A Small Risk of Interstitial Lung Disease Found with Use of Nonwarfarin Anticoagulants
A large nationwide population-based retrospective cohort study is the first to investigate the reported increased risk of interstitial lung disease (ILD) in patients with atrial fibrillation receiving direct oral anticoagulants (DOACs). These anticoagulants, which include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have been steadily displacing warfarin as the preferred anticoagulants for stroke prevention in atrial fibrillation. In clinical trials, cough and dyspnea were noted as adverse events, but ILD, a rare event, only became evident in large postmarketing studies and in case reports.
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Using the Taiwan National Health Insurance Research Database, the cohort study collected data on 106,044 patients (mean age, 73.4; 56.6% men) with nonvalvular atrial fibrillation (NVAF) and no preexisting chronic lung disease who received oral anticoagulation between June 2012 and December 2017; 60.9% of patients received one of the factor Xa inhibitors, 21.2% of patients received dabigatran, and 17.9% of patients received warfarin.
After adjusting for patient differences at baseline, the factor Xa inhibitors as a group and individually were associated with a slightly greater risk of ILD compared to warfarin. The rate of incident ILD was 0.29 per 100 patient-years compared to 0.17 per 100 patient-years with warfarin (hazard ratio [HR], 1.54). Apixaban was associated with a rate of 0.35 per 100 patient-years, edoxaban with a rate of 0.37 per 100 patient-years, and rivaroxaban with a rate of 0.27 per 100 patient-years. Dabigatran was not associated with a greater risk of ILD on analysis. Concomitant use with amiodarone, which was frequent in this study, was associated with a higher risk of ILD regardless of the anticoagulant used; hazard ratios were as follows:
· factor Xa inhibitors and amiodarone: HR, 1.41
· dabigatran and amiodarone: HR, 1.62
· warfarin and amiodarone: HR, 1.97
Due to this study’s observational nature, it cannot definitively delineate the causal relationships it explores; additional research is needed to explore potential mechanisms. These results shouldn’t discourage clinicians from prescribing these drugs; numerous studies have demonstrated significant benefits with factor Xa inhibitors. On risk-benefit analysis, absolute increases in ILD with factor Xa inhibitors and dabigatran (-0.12 and -0.05 per 100 patient-years, respectively, vs. warfarin) were much smaller than the absolute reduction in ischemic stroke/systemic embolism (0.78 and 0.64 per 100 patient-years, respectively) and major bleeding (0.78 and 1.01 per 100 patient-years, respectively). The authors of the study recommend that clinicians vigilantly monitor any potential adverse lung outcomes associated with use of these drugs but note that there is no need to make any major changes to current practices. (Neale, T. (2022). Slight risk of interstitial lung disease seen with certain DOACs. tctMD. Retrieved November 2022 from
https://www.tctmd.com/news/slight-risk-interstitial-lung-disease-seen-certain-doacs; Chan, Y.-H., et al. (2022). Development of interstitial lung disease among patients with atrial fibrillation receiving oral anticoagulants in Taiwan. JAMA Netw Open, 5(11), e2443307. Retrieved November 2022 from https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2798871)
Released: December 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
FDA Suggests Possibility of OTC Naloxone
The nonselective opioid receptor antagonist naloxone is a critical component of the effort to combat the opioid crisis. Naloxone reverses the effects of the respiratory depression and sedation produced by opioids; when administered at the first signs of opioid overdose (OD), it can prevent opioid-related deaths.
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The FDA has announced that it’s taking steps to encourage the development of nonprescription formulations of naloxone as a component of its FDA Overdose Prevention Framework. That framework has four priorities:
· Support the primary prevention of overdose by limiting initial prescription drug exposure and inappropriate long-term prescriptions.
· Encourage harm reduction through innovative programs (such as this initiative) and education.
· Advance development of evidence-based treatment for substance use disorders.
· Protect public from unapproved, diverted, or counterfeit drugs that present risk of OD.
Naloxone is currently available as a prescription drug in the United States in several dosage strengths and dosage forms. It was originally approved as an injectable product for use by hospital personnel and first responders in the treatment of opioid OD, but increasingly has been used by non-health-care professionals, as initiatives sought to put naloxone into the hands of those who might witness an overdose. Since 2014 the FDA has approved several prescription naloxone drug and device combination products for use in emergency treatment of a known or suspected opioid OD; these are known as “community use” naloxone. In addition, as of 2020, every U. S. state and the District of Columbia have naloxone access laws, with one or more of these features:
· Third-party provisions that allow providers to prescribe naloxone to someone not directly at risk of OD; that is, to a caregiver or family member
· Standing-order provisions that allow for nonpatient-specific prescriptions
· Immunity from civil and criminal prosecutions for prescribers and dispensers.
Taken together, community-based naloxone distribution programs and naloxone access laws help to illustrate the potential public health benefits of nonprescription naloxone use.
On preliminary assessment, naloxone nasal spray up to 4 mg, as well as naloxone autoinjector for IM or subcut use up to 2 mg, are the best candidates for nonprescription use. These dosage forms are used by most consumers. As of 2021, more than 90% of sales of naloxone were for the nasal spray form, although it should be noted that these sales numbers don’t consider donations of naloxone to community-based distribution programs, which are primarily autoinjector products.
Although the benefits of broader use of naloxone are significant, concerns exist with making them available over the counter, such as associated risks that include adverse drug effects and precipitation of opioid withdrawal syndrome. Monitoring for and mitigation of these risks are important. The FDA must ensure that any products developed for nonprescription use are appropriately designed to support the intended users’ needs, including the packaging and labeling, and meet the requirements of the Food Drug and Cosmetic Act, demonstrating a clinically meaningful difference from the prescription product. The FDA has asked for comments on this proposal. (FDA. (2022, November 15). FDA announces preliminary assessment that certain naloxone products have the potential to be safe and effective for over-the-counter use [Press release]. Retrieved November 2022 from https://www.fda.gov/news-events/press-announcements/fda-announces-preliminary-assessment-certain-naloxone-products-have-potential-be-safe-and-effective; Federal Register. (2022). Safety and effectiveness of certain naloxone hydrochloride drug products for nonprescription use; request for comments. Retrieved November 2022 from https://www.federalregister.gov/documents/2022/11/16/2022-24874/safety-and-effectiveness-of-certain-naloxone-hydrochloride-drug-products-for-nonprescription-use)
Released: December 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer
Do Real-Time Prescription Benefits Recommendations Lower Costs for Patients?
The rise in U. S. health care costs, especially out-of-pocket costs for patients, is a major driver for efforts to increase medication price transparency. Real-time prescription benefits (RTPB), an electronic clinical decision support tool, provides patient- and medication-specific out-of-pocket information to prescribers at the point of use. A study published in JAMA Internal Medicine demonstrates that such medication price transparency solutions that make cost information available to the prescriber and recommend clinically appropriate alternatives can be an effective tool for generating savings.
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In the cluster randomized trial, conducted in medical practices in a large academic health system in New York City, all outpatient prescriptions written were randomly assigned to a control arm or to an RTPB recommendation arm. Analysis was limited to those medications for which the tool could recommend an available alternative. Of the 867,757 outpatient prescriptions written at the practices over the study period (January to July 2021), 4.2% (36,419) met the criteria for analysis.
If a prescription was randomized to the RTPB recommendation arm, the RTPB system recommended alternatives: either a different medication, different length of prescription, and/or a different choice of pharmacy. The prescriber could then opt for either the initial order or one of the recommended options. Electronic health record data were used to analyze the effect of the intervention on prescribing, both on out-of-pocket patient costs as well as on use of mail order pharmacy or 90-day supplies. Out-of-pocket costs includes any copay, coinsurance, and deductibles the patient is responsible for under their prescription benefits plan.
The average out-of-pocket costs for a 30-day supply of medication in the intervention arm was $39.90; in the control arm, it was $67.80. Use of the RTPB recommendations resulted in an adjusted 11.2% reduction in costs. Mail-order pharmacy use was 9.6% in the intervention group and 7.6% in the control group; no differences were found in rate of use of 90-day medication supply.
It’s hoped that, by controlling the patient’s out-of-pocket costs, the RTPB system can improve adherence and health outcomes. Further research will be needed to understand the impact of the system on other outcomes, such as prescribing behavior and adherence. (Desai, S. M., et al. (2022). Effects of real-time prescription benefit recommendations on patient out-of-pocket costs: A cluster randomized clinical trial. JAMA Intern Med, 182(11), 1129–1137. Retrieved November 2022 from https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2796059)
Released: December 2022
Nursing Drug Handbook
© 2022 Wolters Kluwer