Extended Apixaban Reduces Recurrence of Venous Thromboembolism in Patients With Provoking Factors and Ongoing Risk
A double-blind, randomized controlled trial (Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients With Provoked Venous Thromboembolism [HI-PRO]) evaluated whether extended low-dose apixaban prevents recurrence of venous thromboembolism (VTE) in patients with transient provoking factors and ongoing risk. The study aimed to determine whether continuing low-dose anticoagulation beyond the standard treatment period could reduce recurrence without increasing major bleeding.
READ MORE...
The appropriate duration of anticoagulation for VTE caused by transient factors such as surgery, trauma, or immobility remains uncertain in patients with additional persistent risk factors. Extended therapy may lower recurrence but raises concerns about bleeding.
Adults who had completed at least 3 months of anticoagulation for provoked VTE were randomized to receive apixaban 2.5 mg twice daily or placebo for 12 months. The primary efficacy outcome was symptomatic recurrent VTE, and the primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis.
A total of 600 patients (mean age, 59.5 years; 57% female) were enrolled in the study. Recurrent VTE occurred in 1.3% of patients treated with apixaban compared with 10.0% of those receiving placebo (hazard ratio, 0.13; 95% CI, 0.04–0.36; P < .001), showing a significant reduction in recurrence with apixaban.
Major bleeding events were rare, with one in the apixaban group and none in the placebo group. Clinically relevant nonmajor bleeding occurred more often with apixaban (4.8% vs 1.7%), but this difference was not statistically significant. Nonhemorrhagic, nonfatal adverse events were infrequent, occurring in 6 patients (2.0%) in each group. Mortality was low and similar between groups, with no cardiovascular or bleeding-related deaths reported.
Extended low-dose apixaban significantly reduced the risk of recurrent VTE in patients with transient provoking factors and ongoing risk, with a low incidence of major bleeding. The findings suggest that continued low-intensity anticoagulation with apixaban may offer an effective and safe option for preventing VTE recurrence in appropriately selected patients. (Piazza, G., et al. [2025]. Apixaban for extended treatment of provoked venous thromboembolism. N Engl J Med, 393[12], 1166–1176. Retrieved September 2025 from https://www.nejm.org/doi/10.1056/NEJMoa2509426)
Released: October 2025
Nursing Drug Handbook
© 2025 Wolters Kluwer N.V., its subsidiaries and/or its licensors. All rights reserved.
Esketamine Nasal Spray as Monotherapy Reduces Symptoms in Treatment-Resistant Depression
A phase 4, double-blind, randomized clinical trial evaluated the efficacy and safety of intranasal esketamine used without an oral antidepressant in adults with treatment-resistant depression (TRD). The study sought to determine whether esketamine administered as monotherapy could reduce depressive symptoms compared with placebo.
READ MORE...
TRD, defined by inadequate response to multiple oral antidepressants, affects millions of adults and remains challenging to treat. Esketamine nasal spray is already approved as an adjunct to oral antidepressants, but its effectiveness as a stand-alone therapy has not been established.
The trial was conducted between November 2020 and January 2024 at 51 outpatient centers in the US. After a two-week or greater antidepressant-free period, adults with major depressive disorder meeting DSM-5 criteria and who had failed at least two oral antidepressant trials were randomized 1:1:2 to receive esketamine 56 mg, esketamine 84 mg, or placebo intranasally twice weekly for four weeks. The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28. A key secondary endpoint was MADRS score at 24 hours after the first dose.
A total of 378 participants (mean age, 45 years; 61% female) were randomized and received at least one dose of study medication. At day 28, both esketamine doses produced significantly greater reductions in MADRS scores compared with placebo (least-squares mean difference –5.1 points for 56 mg and –6.8 points for 84 mg; P < .001 for both). Symptom improvement was also evident within 24 hours after the first dose, with both esketamine groups showing significantly lower MADRS scores than placebo.
The most common treatment-emergent adverse events among participants receiving esketamine were nausea (25%), dissociation (24%), dizziness (22%), and headache (19%). No deaths occurred during the trial.
Esketamine nasal spray administered as monotherapy significantly reduced depressive symptoms compared with placebo in adults with TRD. The findings suggest that esketamine may expand treatment options for patients who do not tolerate or respond to oral antidepressants, with an acceptable short-term safety profile. (Janik, A., et al. [2025]. Esketamine monotherapy in adults with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry, 82[9], 877–887. Retrieved September 2025 from https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2836115)
Released: October 2025
Nursing Drug Handbook
© 2025 Wolters Kluwer N.V., its subsidiaries and/or its licensors. All rights reserved.
Levodopa Does Not Enhance Motor Recovery When Added to Stroke Rehabilitation
A double-blind, placebo-controlled randomized clinical trial (Enhancement of Stroke Rehabilitation With Levodopa [ESTREL]) evaluated whether adding levodopa to standardized stroke rehabilitation improved motor recovery compared with placebo. The study aimed to determine whether levodopa, administered alongside rehabilitation based on active task-oriented training, enhanced motor recovery in patients with acute stroke.
READ MORE...
Levodopa enhances dopamine signaling and may stimulate neuroplasticity. Based on this rationale, it has been used in stroke rehabilitation, but evidence for benefit has been inconsistent.
The trial was conducted at 13 Swiss stroke centers and 11 rehabilitation facilities. Participants were randomized to receive levodopa/carbidopa (100 mg/25 mg) or placebo three times daily for 39 days, in addition to standardized active task-oriented rehabilitation therapy. The primary outcome was change in motor function at 3 months, measured by the Fugl-Meyer Assessment (FMA), a 100-point scale of motor recovery.
A total of 610 patients with acute ischemic or hemorrhagic stroke and clinically significant hemiparesis were enrolled. At 3 months, the median FMA score was 68 in the levodopa group and 64 in the placebo group. The adjusted mean between-group difference was –0.90 points (95% CI, –3.78 to 1.98; P = .54), which was not clinically or statistically significant.
Serious adverse events occurred at similar rates in both groups, most commonly infection. Mortality was low, with 28 deaths by 3 months.
Among patients receiving inpatient rehabilitation for acute stroke, levodopa added to standard therapy did not significantly improve motor function at 3 months. These results suggest that levodopa offers no additional benefit as an adjunct to rehabilitation. (Engelter, S. T., et al. [2025]. Levodopa added to stroke rehabilitation: The ESTREL randomized clinical trial. JAMA. Advance online publication. Retrieved September 2025 from https://jamanetwork.com/journals/jama/article-abstract/2839112)
Released: October 2025
Nursing Drug Handbook
© 2025 Wolters Kluwer N.V., its subsidiaries and/or its licensors. All rights reserved.
Metformin Does Not Shorten Symptom Duration in Adults With Mild-to-Moderate COVID-19
A randomized, double-blind, placebo-controlled trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines–6 [ACTIV-6]) evaluated whether metformin could shorten recovery time in outpatient adults with COVID-19. The study aimed to determine if repurposing metformin, a widely used antidiabetic agent, could speed symptom resolution during acute SARS-CoV-2 infection.
READ MORE...
Metformin has been studied for potential antiviral and anti-inflammatory effects, leading to interest in its possible role in COVID-19 management. While it is safe and inexpensive, evidence of clinical benefit for reducing symptom duration or disease progression in COVID-19 has remained uncertain.
Between September 2023 and May 2024, the trial enrolled adults aged 30 years or older with confirmed SARS-CoV-2 infection and at least two symptoms for seven days or less. Participants were recruited from 90 sites across the US and were randomized to receive metformin (titrated to 1500 mg daily) or placebo for 14 days. The primary outcome was time to sustained recovery, defined as three consecutive days without symptoms, within 28 days after starting the study drug. Secondary outcomes included clinic visits, emergency department visits, hospitalization, or death.
A total of 2,991 participants were randomized (median age, 47 years; 63% female). Time to sustained recovery did not differ significantly between the metformin and placebo groups (adjusted hazard ratio, 0.96; 95% credible interval, 0.89–1.03; P = .11). The median time to sustained recovery was 9 days with metformin versus 10 days with placebo.
A total of 103 participants had clinic visits, emergency department visits, or hospitalizations (54 in the metformin group and 49 in the placebo group). Serious adverse events were uncommon, occurring in 7 participants who received metformin and 3 who received placebo. Mild hypoglycemia was reported in two participants in the metformin group and four in the placebo group. No deaths occurred in either group.
Among outpatient adults with COVID-19, metformin did not shorten time to sustained recovery compared with placebo. Although metformin was well tolerated and safe, these results do not support its use for reducing symptom duration during acute COVID-19 infection. (Bramante, C. T., et al. [2025]. Metformin and time to sustained recovery in adults with COVID-19: The ACTIV-6 randomized clinical trial. JAMA Intern Med, 185[9], 1092–1101. Retrieved September 2025 from https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2836528)
Released: October 2025
Nursing Drug Handbook
© 2025 Wolters Kluwer N.V., its subsidiaries and/or its licensors. All rights reserved.