Thromboprophylaxis, heart failure decongestion, and more

Research summaries from ACP Hospitalist Weekly.

Rivaroxaban after discharge may reduce thromboembolic risk in medically ill

Patients hospitalized for an acute medical illness who receive extended-duration prophylaxis with rivaroxaban at discharge may have a lower risk for fatal and major thromboembolic events, according to a recent industry-funded study.

Researchers used data from the MARINER trial, which was funded by Janssen Research and Development, to determine whether medically ill patients with additional risk factors for venous thromboembolism (VTE) had a lower risk if they received prophylaxis with rivaroxaban for an extended period after hospitalization. Patients were randomly assigned to receive rivaroxaban, 10 mg daily, or placebo at hospital discharge for 45 days if they were at least 40 years of age, had been hospitalized for an acute medical illness for at least three and no more than 10 consecutive days, and had a baseline creatinine clearance of 50 mL/min or more.

The efficacy outcome, a prespecified secondary end point, was a composite of symptomatic VTE, myocardial infarction, nonhemorrhagic stroke, and cardiovascular death. The main safety outcome, major bleeding, was defined as fatal bleeding, bleeding into a critical organ, or bleeding that led to a decrease of at least 2 g/dL of hemoglobin or transfusion of at least 2 units of blood. The results of the study were published June 22 by the Journal of the American College of Cardiology and appeared in the June 30 issue.

The intention-to-treat population included 4,909 patients in the MARINER trial assigned to rivaroxaban and 4,913 assigned to placebo. Mean patient age was 67.8 years, 55.5% were men, and mean baseline creatinine clearance was 87.8 mL/min. Mean hospitalization duration was 6.7 days. Most patients (96.5%) were white. The most common diagnosis at admission was heart failure with reduced ejection fraction of 45% or lower, which was present in 37.2% of patients. Overall, 1.28% of patients in the rivaroxaban group and 1.77% of patients in the placebo group experienced the composite efficacy end point (hazard ratio, 0.72; 95% CI, 0.52 to 1.00; P=0.049). In the safety analysis, which included 4,890 patients each in the rivaroxaban and placebo groups, 0.27% and 0.18%, respectively, experienced major bleeding (hazard ratio, 1.44; 95% CI, 0.62 to 3.37; P=0.398).

The authors noted that their study should be considered exploratory because the MARINER trial did not meet its primary efficacy end point. In addition to other limitations, they also pointed out that approximately 50% of the study population was taking aspirin at baseline. However, they concluded that extended-duration thromboprophylaxis with low-dose rivaroxaban started after discharge in patients hospitalized for a medical illness significantly reduced the combined risk for fatal and major thromboembolic events with no significant increase in major bleeding. The benefit appeared to start after the first week of treatment and continued through the end of the study at 45 days, they said. “These data suggest that in properly selected patients at risk for VTE and at low risk for bleeding, that extended-duration rivaroxaban at 10 mg has a favorable benefit risk profile,” the authors wrote.

The author of an accompanying editorial noted that both rivaroxaban in this substudy of the MARINER trial and betrixaban in a substudy of the APEX trial were associated with a reduction in overall cardiovascular events. “The findings with rivaroxaban and betrixaban suggest that we should abandon a silo approach for the prevention of venous or arterial thrombosis and promote a holistic strategy to vascular disease,” the editorialist wrote. However, he also cautioned that it will be difficult to put the findings of these trials into practice. “The American Society of Hematology guidelines recommend against the use of extended-duration anticoagulant prophylaxis after hospital discharge,” he wrote. “Those physicians who advocate for out-of-hospital VTE prophylaxis will have to convince their colleagues on the hospital formulary committees.”

Kidney function decline linked to adverse outcomes in heart failure only when decongestion isn't succeeding

Decongestion measures in patients hospitalized for acute decompensated heart failure appear to alleviate the risks associated with declines in acute kidney function, a recent study found.

Researchers used data from the EVEREST trial to evaluate the association between in-hospital changes in estimated glomerular filtration rate (eGFR) and death, plus a composite outcome of cardiovascular death and heart failure hospitalization. The study's objective was to evaluate and compare a variety of serum markers of volume overload and hemoconcentration to determine if they can better inform clinicians in interpreting acute declines in kidney function. Declines in eGFR were examined along with changes in markers of volume overload, such as B-type natriuretic peptide (BNP), N-terminal prohormone of BNP (NT-proBNP), and weight, and changes in measures of hemoconcentration, such as hematocrit, albumin level, and total protein level. Results of the study were published by JACC: Heart Failure on June 10 and appeared in the July 1 issue.

Image by Getty Images
Image by Getty Images

A total of 3,715 patients were included in the study, with a median follow-up of 9.9 months. Overall, 2,632 patients (71%) had hypertension and 1,426 (39%) had diabetes. The median eGFR at baseline was 57 mL/min/1.73 m2. Nine hundred thirty-one patients (25%) died and 1,517 (41%) had cardiovascular death or rehospitalization for heart failure during follow-up. In adjusted models, every 30% decline in eGFR during hospitalization was associated with a higher risk of both death (hazard ratio [HR], 1.19; 95% CI, 1.07 to 1.31) and the composite outcome (HR, 1.09; 95% CI, 1.01 to 1.18). Acute decline in eGFR was not associated with higher risk of either outcome, however, when markers indicated decongestion. Examples of such indicators included declines in BNP, NT-proBNP, or weight or increases in hematocrit, albumin level, or total protein level. Interaction testing for decline in eGFR and changes in hematocrit, albumin, and total protein found statistical significance (P<0.01 for the interaction with death and P≤0.01 for the interaction with the composite outcome), but statistical significance was not found for the interaction between change in eGFR and changes in BNP, NT-proBNP, and weight.

The study excluded patients who did not have repeat kidney function measurements and EVEREST did not include patients with a creatinine level above 3.5 mg/dL, among other limitations, the authors noted. They concluded that while acute declines in eGFR are associated with adverse outcomes among patients with acute decompensated heart failure, this association appears to weaken when markers of decongestion are improving. “The relation between acute declines in eGFR and clinical outcomes among patients admitted for [acute decompensated heart failure] is modified by change in a comprehensive panel of markers of decongestion; that is, acute declines in kidney function were only associated with an increased risk of mortality and cardiovascular outcomes when markers of decongestion worsened but not when markers of congestion improved,” the authors wrote. “The interactions were stronger between decline in kidney function and markers of hemoconcentration than with markers of volume overload; however, the trends were consistent.”

CRP-guided or 7-day regimens noninferior to 14 days of antibiotics for bacteremia

In adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for C-reactive protein (CRP)-guided antibiotic treatment duration and fixed seven-day treatment were noninferior to that of fixed 14-day treatment duration, a randomized trial found.

Researchers conducted a point-of-care randomized trial of adults hospitalized with gram-negative bacteremia between April 2017 and May 2019 at three tertiary care hospitals in Switzerland. On day five of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood cultures, patients who were afebrile for 24 hours without evidence of complicated infection (e.g., abscess) or severe immunosuppression were randomized to an individualized CRP-guided antibiotic treatment duration (i.e., discontinuation once CRP level declined by 75% from peak), a fixed seven-day treatment duration, or a fixed 14-day treatment duration. Physicians and patients were blinded between randomization and antibiotic discontinuation. The primary outcome was the clinical failure rate at day 30, defined as the presence of recurrent bacteremia, local suppurative complication, distant complication (i.e., growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death from any cause. A secondary outcome was the clinical failure rate on day 90 of follow-up. Results were published online on June 2 by JAMA.

Five hundred four participants (median age, 79 years; 61% women) were randomly assigned to CRP-guided antibiotics (n=170), seven-day treatment duration (n=169), or 14-day treatment duration (n=165). Overall, 493 (98%) participants completed 30-day follow-up and 448 (89%) completed 90-day follow-up. The primary outcome occurred in four of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the seven-day group, and nine of 163 (5.5%) in the 14-day group (difference in CRP group vs. 14-day group, −3.1% [one-sided 97.5% CI, −∞ to 1.1]; P<0.001; difference in seven-day group vs. 14-day group, 1.1% [one-sided 97.5% CI, −∞ to 6.3]; P<0.001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the seven-day group, and 16 of 153 (10.5%) in the 14-day group. Of note, 34 of the 164 patients (21%) in the CRP group who completed 30-day follow-up had protocol violations related to treatment assignment.

Among other limitations, daily CRP measurements were integrated into routine care (i.e., generally drawn at least every two days) and not strictly enforced, the study authors noted. They added that interpretation of the results is limited by an event rate that was lower than the prespecified noninferiority margin, as well as a relatively lower adherence to assigned treatment durations in the CRP-guided group.

Stroke transitional care model not effective in real-world practice

A transitional care management program for postacute stroke was not used consistently and had no effect on functional status at 90 days, a recent study found.

The pragmatic cluster-randomized trial, the COMPASS (Comprehensive Post-Acute Stroke Services) study, involved 40 hospitals in North Carolina, 20 assigned to provide the transitional care intervention and 20 assigned to provide usual care after stroke. Patients were enrolled if they were hospitalized for stroke or transient ischemic attack and discharged home between 2016 and 2018. The transitional care intervention used social and functional determinants of health to develop individualized care plans that included supported education, secondary prevention, rehabilitation, recovery, referrals to community-based resources, and caregiver support services. Patients received telephone follow-up within two business days of hospital discharge and a clinic visit 7 to 14 days after discharge. Ninety-day outcomes were assessed by blinded telephone interview. The study's primary outcome was functional status as assessed by the Stroke Impact Scale-16. Secondary outcomes were mortality rates, disability, medication adherence, depression, cognition, self-rated health, fatigue, care satisfaction, home blood pressure monitoring, and falls. Results were published by Circulation: Cardiovascular Quality and Outcomes on June 1.

Thirty-nine hospitals participated for at least 12 months between July 2016 and March 2018, and one hospital that enrolled no patients was excluded from analyses. Sixty-four percent of eligible patients were enrolled in the study; 2,689 patients received transitional care, and 3,193 received usual care. Delivery of the transitional care intervention was uninterrupted in 58% of the intervention hospitals, and 35% of intervention hospital patients attended a COMPASS clinic visit. In intention-to-treat analysis, 59% of patients had the primary outcome measured, but it did not appear to be affected significantly by the intervention, with a mean Stroke Impact Scale-16 score of 80.6±21.1 in the intervention group versus 79.9±21.4 in the usual care group. Seventy-two percent of intervention patients and 64% of usual care patients self-reported home blood pressure monitoring (adjusted odds ratio, 1.43; 95% CI, 1.21 to 1.70). No between-group differences were seen in any of the other secondary outcomes.

The authors noted that case ascertainment was not complete, that a low proportion of patients received the intervention, and that unmeasured confounding may have affected their results. They concluded that their trial offers a realistic assessment of the uptake of transitional care in real-world practice among different hospitals and health systems and noted that most clinical practices are not prepared to modify their care systems to provide comprehensive management after acute stroke. A post hoc analysis, however, did suggest a benefit among patients who received the transitional care model versus those who received no comprehensive transitional care, the authors noted. “The escalating prevalence of stroke-related disability and the lack of a decline in secondary stroke mortality require that health systems expand the scope of comprehensive care to include [transitional care],” they wrote. “In addition to CMS reimbursement and policies, expanding the scope of Joint Commission Comprehensive Stroke Certification and Get With The Guidelines programs to include [transitional care] will require policy changes to incentivize health systems to deliver the care we have agreed patients need.”

An accompanying editorial noted the challenges and complexity involved with the trial but said that although it didn't show a significant change in patient outcomes, it is an important landmark for studying large-scale interventions related to transitions of care in acute stroke. “For too long the at-home challenges that patients with stroke and their caregivers face, which occur largely out-of-view of the typical clinical environment, have been ignored,” the editorialist wrote. “The COMPASS study demonstrates that it is time to start addressing the problem of stroke transition with greater seriousness—the problem is complex and the challenges great, but the need of the patient with stroke and caregiver has never been greater.”

Postoperative antibiotic prophylaxis may not reduce risk of surgical-site infection

A recent systematic review and meta-analysis found no conclusive evidence of benefit with postoperative continuation of antibiotic prophylaxis compared to its immediate discontinuation.

Researchers looked at 52 randomized controlled trials with 19,273 participants that compared the effect of postoperative antibiotic prophylaxis continuation versus discontinuation on the incidence of surgical-site infection. The trials involved participants who had any surgical procedure with an indication for antibiotic prophylaxis. The primary outcome was the effect of prophylaxis continuation versus its immediate discontinuation on the occurrence of surgical-site infection, with a prespecified subgroup analysis for studies that did and did not adhere to current best practice standards regarding timing and intraoperative repetition of surgical antibiotic prophylaxis. Results were published online on May 26 by The Lancet Infectious Diseases and appeared in the Oct. 1 issue.

The pooled relative risk (RR) of surgical-site infection with postoperative continuation of antibiotic prophylaxis versus its immediate discontinuation was 0.89 (95% CI, 0.79 to 1.00), with low heterogeneity in effect size between studies. However, the benefits of postoperative continuation were only seen in the 27 trials that did not adhere to best practice standards. While the RR of surgical-site infection was 0.79 (95% CI, 0.67 to 0.94) with continuation versus discontinuation in these trials, the RR was 1.04 (95% CI, 0.85 to 1.27) in trials that met best practice standards (P=0.048 for comparison).

The study authors noted that fewer than half of included trials used current best practices of surgical antibiotic prophylaxis; therefore, the findings may overestimate the true effect of postoperative antibiotic prophylaxis continuation. Other limitations include the use of aggregate data versus individual patient data and the fact that an exploratory subgroup analysis of certain surgical subspecialties was restricted because many subgroups had too few patients.

Increased awareness and education about surgical antibiotic prophylaxis are warranted for both clinicians and patients, and surgeons and anesthesiologists should prioritize antimicrobial stewardship efforts, the study authors noted. “Our findings support [World Health Organization] recommendations against the practice of continuing surgical antibiotic prophylaxis postoperatively,” they concluded. “Considering the associated adverse effects—in particular, antimicrobial resistance—this prevalent practice has no basis.”

Compression stockings may be unnecessary for VTE prophylaxis in most patients undergoing elective surgery

In patients at moderate or high risk of venous thromboembolism (VTE) who are having elective surgery, compression stockings may not be a necessary add-on to pharmacological thromboprophylaxis, a trial found.

Researchers conducted an open randomized controlled noninferiority trial at seven National Health Service (NHS) tertiary hospitals in the U.K. to assess whether stockings offer any adjuvant benefit to low-molecular-weight heparin (LMWH) for VTE prophylaxis in adult patients undergoing elective surgery. Participants were randomly assigned 1:1 to receive LMWH alone or LMWH plus graduated compression stockings. The primary outcome was imaging-confirmed lower-limb deep venous thrombosis (with or without symptoms) or pulmonary embolism with symptoms within 90 days of surgery. Secondary outcome measures included quality of life, lower-limb complications related to stockings, and adverse reactions to LMWH. Results were published May 13 by The BMJ.

Image by Getty Images
Image by Getty Images

Between May 2016 and January 2019, 1,905 elective surgical inpatients at moderate or high risk for VTE were randomized. Of these, 17 were identified as ineligible after randomization and 30 did not have surgery, leaving 1,858 participants who were included in the intention-to-treat analysis (937 in the LMWH group and 921 in the combination group). A primary outcome event occurred in 16 (1.7%) patients in the LMWH-alone group, compared with 13 (1.4%) in the combination group. The risk difference between the two groups was 0.30% (95% CI, −0.65% to 1.26%). Because the 95% CI did not cross the noninferiority margin of 3.5% (P<0.001 for noninferiority), LMWH alone was confirmed to be noninferior to LMWH and stockings. This finding was sustained in subgroup analyses based on participant age (<65 years or ≥65 years) and baseline VTE risk (moderate or high). In secondary outcome analyses, there were no differences in quality-of-life outcomes between groups at baseline, at one week or hospital discharge, at 14 to 21 days, or at 90 days. Fifty-five of those who received compression stockings reported related complications (mostly discomfort), and eight patients had adverse reactions to LMWH (mostly abnormal liver enzymes).

Among other limitations, 281 (15.1%) participants did not receive a duplex ultrasound scan, which could have detected more patients with deep venous thrombosis without symptoms, the authors noted, although the number of missed scans was comparably distributed between groups. “If we consider the potential adverse events and cost of [graduated compression stockings], urgent revision of national and international VTE prevention guidelines is recommended,” they concluded.

Intensity of renal replacement associated with mechanical ventilation duration

Critically ill patients who have acute kidney injury (AKI) may spend more time on mechanical ventilation if they receive more versus less intensive renal replacement therapy (RRT), according to a recent study.

Researchers performed a post hoc analysis of data from a previous randomized multicenter trial to determine whether more intensive RRT increased time to extubation, due to loss of phosphate or other small solutes, in patients with AKI. More intensive RRT was defined as hemodialysis or sustained low-efficiency dialysis six times per week or continuous venovenous hemodiafiltration at 35 mL/kg per hour, and less intensive RRT was defined as hemodialysis or sustained low-efficiency dialysis three times per week or continuous venovenous hemodiafiltration at 20 mL/kg per hour. The study's primary outcome was time to first successful extubation from study initiation through day 14, defined as at least 48 consecutive hours without ventilator support. Results were published May 25 by CHEST and appeared in the Oct. 1 issue.

Nine hundred seven patients with AKI receiving mechanical ventilation on study day 1 were included in the current analysis, 451 in the less intensive RRT group and 456 in the more intensive group. The mean age was 59 years, most (70.4%) were men, and 15.9% were black. No difference in survival was seen at 14 days between the more intensive and less intensive groups (64.3% vs. 63.9%, respectively). Those randomly assigned to receive more intensive RRT were less likely to be successfully extubated than those in the less intensive group (hazard ratio, 0.67; 95% CI, 0.52 to 0.88; P<0.001). On average, over the first 14 days of the study, the more intensive group had 2.07 ventilator-free days versus 3.08 ventilator-free days in the less intensive group (P<0.001). The more intensive group had a larger reduction in serum phosphate levels (1.9 mg/dL vs 1.0 mg/dL; P<0.001), and 61% of patients in the more intensive group had at least one hypophosphatemic event, defined as a phosphate level below 2.5 mg/dL, versus 38% in the less intensive group (P<0.05).

The authors noted that their study involved mainly tertiary care academic medical centers and Veterans Administration hospitals and was not designed to assess the effect of serum phosphorus levels in the ICU on outcomes. “More intensive RRT may lead to a greater risk of failure to extubate from mechanical ventilation, potentially from loss of small solutes such as phosphate,” they concluded. “More aggressive repletion strategies of phosphate or other small solutes—potentially as additions to replacement or dialysate solutions—should be tested to optimize the safety and effectiveness of [continuous] RRT delivery.”