Trending Topics in Health-System Pharmacy
APhA Staff
Approval stalled for tramadol I.V.
In an early February 2022 joint meeting, FDA’s Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee voted no to the question of whether the data provided to support the benefits of I.V. tramadol outweigh the risks for the management of acute pain severe enough to require an opioid analgesic in an inpatient setting. The vote, while nonbinding, represents another setback for Avenue Therapeutics, which submitted a New Drug Application (NDA) in December 2019 for the I.V. version of tramadol.
Although the data from two phase 3 clinical trials showed that I.V. tramadol met all of the primary endpoints, the NDA relied in part on safety and efficacy data for tramadol HCl tablets. Analysis of the data by FDA’s Division of Anesthesiology, Addiction Medicine, and Pain Medicine (DAAP) concluded that tramadol I.V. was effective in relieving acute pain but expressed concern about the safety of a delayed onset of analgesia.
DAAP suggested that patients whose pain is not adequately controlled with the first dose of tramadol I.V. will likely require another analgesic, likely another immediate-release opioid, resulting in opioid stacking and an increase in the potential for opioid-related adverse events such as oversedation and respiratory depression.
FDA then asked the company to address the safety issue and identify a population for which the drug would be both safe and effective. In February 2021, Avenue Therapeutics resubmitted the NDA, which did not include any new clinical data and proposed that tramadol I.V. be used alone or in combination with other analgesics. It also proposed adding language to the label recommending nonopioid analgesics for patients who experience a delay in pain relief.
FDA concluded that the proposed labeling did not adequately address the drug’s clinical deficiency and reiterated its concern about the use of opioids for management of pain that can be controlled by other analgesics. It also expressed concern that the clinical trials detailed in the NDA were not designed to evaluate the analgesic effect of tramadol I.V. combined with another analgesic.
After two formal dispute resolution requests from the company, which maintains that opioid stacking is not a safety concern, FDA concluded that advisory committee input was needed before a decision on the appeal could be made. Now that the advisory committees have indicated agreement with the original FDA conclusion, it seems unlikely that FDA’s Office of New Drugs will approve tramadol I.V. under the terms of the NDA. FDA has indicated that it will reach a decision on the most recent formal appeal within 30 days.
Is icosapent ethyl cost-effective for treatment of high-risk patients with hypertriglyceridemia?
The REDUCE-IT trial demonstrated the efficacy of icosapent ethyl (IPE) in reducing cardiovascular events for high-risk patients with hypertriglyceridemia and known cardiovascular disease or diabetes and at least one other risk factor who were treated with statins. While the trial showed a 30% relative risk reduction among those randomly assigned to receive IPE, the cost effectiveness of such treatment has not been explored.
A group of researchers led by William S. Weintraub, MD, at MedStar Washington Hospital Center, conducted a cost-effectiveness study using patient-level study data from REDUCE-IT to estimate the incremental in-trial and lifetime health gains, health care costs, and cost-effectiveness of adding 4 g per day of IPE to statin therapy. The study, published on February 14, 2022, in JAMA Network Open, included ~8,000 patients randomly assigned to receive IPE or standard care. The wholesale acquisition cost of IPE was $9.28 per day, with a cost of $4.16 per day after rebates.
Results of the study indicated that treatment with IPE yielded higher incremental quality-adjusted life-years (QALYs) than standard care both in trial (3.34 vs. 3.27) and over a lifetime projection (10.59 vs. 10.35), with a high probability of costing less than $100,000 per QALY gained. The authors suggest that treatment with IPE offers better cardiovascular outcomes than standard care in REDUCE-IT participants at common willingness-to-pay thresholds.
Combination therapy shows promise for esophageal squamous-cell carcinoma
Treatment of advanced esophageal squamous-cell carcinoma with first-line chemotherapy often results in poor outcomes. A recent study, published in NEJM on February 3, 2022, showed that combination therapy using monoclonal antibodies resulted in improved survival of these patients.
A worldwide group of researchers (the CheckMate 648 Trial Investigators) conducted an open-label, phase 3 trial, randomly assigning adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone. The primary endpoints were overall survival and progression-free survival, as determined by blinded independent central review.
After a minimum of 13 months of treatment, both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone with no new safety signals identified. The incidence of treatment-related adverse events was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. The authors noted that the open-label trial design may have influenced assessment of the causes of adverse events. They also indicated that whether one regimen is more effective than the other for patient subgroups is unknown and requires further research.
Evaluation of Lyme disease screening results can lead to fewer unnecessary antibiotics
The standard two-tiered testing algorithm for Lyme disease screening involves an initial ELISA test followed by a more specific Western immublot (WB) for confirmation. Recent research indicates that up to 50% of the antibiotics prescribed for Lyme disease may be unnecessary due to clinicians not waiting for the confirmatory test before starting patients on antibiotics. In August 2015, a large health care system in Massachusetts began to report positive Lyme disease ELISA test results in their EHR as “WesternToFollow” rather than “Positive” to encourage clinicians to wait for the confirmatory WB before prescribing antibiotics.
A follow-up study by Willis and colleagues, published in JAMA Network Open on January 25, 2022, compared antibiotic prescribing behavior between two large practice groups in eastern Massachusetts: Atrius Health, which revised reporting of Lyme disease ELISA test results, and Cambridge Health Alliance, which did not.
The results of the study showed that the revised ELISA test language resulted in a 70% decrease in cases in which the patient was treated without confirmed Lyme disease at a practice using the standard two-tiered testing algorithm. While the authors note that their study had limitations, including that some antibiotics may have been prescribed for reasons other than Lyme disease and that the demographic characteristics of the two sites differ, they believe that such a simple, low-cost intervention can change prescribing behavior and lower the adverse effects and expense related to overtreatment of Lyme disease.
Oral anticoagulants could benefit patients with diabetes and Afib
Patients with both diabetes and atrial fibrillation (Afib) are at risk for diabetes complications resulting from their use of oral anticoagulants. A recent study, published in Annals of Internal Medicine on February 15, 2022, showed that nonvitamin K antagonist oral anticoagulants (NOACs) were associated with lower hazards of diabetes complications and mortality than warfarin in patients with both diabetes and Afib.
Researchers from several medical centers in Taiwan led by Yu-Kang Tu, DDS, MSc, PhD, at National Taiwan University performed a retrospective cohort study using nationwide data on patients with Afib and diabetes who received NOACs or warfarin between 2012 and 2017 from Taiwan’s National Health Insurance Research Database. Hazards of diabetes complications (macrovascular complications, microvascular complications, and glycemic emergency) and mortality in the NOAC and warfarin users were investigated with a target trial design. Propensity score methods with stabilized inverse probability of treatment weighting were used to balance potential confounders between treatment groups.
In total, 19,909 patients who received NOACs and 10,300 patients who received warfarin were included. Patients receiving NOACs had significantly lower hazards of developing macrovascular complications, microvascular complications, glycemic emergency, and mortality than those receiving warfarin. Analyses with propensity score matching showed similar results. Several sensitivity analyses further supported the robustness of the findings, although the claims-based data did not allow for detailed information on patients’ lifestyles and laboratory examinations to be considered.
How safe are aspirin and heparin in treating stroke?
Aspirin and unfractionated heparin are often used to treat endovascular stroke, but the safety of this treatment has been questioned. According to a recent study published in the Lancet on March 12, 2022, I.V. aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of intracranial hemorrhage with no evidence of benefit.
An international group of investigators, led by Wouter van der Steen, MD, from the Erasmus University Medical Center (the Netherlands) performed an open-label, multicenter, randomized controlled trial in 15 medical centers in the Netherlands. Adult patients with ischemic stroke with no intracranial hemorrhage due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 hours of symptom onset were eligible for the study. Patients were randomly assigned to receive either I.V. aspirin (300 mg bolus) or no aspirin, and randomly assigned to receive moderate-dose unfractionated heparin (5,000 IU bolus followed by 1,250 IU/hour for 6 hours), low-dose unfractionated heparin (5,000 IU bolus followed by 500 IU/hour for 6 hours), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days and symptomatic intracranial hemorrhage was the primary safety outcome.
Between January 22, 2018, and January 27, 2021, 663 patients were enrolled in the study. Shortly thereafter, upon analysis of the data, the trial steering committee permanently ended patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial hemorrhage was higher in patients who received aspirin than in those not receiving aspirin (14% vs. 7%) as well as in patients who received unfractionated heparin than in those not receiving unfractionated heparin (13% vs. 7%). Both aspirin and unfractionated heparin led to a nonsignificant shift toward worse modified Rankin Scale scores.