlie the observed association between antipsychotic drug use and [acute MI] … but we must await further research to clarify the mechanisms contributing to this association,” the commenting authors wrote. “Meanwhile, physicians should limit prescribing of antipsychotic drugs to patients with dementia and instead use other techniques when available, such as environmental and behavioral strategies, to keep these patients safe and engaged.”

Association of race questioned in differences with bleeds during reperfusion

Black patients with ST-elevation myocardial infarction (STEMI) treated with either fibrinolysis or primary percutaneous coronary intervention (PPCI) had higher risk of bleeding events.

Researchers evaluated data on blacks and whites with STEMI or presumed new left bundle branch block on electrocardiogram treated with either fibrinolysis or PPCI between July 2000 and December 2006. They were stratified into four groups: whites treated with fibrinolysis, whites treated with PPCI, blacks treated with fibrinolysis and blacks treated with PPCI. Results were published in the April 10 Circulation.

In fibrinolytic-treated STEMI patients, blacks (n=2,283) had higher bleeding rates than whites (n=42,243) (10.9% vs. 10.3%, adjusted odds ratio [OR] 1.21; 95% CI, 1.02 to 1.43). Similarly, in PPCI-treated patients, blacks (n=2,826) had higher bleeding rates than whites (n=46,332) (10.3% vs. 7.8%, adjusted OR 1.33; 95% CI 1.13 to 1.56). Bleeding was higher among blacks compared with whites treated with any form of reperfusion (adjusted OR, 1.35; 95% CI, 1.13 to 1.60; P<0.001).

Overall in-hospital mortality was similar between blacks and whites treated with fibrinolysis (OR, 0.99; 95% CI, 0.70 to 1.40) or with PPCI (OR, 1.05; 95% CI, 0.76 to 1.46). For either reperfusion strategy, bleeding in general was associated with higher mortality than those with no bleeding. Mortality did not differ significantly between blacks and whites when they were grouped by those who did or did not have any bleeding.

Blacks treated with fibrinolysis had a higher risk of bleeding despite younger age and higher body mass index and regardless of whether they underwent invasive procedures, the authors noted. “Our findings that ethnicity had no influence on in-hospital mortality in absence of bleeding after either chemical or mechanical reperfusion and that bleeding was consistently associated with increased in-hospital mortality suggest that efforts should be directed at understanding and implementing strategies for reducing bleeding in those receiving either form of reperfusion,” they wrote.

An editorialist commented that determining causality between two post-baseline clinical events in a registry dataset “is fraught with confounding and bias” and adding race makes the analysis more treacherous. Management by transfusion, the location of the bleed and other intervening medical events further compound the analysis.

“[T]he authors have overextended their data, speculating that higher rates of bleeding in African Americans may explain higher long-term mortality observed in other datasets,” he wrote. “In fact, temporal analyses of bleeding and mortality demonstrate a waning of the strength of the association as the time interval increases, with no significant effect after 40 days.”

Fixed-dose rivaroxaban noninferior to standard therapy for PE

Fixed-dose rivaroxaban is as effective as standard anticoagulant therapy for pulmonary embolism (PE) and may have a lower bleeding risk, a recent study found.

Researchers conducted a four-year, randomized, open-label noninferiority trial with 4,832 patients who had acute symptomatic PE with or without deep vein thrombosis (DVT). Patients came from 263 sites in 38 countries.

Half received 15 mg of rivaroxaban twice a day for three weeks, followed by 20 mg once daily. The other, “standard therapy” patients received enoxaparin at a dose of 1.0 mg per kilogram of body weight twice daily, plus warfarin or acenocoumarol. Treatment lasted for three, six, or 12 months, with duration determined by the treating physician before randomization.

The primary efficacy outcome was symptomatic recurrent venous thromboembolism (VTE), and the primary safety outcome was a first major or clinically relevant nonmajor bleeding event. The study was supported by Bayer Healthcare and Janssen Pharmaceuticals.

There were 50 symptomatic recurrent VTE events in the rivaroxaban group (2.1%), which was noninferior to the 44 events in the standard therapy group (1.8%; hazard ratio [HR], 1.12; noninferiority margin, 2.0; P=0.003). The primary safety outcome occurred in 10.3% of rivaroxaban patients and 11.4% of standard-therapy patients (HR, 0.90; P=0.23). Major bleeding was seen in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (HR, 0.49; P=0.003). Rates of other adverse outcomes were similar between the two groups. Results were published in the April 5 New England Journal of Medicine.

Study strengths included that the population represented the real-life spectrum of patients who present with symptomatic PE, excluding those for whom fibrinolysis is planned, the authors said. Nearly 25% had extensive disease, and nearly 25% had concomitant symptomatic DVT, for example.

The study's open design may have caused a slight diagnostic-suspicion bias against rivaroxaban, the authors noted. There was a higher number of suspected VTE events in the rivaroxaban group than in the enoxaparin group, yet confirmed event rates were similar.

Overall, this study's findings, combined with the authors' previous study in DVT patients, “support the use of rivaroxaban as a single oral agent for patients with (VTE),” they said. The fixed-dose regimen will simplify treatment by obviating the need for laboratory monitoring that accompanies standard therapy, they said.

Bupivacaine, propofol could be easily confused, safety group warns

A medication safety coalition recently warned that local anesthetic bupivacaine (Exparel) looks similar to propofol, and its accidental use could cause serious adverse events and death.

Bupivacaine (Exparel) and propofol are both white emulsions used in similar settings and are packaged in vials that look similar. “When prepared in syringes these products essentially look identical,” according to the alert by the National Alert Network, a coalition of members of the National Coordinating Council on Medication Error Reporting and Prevention.

If bupivacaine is accidentally administered intravenously instead of propofol, it may result in toxic blood concentrations and depressed cardiac conductivity and excitability. These may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, the alert said. To date, there have been no reports of mix-ups of these two medications, it said.

To prevent the possibility of errors, the two products should be stored in separate areas and staff members should be reminded not to leave any medication or syringe unlabeled, it said. Directions for treatment of bupivacaine toxicity should be available in all surgical areas where bupivacaine is used.

Colistin safe, effective in treating ventilator-associated pneumonia

Colistin seems to be as effective and safe as usual antibiotics for treating ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) gram-negative organisms, a review found.

Researchers searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews for studies that compared intravenous and/or adjunctive aerosolized colistin to other antibiotics for treating VAP in people without cystic fibrosis. Pneumonia was considered VAP if the onset occurred at least 48 hours after intubation and the infection had not been incubating before. The researchers standardized the doses used to colistin base activity (since there is no standard formulation of colistimethate sodium used worldwide). Results were published in the March Clinical Infectious Diseases.

In the six controlled studies that met inclusion criteria, there was no significant difference in clinical response between colistin (72% favorable response) and control groups (odds ratio [OR], 1.14; P=0.56). Colistin's efficacy was independent of study design, and there was no significant change in clinical response after controlling for concomitant antibiotics (P=0.95) or for the administration route of colistin. In-hospital mortality (34% with colistin), length of stay in the intensive care unit, and nephrotoxicity didn't differ significantly by treatment with colistin versus controls. The results from 14 single-arm studies lined up with the results from the controlled studies.

Study limitations include variability in the quality of studies analyzed, as well as in the methods and interpretation of susceptibility testing used, the authors noted. Strengths include the rigorous design, sample size, uniform definition of VAP, and the fact that the groups in the study had similar severity-of-illness scores, they said. The researchers stressed that they do not suggest colistin as first-line therapy for VAP caused by MDR gram-negative organisms; rather, “it should be considered as an alternative option once the susceptibility results are available,” they wrote.

Harms of antiplatelet therapy may outweigh benefits in chronic kidney disease

Antiplatelet therapy may have uncertain benefits that could be outweighed by bleeding risk in patients with chronic kidney disease (CKD), according to a recent study.

Researchers performed a systematic review and meta-analysis to determine how antiplatelet therapy affected cardiovascular events and mortality and bleeding rates in CKD patients. They searched the EMBASE and Cochrane databases through November 2011 to find 40 randomized trials in adult CKD patients that compared antiplatelet agents with standard care, no treatment, or placebo. Nine of the included trials reported on 9,969 patients with CKD who had acute coronary syndromes or were undergoing percutaneous coronary intervention; all of these data were post hoc analyses of CKD patients from larger trials. The remaining 31 trials reported on 11,701 CKD patients with stable cardiovascular disease or no cardiovascular disease. The study results were published in the March 20 Annals of Internal Medicine.

In the nine trials involving post hoc analyses, glycoprotein IIb/IIIa inhibitors or clopidogrel added to standard care increased serious bleeding compared with standard care alone, but had little or no effect on all-cause or cardiovascular mortality or myocardial infarction rates in patients with acute coronary syndromes. In the 31 trials of patients with CKD and stable or no cardiovascular disease, antiplatelet agents compared with placebo or no treatment protected against myocardial infarction but did not necessarily improve mortality rates and they increased rates of minor bleeding. All of these findings were based mainly on low-quality evidence.

The authors noted that their conclusions were based on trial-level rather than individual-patient data, that the available data overall were limited, and that the included trials were of different durations and used different definitions of bleeding outcomes, among other limitations. However, they concluded that the evidence supporting antiplatelet therapy in patients with CKD is of low quality. “Bleeding hazards and lack of clear efficacy in reducing cardiovascular morbidity and mortality need to be acknowledged when patients with CKD are being counseled about acute or long-term antiplatelet therapy,” they wrote.

Hospital Compare website didn't reduce mortality

Public reporting on hospital quality via the Hospital Compare website had minimal impact on mortality rates for three key conditions, a recent study found.

Researchers used Medicare claims data from 2000-2008 to estimate the effect of Hospital Compare (which went public in April 2005) on 30-day mortality rates for heart attack, heart failure and pneumonia. In their first analysis, the study authors compared only the mortality rates before and after Hospital Compare launched and found significant improvements for all three conditions: Relative risk for 30-day mortality after quality reporting began was 0.83 for heart attack, 0.87 for heart failure and 0.78 for pneumonia compared to before.

However, in the next analysis, researchers adjusted for quality improvement that was likely unrelated to Hospital Compare. They used trend data from before the reporting initiative to show that mortality had already been steadily improving, and comparison data from three conditions that were not publicly reported but also improved: stroke, gastrointestinal hemorrhage and hip fracture. Once the statistics were adjusted for those factors, Hospital Compare was associated only with a small reduction in heart failure mortality. Relative risk ratios were 1.01 for heart attack, 0.97 for heart failure and 1.07 for pneumonia. According to the authors, “the entire effect of Hospital Compare was a result of within-hospital changes in mortality.”

The study also looked for any effect of Hospital Compare on patients' selection of hospitals and found little impact, which may indicate that patients and physicians weren't using the quality reporting info or that patients didn't understand how it should inform their hospital choice, the authors speculated. The results were published in the March Health Affairs.

Although the study indicates that the development of Hospital Compare had very little impact on mortality for these conditions, that does not imply that public quality reporting, and even Hospital Compare itself, cannot improve patient outcomes, the authors concluded. They called for future research to improve the structure of Hospital Compare to encourage better patient outcomes and to encourage the use of high quality hospitals.

Guidelines advise restrictive strategy for red blood cell transfusion

The American Association of Blood Banks (AABB) recommends a restrictive red blood cell transfusion strategy for hospitalized, stable patients, according to recent guidelines.

Physicians should consider transfusing at a hemoglobin threshold of 7 to 8 g/dL, as existing evidence shows no difference in mortality, ability to walk independently, or length of hospital stay between patients on a liberal transfusion strategy or a restrictive strategy, the guidelines said. This recommendation grade was “strong” and based on high-quality evidence.

Other recommendations include the following:

  • Adhere to a restrictive transfusion strategy in hospitalized patients with preexisting cardiovascular disease and consider transfusion for patients with symptoms of anemia or a hemoglobin less than or equal to 8 g/dL. There is some uncertainty about the risk for perioperative myocardial infarction with this approach (weak recommendation; moderate-quality evidence).
  • There is insufficient evidence to recommend for or against a liberal or restrictive transfusion strategy for hospitalized, hemodynamically stable patients with acute coronary syndrome (uncertain recommendation; very low-quality evidence).
  • Consider symptoms as well as hemoglobin concentration when making transfusion decisions (weak recommendation; low-quality evidence).

The guidelines were crafted by a panel of 20 experts who systematically reviewed randomized clinical trials from 1950 to 2011 that evaluated transfusion thresholds. They examined the proportion of patients who received any red cell transfusion and the number of red cell units transfused to determine the impact of restrictive transfusion strategies on red blood cell usage.

The experts also examined the following clinical outcomes of restrictive strategies: overall mortality, nonfatal myocardial infarction, cardiac events, pulmonary edema, stroke, thromboembolism, renal failure, infection, hemorrhage, mental confusion, functional recovery, and length of hospital stay.

The guidelines were published online March 26 by Annals of Internal Medicine.