Drug News Abstracts - October 2021

Empagliflozin in Heart Failure and Preserved Ejection Fraction

EMPEROR-Preserved is the first trial to show unequivocal benefit of a medication for treatment of patients with heart failure with preserved ejection fraction (HFpEF). The sodium-glucose transporter-2 (SGLT2) inhibitor empagliflozin lowered the combined risk of cardiovascular (CV) death or hospitalization for heart failure in patients with HFpEF, regardless of the presence or absence of diabetes.


Maternal COVID-19 Vaccination

A cohort study published in the American Journal of Obstetrics and Gynecology provided data on maternal antibody generation and suggests that COVID-19 vaccination of women who are pregnant and lactating can confer robust maternal and neonatal immunity against SARS-CoV2 infection. Although the absolute risk of severe COVID-19 is low in women who are pregnant, pregnancy is a risk factor for severe disease. Mothers with severe COVID-19 infections and their neonates are at increased risk for a number of perinatal complications, including cesarean birth, hypertensive disease of pregnancy, venous thromboembolism, preterm birth, low birthweight, and NICU admission. COVID-19 infection in pregnancy is also associated with an increased risk for ICU admission, need for extracorporeal membrane oxygenation, and maternal death.


Quadruple Pill for Hypertension

A study conducted by the University of Sydney and the George Institute for Global Health showed that a strategy of combining one-quarter doses of four antihypertensive medications into one pill (quadpill) as a first intervention against high blood pressure is more effective than the currently recommended single-drug therapy. This multicenter, double-blind, parallel-group, randomized, phase 3 trial, published in The Lancet and presented at the European Society of Cardiology Conference on August 29th, enrolled 591 patients across 10 Australian centers; participants had high blood pressure (BP) (baseline mean BP: 141/85 mm Hg) and were receiving no therapy or were receiving their first single antihypertensive treatment.


Ranibizumab against Retinopathy of Prematurity

Analysis of 2-year outcomes of the RAINBOW extension study, which compares results of intravitreal injection with the vascular endothelial growth factor (VEGF) inhibitor ranibizumab versus laser therapy for treatment of very-low-birthweight infants with retinopathy of prematurity (ROP), were published in Lancet Child and Adolescent Health. Because the retina develops late in fetal development, very premature babies can have incomplete development of the blood vessels needed to provide oxygen to the retina. After birth, blood vessels develop abnormally, causing the vision loss known as ROP. It’s known that an overabundance of VEGF can produce the abnormal blood vessels seen in ROP.


New Capsules Archive

Drug News Abstracts - October 2021
Empagliflozin in Heart Failure and Preserved Ejection FractionEMPEROR-Preserved is the first trial to show unequivocal benefit of a medication for treatment of patients with heart failure with preserved ejection fraction (HFpEF). The sodium-glucose transporter-2 (SGLT2) inhibitor empagliflozin lowered the combined risk of cardiovascular (CV) death or hospitalization for heart failure in patients with HFpEF, regardless of the presence or absence of diabetes.READ MORE...The randomized, double-blind, parallel-group, placebo-controlled trial enrolled 5,988 patients with NYHA Class II to IV heart failure and left ventricular ejection fraction (LVEF) >40% (mean age, 72 years; 45% women; mean LVEF, 54%). Nearly half of all patients also had diabetes and nearly half had an eGFR (estimated glomerular filtration rate) of <60 mL/min/1.73 m2. They were randomized to empagliflozin 10 mg once daily (n = 2,997) or to placebo (n = 2,991).SGLT2 inhibition with empagliflozin led to a 21% lower relative risk in the primary composite outcome of death from CV causes and hospitalization for heart failure. The composite outcome occurred in 415 patients (13.8%) in those receiving empagliflozin and in 511 patients (17.1%) in those on placebo. This reduction was mostly attributed to a lower number of hospitalizations for heart failure, with fewer admissions—407 in the empagliflozin arm vs. 514 in the placebo arm (hazard ratio, 0.73). Breaking the composite down into its parts, deaths from CV causes occurred in 219 patients (7.3%) in the empagliflozin arm and in 244 patients (8.2%) in the placebo arm (hazard ratio, 0.91); hospitalization for heart failure occurred in 259 patients (8.6%) in the empagliflozin arm and 352 patients (11.8%) in the placebo arm (hazard ratio, 0.7). The trial also showed a slower decline in renal function over time in those treated with empagliflozin. The rate of decline in eGFR was −1.25 mL/min/1.73 m2/yr in the empagliflozin arm vs. −2.62 mL/min/1.73 m2/yr in the placebo arm.These results are likely to result in a change in clinical practice, as clinicians now have an option for treatment of patients with HFpEF. (Neale, T. (2021). EMPEROR-Preserved: Empagliflozin improves outcomes in HFpEF. Retrieved September 2021 from https://www.tctmd.com/news/emperor-preserved-empagliflozin-improves-outcomes-hfpef; New Engl J Med. 27 August 2021. Empagliflozin in heart failure with preserved ejection fraction. Retrieved September 2021 from https://www.nejm.org/doi/full/10.1056/NEJMoa2107038?query=recirc_curatedRelated_article)Released: October 2021Nursing Drug Handbook© 2021 Wolters KluwerMaternal COVID-19 VaccinationA cohort study published in the American Journal of Obstetrics and Gynecology provided data on maternal antibody generation and suggests that COVID-19 vaccination of women who are pregnant and lactating can confer robust maternal and neonatal immunity against SARS-CoV2 infection. Although the absolute risk of severe COVID-19 is low in women who are pregnant, pregnancy is a risk factor for severe disease. Mothers with severe COVID-19 infections and their neonates are at increased risk for a number of perinatal complications, including cesarean birth, hypertensive disease of pregnancy, venous thromboembolism, preterm birth, low birthweight, and NICU admission. COVID-19 infection in pregnancy is also associated with an increased risk for ICU admission, need for extracorporeal membrane oxygenation, and maternal death.READ MORE...The study enrolled 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, 16 nonpregnant). Researchers measured titers of SARS-CoV2 spike and reception-binding domain IgA, IgG, and IgM in the recipients’ blood and human milk at the time of the first vaccine dose, at the time of the second dose, 2 to 6 weeks after the second dose, and at delivery (for patients who were pregnant). Umbilical cord titers (n = 10) were assessed at delivery. These titers were then compared with those of women who were pregnant 4 to 12 weeks after a SARS-CoV2 infection (n = 37) by enzyme-linked immunosorbent assay.The mRNA vaccine was highly effective in inducing antibody titers in women who were pregnant (median titer, 5.74) and lactating (median titer, 5.62), results similar to those in women who were not pregnant (median titer, 5.59). Higher levels of antibodies were observed in all women who were vaccinated compared to those of the women who were pregnant who had experienced natural SARS-CoV2 infection. Antibodies were also present in all umbilical cord blood and human milk samples. In particular, a boost in human milk IgG levels was observed, paralleling the boost seen in maternal IgG levels in serum after the second dose. Interestingly, IgA was not increased in the blood or human milk of the women in the study, an unexpected finding, as IgA is the largest component of the immune response in the human milk of women with natural SARS-CoV2 infection.Vaccine-related fever and chills were reported by 32% of women who were pregnant (25/77) and by 50% of women who were not pregnant (8/16) after the second dose. Cumulative symptom score after the first dose was low in all groups, and there were no significant differences between groups in cumulative symptom score after the second dose (median score of 2 for women who were pregnant, 3 for women who were lactating, and 2.5 for women who were not pregnant).Further research in larger populations is needed to support recommendations for vaccine administration in women who are pregnant, as well as providing a greater understanding of vaccine-induced and antibody transfer kinetics across all trimesters. (Pham, A., et al. (2021). Maternal COVID-19, vaccination safety in pregnancy, and evidence of protective immunity. J Allergy Clin Immunol, 148(3), 728–731. Retrieved September 2021 from https://www.jacionline.org/article/S0091-6749(21)01133-7/fulltext; Gray, K. J., et al. (2021). Coronavirus disease 2019 vaccine response in pregnant and lactating women: A cohort study. Am J Obstet Gynecol, 225(3), P303.E1–303.E17. Retrieved September 2021 from https://www.ajog.org/article/S0002-9378(21)00187-3/fulltext#secsectitle0060)Released: October 2021Nursing Drug Handbook© 2021 Wolters KluwerQuadruple Pill for HypertensionA study conducted by the University of Sydney and the George Institute for Global Health showed that a strategy of combining one-quarter doses of four antihypertensive medications into one pill (quadpill) as a first intervention against high blood pressure is more effective than the currently recommended single-drug therapy. This multicenter, double-blind, parallel-group, randomized, phase 3 trial, published in The Lancet and presented at the European Society of Cardiology Conference on August 29th, enrolled 591 patients across 10 Australian centers; participants had high blood pressure (BP) (baseline mean BP: 141/85 mm Hg) and were receiving no therapy or were receiving their first single antihypertensive treatment.READ MORE...The patients were assigned to the quadpill (n = 300), which contained 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to standard-dose monotherapy (n = 291) with 150-mg irbesartan. Patients who didn’t reach the target BP within 12 weeks could have additional medications added to the regimen, starting with amlodipine at 5 mg. A subgroup continued their randomly assigned treatment for 12 months to assess long-term effects.Blood pressure was brought under control in 76% of participants receiving the quadpill in 12 weeks, compared to 58% in the control group. Mean BP at 12 weeks was 121/71 mm Hg on quadpill therapy versus 127/79 mm Hg on monotherapy; the mean difference in systolic BP was −6.9 mm Hg. The differences in outcome were sustained, with continued better BP control with the quadpill approach at 52 weeks. Mean systolic BP at that time remained lower on quadpill therapy (−7.7 mm Hg); rates of BP control remained higher in the quadpill group (81%) versus controls (62%).Traditional medication treatment for hypertension starts with one antihypertensive and then adds other medications as needed, but this is not always successful; in some regions of the world, as few as 1 in 10 patients have their BP under control. These results could reduce risks of myocardial infarction or stroke by about 20% in areas with access to high levels of specialized treatment; in areas with little or no existing treatment, the benefits could be even greater. (George Institute for Global Public Health. News release. (2021, 30 August). Ground breaking study shows 4 in 1 blood pressure pill is more effective than current treatment. Retrieved September 2021 from https://www.georgeinstitute.org/media-releases/ground-breaking-study-shows-4-in-1-blood-pressure-pill-is-more-effective-than; University of Sydney. Media Release. (2021, 29 August). 4 in 1 blood pressure pill: Safe and much more effective than usual hypertension treatment. Retrieved September 2021 from https://cdn.georgeinstitute.org/sites/default/files/quartet_mr_final.pdf; Chow, C. K., et al. (2021). Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): A phase 3, randomised, double-blind, active-controlled trial. The Lancet, 398(10305), P1043–1052.)Released: October 2021Nursing Drug Handbook© 2021 Wolters KluwerRanibizumab against Retinopathy of PrematurityAnalysis of 2-year outcomes of the RAINBOW extension study, which compares results of intravitreal injection with the vascular endothelial growth factor (VEGF) inhibitor ranibizumab versus laser therapy for treatment of very-low-birthweight infants with retinopathy of prematurity (ROP), were published in Lancet Child and Adolescent Health. Because the retina develops late in fetal development, very premature babies can have incomplete development of the blood vessels needed to provide oxygen to the retina. After birth, blood vessels develop abnormally, causing the vision loss known as ROP. It’s known that an overabundance of VEGF can produce the abnormal blood vessels seen in ROP.READ MORE...Families of the 201 infants who completed the core RAINBOW study were approached for consent to enter an extension study through age 5; 180 infants were enrolled in the extension study, and 153 (85%) were evaluated at age 20 to 28 months for ophthalmic, developmental, and health outcomes, after correcting age for prematurity.No child in this cohort developed new ocular abnormalities (the primary outcome). Structural abnormalities were present in 1 (2%) of the 56 infants in the ranibizumab 0.2-mg group, 1 (2%) of the 51 infants in the ranibizumab 0.1-mg group, and 4 (9%) of 44 infants in the laser therapy group. The odds ratio for structural abnormality was 5.68 for ranibizumab 0.2 mg versus laser therapy, 4.82 for ranibizumab 0.1 mg versus laser therapy, and 1.21 for ranibizumab 0.2 mg versus ranibizumab. 0.1 mg. High myopia, defined as −5 diopters or worse, was less frequent after the 0.2-mg dose of ranibizumab (5/110 eyes [5%]) than with laser therapy (16/82 eyes [20%]); odds ratio, 0.19. In addition, composite vision-related quality of life scores, based on parents’ reports using the Children’s Visual Function Questionnaire, were higher among patients receiving 0.2 mg ranibizumab (mean score, 84) compared with those receiving laser therapy (mean score, 77). Developmental scores, as assessed by the Mullen Scales of Early Learning, were similar across the three groups. (Marlow, N., et al. (2021). 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): Prospective follow-up of an open label, randomised controlled trial. Lancet Child Adolesc Health. Advanced online publication. Retrieved September 2021 from https://www.thelancet.com/pdfs/journals/lanchi/PIIS2352-4642(21)00195-4.pdf)Released: October 2021Nursing Drug Handbook© 2021 Wolters Kluwer
Drug News Abstracts - September 2021
COVID Boosters Supported by CDC, FauciIn a White House press briefing, U.S. health officials laid out the case for a scientific rationale for administering a third dose of the COVID-19 mRNA vaccines for all U.S. adults. CDC Director Rochelle Walensky presented evidence that showed that vaccine effectiveness has been decreasing over time against both symptomatic and asymptomatic infections, although protection against severe disease, hospitalizations, and death remains relatively high. Dr. Walensky presented evidence from several studies published in MMWR and by the Mayo Clinic (posted on medRxiv).READ MORE...MMWR data from New York showed a decline in vaccine effectiveness against infection from May 3 to July 25, from 91.7% to 79.8%. Overall age-adjusted vaccine effectiveness against hospitalization was relatively stable: from 91.9% to 95.3%. The total of new cases was 9,675 among fully vaccinated adults, compared with 38,505 among unvaccinated persons (rate of 1.31 per 1,000 person-days vs.10.69 per 1,000 person-days).Data from the Mayo Clinic found a similar decrease in vaccine effectiveness in Minnesota. Moderna vaccine effectiveness fell from 86% earlier in the year to 76% during July, and Pfizer vaccine effectiveness fell from 76% to 42% over the same time. The analysis also found that both mRNA vaccines were effective at protecting against COVID-associated hospitalizations (91.6% for Moderna, 85% for Pfizer) and ICU admissions (93.3% for Moderna, 87% for Pfizer), with no deaths in either cohort.New nursing home data reported in MMWR also showed a reduction in protection against infection, from 78% in March to 53% by August 1. These results may reflect the effect of the greater transmissibility of the Delta variant along with demonstrating waning immunity: adjusted effectiveness against infection in the pre-Delta period (March 1 to May 9) was 74.7%, fell to 67.5% in the intermediate period (May 10 to June 20), and to 53.1% during the Delta-dominant period (June 21 to August 1).At the briefing, Anthony Fauci provided the immunologic evidence supporting booster shots. A paper published in Science showed that antibody levels peaked 43 days after the second dose of Moderna, but fell by 209 days after vaccination. Additional research demonstrated that a serum neutralizing titer of 1:100 is needed to produce a vaccine efficacy rate of 91%. Dr. Fauci believes that the booster shot should increase antibody titers by tenfold and that such higher antibody levels are likely to be necessary to protect against the Delta variant. (Fiore, K. (2021). The science supporting the U.S. case for COVID boosters. MedPage Today. Retrieved August 2021 from https://www.medpagetoday.com/infectiousdisease/covid19vaccine)Released: September 2021Nursing Drug Handbook© 2021 Wolters KluwerTriple-Drug Therapy Effective for Cystic FibrosisUse of a three-drug combination improved lung functionand sweatchloride concentration relative to an active control in a subclass of patients with cystic fibrosis.In a phase 3, double-blind, randomized, active-control trial, the three-drug combination ivacaftor–tezacaftor–elexacaftor was tested as treatment for cystic fibrosis in patients who had Phe508del-gating or Phe508del-residual function genotypes. In cystic fibrosis, deficiencies in the cystic fibrosis transmembrane conductance regulator (CFTR) proteins manifests in progressive respiratory impairment, exocrine pancreatic insufficiency, hepatobiliary disease, and abnormal sweat composition. Cystic fibrosis results from biallelic mutations in the CFTR gene, among them processing mutations, which reduce the quantity of CFTR protein on the cell surface; channel-gating defects, which limit anion transport; and residual function mutations, which result in lesser impairment of CFTR protein activity. Ivacaftor is a CFTR potentiator that augments gating of mutant CFTR proteins, tezacaftor is a CFTR corrector that acts to ease the defects of CFTR processing and cell-surface trafficking intrinsic to Phe508del, andelexacaftor is a CFTR corrector with a mechanism of action complementary to tezacaftor.READ MORE...The trial aimed to determine whether additional clinical benefit could be derived from that complementarity. The trial enrolled 258 patients and randomized them to receive the three-drug combination at 200 mg/day (n = 132) or to one of two active control regimens (n = 126): ivacaftor 150 mg b.i.d. or ivacaftor 150 mg b.i.d. and tezacaftor 100 mg/day, based on the patients’ specific genotype and approvals in their country. At baseline, the mean sweat chloride concentration was 58 mmol/L; the mean forced expiratory volume in 1 second (FEV1) was 67% to 68%, with about half in the 40% to 70% range and the rest at 70% to 90%; and the mean score on the Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain was 77.The mean absolute change in percentage of predicted FEV1 from baseline through week 8 was 3.7 percentage points (range, 2.8 to 4.6) in patients receiving the three-drug combination and 0.2 percentage points (range, –0.7 to 1.1) in patients on active control, reflecting a between-group difference of 3.5 percentage points. The mean absolute change in sweat chloride concentration from baseline through week 8 with the three-drug combination was –22.3 mmol/L (range, –24.5 to –20.2 mmol/L) and with active controls was 0.7 mmol/L (range, –1.4 to –2.8 mmol/L), a between-group difference of –23.1 mmol/L. Change from baseline in scores on the CFQ-R respiratory domain was 10.3 points (range, 8.0 to 12.7) on the three-drug combination and 1.6 points (range, –0.8 to 4.1 points) on active control, reflecting a between-group difference of 8.7 points.Two-thirds of patients experienced an adverse event, but most were mild or moderate in severity and resolved during the trial. Serious events were reported in 5 patients (3.8%) in the treatment group and 11 patients (8.7%) in the control group. (Gever, J. (2021). Three drugs better than two (or one) in cystic fibrosis. MedPage Today. Retrieved August 2021 from https://www.medpagetoday.com/pulmonology/cysticfibrosis; Barry, P. J., et al. (2021). Triple therapy for cystic fibrosis Phe508del–gating and –residual function genotypes. New Engl J Med 385, 815–825.)Released: September 2021Nursing Drug Handbook© 2021 Wolters KluwerAtopegant: An Effective Oral Migraine PreventiveOnce-daily oral treatment with atopegant, a small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist, was effective in reducing the number of migraine days and headache days over 12 weeks in patients with episodic migraine. These are the findings of ADVANCE, a phase 3multinational, randomized, double-blind, parallel-group, placebo-controlled trial that examined three dosage strengths of atopegant for prevention of migraine.READ MORE...In the trial, adults with 4 to 14 migraine days/month were randomly assigned to receive once-daily doses of 10 mg, 30 mg, or 60 mg of atopegant or to placebo for 12 weeks. Patient characteristics were similar across all groups: mean age, 41.6 years; 88% female and 83.4% white; with a mean BMI of 30.6. Overall, patients reported an average of 7.4 migraine days/month over the previous 3 months; at screening, 99.3% reported current use of medications to treat migraine attacks, and 70.3% reported having previously used a preventive medication for migraine.After screening and randomization, patients returned to the clinic five times during the double-blind 12-week period, with another visit at 16 weeks. The protocol was amended due to the COVID-19 pandemic to allow remote visits, with the final visit being conducted remotely for all participants. In an electronic diary, patients recorded headache duration, the clinical features of the headache (pain severity, location, and the effect of routine physical activity on migraine), nonheadache-associated symptoms (nausea/vomiting, photophobia, phonophobia, aura), and any medications used to treat the migraine attacks.Analysis included 873 patients: 214 in the 10-mg group, 223 in the 30-mg group, 222 in the 60-mg group, and 214 in the placebo group. Oral atopegant at any of the doses resulted in significantly greater reductions in the number of migraine days per month versus placebo. The change from baseline was –3.7 days for the 10-mg dose, –3.9 days for the 30-mg dose, and –4.2 days for the 60-mg dose, compared to –2.5 days with placebo. The differences with placebo in secondary outcomes were also significant: The change from baseline in mean number of headache days/month was –3.9 days for the 10-mg dose, –4.0 days for the 30-mg dose, and –4.2 days for the 60-mg dose, compared to –2.5 days with placebo. The change in the mean number of days of medication use to treat migraine was –3.7 days for the 10-mg dose, –3.9 days for the 30-mg dose, and –3.9 days for the 60-mg dose, compared to –2.4 days with placebo. The percentage of participants with a reduction of at least 50% in the 3-month average of migraine days/month has been recommended as a particularly relevant endpoint in controlled trials of preventive treatments for migraine; in this trial, this goal was reached at all three dosage levels: 55.6% of those receiving the 10-mg dose, 58.7% of those receiving the 30-mg dose, and 60.8% of those receiving the 60-mg dose, compared to 29.0% of those receiving placebo.Adverse events were reported in 486/902 participants (53.9%) with similar frequency across all groups. The most common adverse events were constipation, nausea, and upper respiratory infections. Serious adverse events were reported in 4 participants, 2 on the 10-mg dose and 2 on placebo. Because of potential hepatotoxicity, elevated ALT or AST levels at least three times the upper level of normal were evaluated throughout the trial. These elevated levels were found in 2 participants in the 10-mg group, 2 in the 30-mg group, 1 in the 60-mg group, and 4 in the placebo group.Previous studies have shown an association between CGRP blockade and decreased GI motility, so continued monitoring for constipation, as well as measuring for hepatotoxicity, is appropriate going forward. In addition, longer, larger trials are necessary to examine the long-term safety of once-daily atopegant as a migraine preventative; a 52-week trial is currently underway. (Ailani, J., et al. (2021). Atogepant for the preventive treatment of migraine. New Engl J Med; 385: 695–706.)Released: September 2021Nursing Drug Handbook© 2021 Wolters Kluwer
Drug News Abstracts - August 2021
Combination of Atezolizumab and Bevacizumab Effective in Peritoneal MesotheliomaCombination treatment with atezolizumab and bevacizumab was well-tolerated and led to strong, durable responses in patients with malignant peritoneal mesothelioma whose disease progressed with platinum-pemetrexed chemotherapy or were intolerant to that prior therapy. A phase 2 single-center study conducted at the University of Texas MD Anderson Cancer Center and published in Cancer Discovery examined results in patients with this rare but aggressive disease, a cancer in the lining of the abdomen. Malignant peritoneal mesothelioma has an annual incidence of 0.11/100,000 (300 to 500 Americans each year) and a 5-year survival rate lower than 20%.READ MORE...Malignant peritoneal mesothelioma is usually treated following recommendations developed for pleural mesothelioma, with first-line treatment with platinum-based/pemetrexed chemotherapy, but there are no approved treatments if that fails. The single-center study evaluated the combination of atezolizumab and bevacizumab as treatment for various advanced cancers. Atezolizumab is an immune checkpoint inhibitor that targets PD-L1, and bevacizumab is a VEGF inhibitor that slows the growth of new blood vessels and therefore tumor growth. The malignant peritoneal mesothelioma cohort included 20 participants, median age 60. Mean follow-up was 23.5 months. These patients had experienced disease progression at a median of 8.3 months with prior platinum-pemetrexed therapy.The confirmed objective response rate to treatment with this combination, as measured by RECIST (Response Evaluation Criteria in Solid Tumors) was 40% (8/20 patients). Median duration of response was 12.8 months, and responses were ongoing at cutoff in 6 patients. Median progression-free survival was 17.6 months, and the 1-year progression-free survival rate was 61%. Overall survival rate at 1 year was 85%. Disease control per RECIST was 95% (19/20) at 12 weeks, and 85% (17/20) at 18 weeks. Responses occurred no matter the tumor mutational burden or PD-L1 expression status. Treatment was well-tolerated; grade 3 adverse events occurred in 10 patients, most commonly hypertension and anemia. No grade 4 or 5 events occurred.These results address the challenges of caring for advanced forms of this orphan disease. Further studies that enroll more patients and that examine this combination as front-line treatment or as preoperative treatment are needed. (University of Texas MD Anderson Cancer Center. (2021). Drug combination shows meaningful responses for malignant peritoneal mesothelioma patients. ScienceDaily. Retrieved August 2021 from https://www.sciencedaily.com/releases/2021/07/210714110422.htm; Raghav, K., et al. (2021). Efficacy, safety and biomarker analysis of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in advanced malignant peritoneal mesothelioma. Cancer Discovery: American Association for Cancer Research. Advance online publication. Retrieved August 2021 from https://cancerdiscovery.aacrjournals.org/content/candisc/early/2021/07/01/2159-8290.CD-21-0331.full.pdf)Released: August 2021Nursing Drug Handbook© 2021 Wolters KluwerA Booster COVID Shot May Produce Antibody Response in Kidney Transplant RecipientsA French study offers evidence that a third dose of a COVID-19 mRNA vaccine can be beneficial to transplant recipients who failed to maintain sufficient antibody responses to the first two doses. Studies have reported low seroconversion rates (58%) after the second dose insolid organ transplant recipients. In April 2021, the French National Authority for Health recommended administration of a third dose of the mRNA vaccines in immunosuppressed patients who hadn’t responded after two doses.READ MORE...The single-center study enrolled 159 kidney transplant recipients at the outpatient Kidney Transplantation Department of Strasbourg University Hospital in the first half of 2021. Median age was 57.6 years, 61.6% were men, and median time from transplantation was 5.3 years. More than half were receiving tacrolimus or mycophenolate mofetil and steroids as immunosuppressive maintenance therapy. All had a negative history of COVID-19 and, though they had been vaccinated, had SARS-CoV2 antispike IgG levels of less than 50 AU/mL. Of these patients, 95 (59.7%) had no antibody response at all, with titers less than 6.8 AU/mL, and 64 (40.3%) had a response below the positivity level, with titers between 6.8 and 49.9 AU/mL.Patients received a third dose of the Moderna mRNA vaccine about 51 days after the second dose; serologic response was measured a median of 28 days later. That measure demonstrated that 78 patients (49%) did have an antibody response greater than 50 AU/mL. Those who had a weak response after the second dose were more likely than those with no response to reach this level: 81.3% vs. 27.4%, respectively. Those who were taking tacrolimus, mycophenolate mofetil, and steroids for immunosuppression were less likely to develop antibodies than those treated with other regimens: 35% vs. 63%, respectively. No serious adverse events were reported after the third dose. (Benotmane, I., et al. (2021). Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses. JAMA. Retrieved August 2021 from https://jamanetwork.com/journals/jama/fullarticle/2782538;Monaco, K. (2021). Case mounts for COVID vaccine boosters in kidney transplant recipients. MedPage Today. Retrieved August 2021 from https://www.medpagetoday.com/infectiousdisease/covid19vaccine)Released: August 2021Nursing Drug Handbook© 2021 Wolters KluwerTofacitinib Improves Inflammatory Bowel Disease SymptomsTreatment with tofacitinib improved results versus placebo on all items on an Inflammatory Bowel Disease Questionnaire (IBDQ) in patients with ulcerative colitis, reflecting improvements in health-related quality of life, with the greatest benefits reported in bowel symptoms.The 8-week, randomized, double-blind, phase 3 OCTAVE Induction 1 and 2 studies examined the oral, small-molecule Janus kinase inhibitor as treatment of ulcerative colitis. The objective of this analysis was to enrich understanding of the treatment effect of tofacitinib versus placebo on individual items in the IBDQ at week 4 and week 8.READ MORE...Patients in the study had moderately to severely active ulcerative colitis with a confirmed diagnosis of at least 4 months, and treatment failure or intolerance to oral or IV glucocorticoids, azathioprine, mercaptopurine, infliximab, or adalimumab. The pooled OCTAVE 1 and 2 studies randomized 234 patients to placebo and 905 to tofacitinib. The patients self-administered the IBDQ questionnaire at baseline, week 4, and week 8, with higher scores indicating better health-related quality of life. Significant improvements were observed in all 32 IBDQ items from baseline, grouped into four domains—bowel symptoms, systemic symptoms, emotional function, and social function. The largest differences reported in the bowel symptom domains were in loose bowel movements (1.1-point improvements at weeks 4 and 6) and rectal bleeding (1.1-point improvement at week 8). The largest differences reported in the systemic symptoms domain were reported in improvements in sleep (0.8-point improvement at week 4 and 0.9-point improvement at week 8). The largest improvements reported in the emotional function domain were seen in “fear of not finding a restroom” (0.6-point improvement at week 4 and 0.8-point improvement at week 8) and in embarrassment and anger (both improved by 0.6 points at week 4). The largest improvements reported in the social function domain were seen in avoidance of attendance at events (0.8-point improvement at week 4 and 1-point improvement at week 8) and in “difficulty doing leisure/sports” (1.0-point improvement at week 8).Larger effect sizes (above 0.65 points) were seen, therefore, in two bowel symptoms (loose bowel movements and rectal bleeding), and small or medium effect sizes in all other components of the IBDQ except for “problems with maintaining weight” and “lack of understanding from others.” The effect sizes were mostly unchanged between week 4 and week 8 for many items, indicating that most of the treatment effect was observed early as the patient’s inflammatory burden and symptoms improved. (Dubinsky, M. C., et al. (2020). Tofacitinib in patients with ulcerative colitis: Inflammatory Bowel Disease Questionnaire items in phase 3 randomized controlled induction studies. Inflammatory Bowel Dis; 27(7): 983–993. Retrieved August 2021 from https://academic.oup.com/ibdjournal/article/27/7/983/5892619)Released: August 2021Nursing Drug Handbook© 2021 Wolters KluwerAntidepressants May Improve Outcomes in People with Diabetes and DepressionA new study published in the Journal of Clinical Endocrinology and Metabolism suggests that patients with both diabetes and depression who take antidepressants have a lower riskof death and of serious diabetes complications. The nationwide retrospective cohort study identified 36,276 patients with depression and diabetes using Taiwan’s universal health insurance database.The majority of the study population was female and between ages 45 and 64. The study classified antidepressant treatment patterns within a 6-month window as none, poor, partial, and regular use. Macrovascular and microvascular diabetes complications and all-cause mortality were the main outcomes of the study.READ MORE...Patients with greater adherence to antidepressants appeared to experience fewer complications and a lower risk of mortality when compared to those with suboptimal use of their antidepressant medications. Overall, 9,670 patients developed macrovascular diabetes complications, 6,837 patients developed microvascular diabetes complications, and 3,820 patients died. Compared with poor use, regular use of oral antidepressants was associated with an 8% decreased risk for macrovascular complications (adjusted hazard ratio [HR], 0.92) and a 14% decreased risk for all-cause mortality (adjusted HR, 0.86). It was not associated with changes in risk of microvascular complications.On further analysis, regular use of SSRIs was associated with a 17% decreased risk for macrovascular complications (adjusted HR, 0.83) and a 25% reduced risk for all-cause mortality (adjusted HR, 0.75). Regular use of tetracyclic or tricyclic antidepressants was associated with a 22% decreased risk for all-cause mortality (adjusted HR, 0.78). Regular use of benzodiazepines, on the other hand, showed no association with diabetic outcomes.Patients with diabetes are at higher risk for depression, and depression worsens diabetes complications related to stress, body weight changes, and lack of exercise. This makes these patients more likely to develop diabetes complications, including heart and kidney disease, stroke, and eye and foot problems. Controlling comorbid depression is therefore important in these patients. Clinicians should encourage antidepressant treatment adherence among patients with diabetes and depression. (The Endocrine Society. (2021). Antidepressants may improve outcomes in people with diabetes and depression. ScienceDaily. Retrieved August 2021 from https://www.sciencedaily.com/releases/2021/07/210714131927.htm; Wu, C-S., et al. (2021). Associations between Antidepressant Use and Advanced Diabetes Outcomes in Patients with Depression and Diabetes Mellitus. J Clin Epidemiol Metab, Article dgab443. Retrieved August 2021 from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgab443/6321009?redirectedFrom=fulltext)Released: August 2021Nursing Drug Handbook© 2021 Wolters Kluwer
Drug News Abstracts - July 2021
Research into Antivirals for Outpatient Treatment of COVID-19Antiviral treatment of early COVID-19—before hospitalization—is needed to prevent progression of disease, the generation of variants, and secondary transmission of the virus. An article in Clinical Infectious Diseases discusses the current outpatient treatment landscape, outlining the difficulties in treating this disease, and describing ongoing research into antivirals.READ MORE...The ability to provide early antiviral treatment to prevent progression of the disease is hampered by the difficulties in detecting COVID-19 and in predicting which infected individuals will become symptomatic. This remains a major challenge to management of the pandemic, as some persons who appear to have few risk factors have been known to develop serious, even fatal, infections.The FDA has issued emergency use authorization for two monoclonal antibody (MAb) combinations—casirivimab + imdevimab and bamlanivimab + etesevimab—for patients with mild to moderate COVID-19. Research shows that these treatments are most effective in those patients who are slow to mount a SARS-CoV2-specific immune response. When given early in the course of symptomatic infection, these MAb regimens demonstrate both reductions in the SARS-CoV2 detected on polymerase chain reaction and in the risk of more severe illness. But timely use of MAbs is difficult, given the problems with obtaining testing results in many populations.The IV administration route for MAbs also presents a barrier to their use in outpatients. Research is ongoing into developing agents that can be administered by more user-friendly routes, including oral and inhaled agents. The Centers for Disease Control and Prevention’s ACTIV-2 study is part of ongoing efforts to develop antiviral agents that are easier to administer, and thus can be used in the outpatient setting; these agents include:· AZD8895 and AZD1061, a MAb combination that is in phase 2 studies and is being examined in both IV and IM formulations· Camostat mesylate, an oral serine protease inhibitor that blocks entry of the virus into cells· Interferon beta is an inhaled formulation delivered by nebulizer that is also in phase 2.A final emerging consideration in development of antiviral treatments for early COVID-19 infection is any interaction between these treatments and the vaccines. COVID-19 in a person who is fully vaccinated suggests either an inadequate immune response or infection with a variant. The struggle to contain this outbreak continues. (Cohen, M. S., et al. (2021). Outpatient treatment of SARS-CoV-2 infection to prevent COVID-19 progression. Clin Infect Dis. Advance online publication. Retrieved June 2021 from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab494/6287650)Released: July 2021Nursing Drug Handbook© 2021 Wolters KluwerRisks of Discontinuing Statins in Older PatientsOlder people are at risk for polypharmacy, and increasingly there have been calls for deprescribing to simplify medication regimens because of fears of negative clinical consequences, including cognitive impairment and drug-drug interactions, arising from such use. But deprescribing carries risks of its own. A population-based observational study demonstrated that when older patients who are taking numerous drugs for multiple conditions stop taking statins, they are at higher risk for heart failure or other CV events and of death compared to patients who continue statins.READ MORE...The study collected data from an Italian health care utilization database and included 24,097 patients who were taking statins, antihypertensives, antidiabetic agents, and antiplatelets. Using the Multisource Comorbidity Score (MCS), an index of clinical status based on the presence of conditions derived from inpatient diagnostic information and outpatient drug prescriptions, 11.7% of these patients were considered to have a “severe” clinical profile. After approximately 2 ½ years of follow-up, 9,204 patients (31.7%) discontinued taking statins, including 5,819 patients who stopped statins before discontinuing other drug therapy. The researchers matched 4,010 patients who stopped statins alone (discontinuing group) with 4,010 patients who maintained adherence to all four drug classes (maintenance group) and then followed both groups to estimate the hazard of negative outcomes. The discontinuing group was 60% men, with a mean age of 76.5 years, and 12.6% had MCS scores of 4 to 5. In the maintenance group, 61.7% were men, with a mean age of 76.1 years, and 12.6% had MCS scores of 4 to 5. Compared with the maintenance group, the discontinuing group had an increased risk of hospital admissions for heart failure or any CV outcome, death from any cause, and emergency admissions for any cause. After a mean follow-up of 20.6 months and 20.4 months, respectively, for patients who discontinued and maintained statins, the results were as follows:· Hospital admissions for heart failure: 408 vs. 337 events, with an incidence rate of 64 per 1,000 patient-years vs. 51.5 per 1,000 patient-years· Hospital admissions for ischemic heart disease: 439 vs. 413 events, with an incidence rate of 69.7 per 1,000 patient-years vs. 64.6 per 1,000 patient-years· Deaths from any cause: 528 vs. 463 events, with an incidence rate of 77.5 per 1,000 patient-years vs. 67.4 per 1,000 patient-years· Emergency department (ED) admissions for any cause: 2,209 vs. 2,055 events, with an incidence rate of 506.2 per 1,000 patient-years vs. 449.8 per 1,000 patient-years.Stopping statins was associated with a 12% higher risk of ED admissions for any cause, a 24% higher risk of heart failure, and a 15% higher risk of death from any cause. But the simplification of the patient’s medication regimen didn’t generate a significant reduction in ED access for neurologic causes, a proxy for episodes of delirium.This study was limited by its design, in which adherence to medication was determined by prescriptions rather than actual use. In addition, researchers didn’t know why prescriptions were discontinued. It’s possible that the patients who discontinued were not following other health guidelines or effectively managing their CV risk factors. But some discontinuations could be due to adverse drug effects, perceived adverse effects, or to a physician’s judgment that the patient is low risk. Further research is necessary to understand these findings. (O’Riordan, M. (2021). Stopping statins ups CVD and mortality risks in pill-burdened seniors. TCTMD. Retrieved June 2021 from https://www.tctmd.com/news/stopping-statins-ups-cvd-and-mortality-risks-pill-burdened-seniors; Rea, F., et al. (2021). Cardiovascular outcomes and mortality associated with discontinuing statins in older patients receiving polypharmacy. JAMA Netw Open. 4(6), Article e2113186. Retrieved June 2021 from https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780952)Released: July 2021Nursing Drug Handbook© 2021 Wolters KluwerAcute Medication Overuse in Patients with MigraineAcute medication overuse (AMO) is common in people with migraine and is associated with risk of disease progression from episodic migraine to chronic migraine. Analysis of data from the CaMEO study (Chronic Migraine Epidemiology and Outcomes) published in Neurology Clinical Practice sought to estimate the frequency of AMO and to characterize the type of medications involved.READ MORE...CaMEO was a cross-sectional, longitudinal web-based survey of the U.S. population. From September 2012 to November 2013, data was collected on the clinical course of migraine, family burden, barriers to care, migraine type, and comorbidities. In patients who met criteria for migraine consistent with the International Classification for Headache Disorders (ICHD-3), this analysis evaluated the types of medications used to treat or prevent migraine and the frequency of their use, comorbidities, and the number of emergency department (ED) and urgent care visits.Medication overuse headache (MOH) is defined by the ICHD-3 as headache occurring at least 15 days per month in individuals with preexisting headache disorder and regular overuse of acute medications for longer than 3 months. AMO in the ICHD-3 refers to taking medications for at least 10 days per month (or at least 15 days per month for simple analgesics). Of 16,789 CaMEO respondents with migraine, 2,975 (17.7%) met criteria for AMO; about 67.9% reported fewer than 15 monthly headache days and 49% reported fewer than 10 monthly headache days; this finding suggests that these respondents are taking their antimigraine medications on days when they don’t have a headache (perhaps in anticipation of a headache), or were taking multiple drugs to treat each headache, thus meeting the criteria for AMO.The majority of respondents met the criteria for at least one medication class (2,753/2,975 [92.5%]), including at least 15 days’ use for simple analgesics like naproxen sodium, aspirin, ibuprofen, acetaminophen, and prescription, or at least 10 days’ use for ergotamines, triptans, opioids, or combination analgesics. A much smaller group met the criteria for AMO when their use of multiple medications was considered (222/2,975 [7.4%]); use of two or more simple analgesics cumulatively, but not any single medication, for more than 15 days; or use of two or more ergotamines, triptans, opioids, or combination analgesics, but not any single medication, for more than 10 days. Of the respondents with migraine, 14,936 (89%) reported using any acute medication; use of any OTC medication for headache was reported by 14,279 (85%) and of prescription medications was reported by 4,902 (29.2%).Those with AMO were more likely than other respondents to have moderate to severe depression, anxiety, headache-related disability, and burden of disease between attacks. They also reported a higher incidence of ED and urgent care visits related to their headaches within the past 6 months. These findings illustrate the need for comprehensive migraine treatment plans that include improved acute treatment options as well as guideline-based preventive treatments, which include both nonpharmacologic and pharmacologic methods, to reduce frequency of AMO and the associated burden from possible MOH. (Schwedt, T. J., et al. (2021). Medication overuse and headache burden: Results from the CaMEO study. Neurol Clin Pract; 11(3): 216–222. Retrieved June 2021 from https://cp.neurology.org/content/11/3/216)Released: July 2021Nursing Drug Handbook© 2021 Wolters KluwerSotorasib Has Anticancer Activity in NSCLCKRAS is one of the most highly mutated genes in human cancers, found in 32% of lung adenocarcinomas. The KRASG12C variation is the most common variant in non–small-cell lung cancer (NSCLC), with a prevalence of 13%. The New England Journal of Medicine reported results from the phase 2 CodeBreak100 trial, a multicenter, single-group, open-label trial that evaluated the efficacy and safety of the highly selective irreversible KRASG12C inhibitor sotorasib in patients with KRASG12C mutated advanced NSCLC.READ MORE...The study enrolled 126 patients, of whom 124 had measurable disease at baseline and so were evaluated for their response to sotorasib. The patents were older than age 18, had locally advanced or metastatic NSCLC with the KRASG12C mutation, with disease progression after receipt of anti-PD-1 or anti-PD-L1 immunotherapy or platinum-based combination chemotherapy, ECOG performance status scale of 0 to 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). Patients were enrolled from August 2019 to February 2020 and received at least one dose of sotorasib (960 mg/day PO).Median duration of treatment was 5.5 months. As of the data cutoff date, 103 patients (81.7%) had discontinued treatment with sotorasib, 83 due to disease progression and 11 due to adverse effects. Dose reduction was seen in 26 patients (20.6%). Objective tumor response was observed in 46 patients (37.1%), 4 (3.2%) with a complete response and 42 (33.9%) with a partial response. Among those 46 patients, median time to response was 1.4 months and median duration of response was 11 months. As of data cutoff, 16 patients (34.7%) were continuing to receive sotorasib without disease progression. Median progression-free survival was 6.8 months, and median overall survival was 12.5 months. Treatment-related adverse events occurred in 88 patients (69.8%), including grade 3 events in 25 patients (19.8%) and grade 4 events in 1 patient (0.8%).Further analysis evaluated the potential association between response to sotorasib therapy and these variables:· baseline PD-L1 expression (86 patients assessed): objective response and tumor shrinkage were observed in 48% of patients in the PD-L1-negative group and in 42% of those in the PD-L1-positive group· tumor mutational burden (84 patients assessed: objective response and tumor shrinkage were observed in 42% of patients with low tumor mutational burden and 40% of patients with high tumor mutational burden· co-occurring genomic alterations (104 patients assessed): objective response was seen in 50% of patients with mutated STK11 and wild-type KEAP1, in 23% of those with mutations in both KEAP1 and STK11, and in 14% of those with mutated KEAP1 and wild-type STK11.These data provide further evidence in support of the use of sotorasib in this population. A phase 3 trial comparing sotorasib to docetaxel in patients with previously treated, locally advanced, unresectable or metastatic NSCLC with KRASG12C mutation is underway. (Rosen, N. (2021). Finally, effective inhibitors of mutant KRAS. New Engl J Med; 384: 2447–2449. Retrieved June 2021 from https://www.nejm.org/doi/full/10.1056/NEJMe2107884; Skoulidis, F., et al. (2021). Sotorasib for lung cancers with KRAS p.G12C mutation. New Engl J Med; 384: 2371–2381. Retrieved June 2021 from https://www.nejm.org/doi/full/10.1056/NEJMoa2103695?query=featured_home)Released: July 2021Nursing Drug Handbook© 2021 Wolters Kluwer
Drug News Abstracts - June 2021
Understanding Nonadherence to Bipolar Disorder TreatmentNearly half of people with bipolar disorder (BPD) fail to take their medications as prescribed; such nonadherence can lead to relapse, hospitalization, and an increased risk of suicide, as well as putting strain on work and relationships. Efforts to increase medication adherence have not significantly shifted that statistic.READ MORE...Difficulties in addressing nonadherence may be caused by a lack of understanding of modifiable factors. Researchers from the University of East Anglia and the UK’s National Health Service Foundation Trust performed a systematic review of 57 studies involving more than 30,000 patients, mostly in the United States and Europe, to examine studies that reported these modifiable factors. The study, led by a team of pharmacists, psychiatrists, and experts in behavioral health, placed the identified factors in Theoretical Domains Framework (TDF) domains.This study showed that major contributors to nonadherence in patients with BPD were negative emotions evoked by the idea of taking medications and intentional nonadherence. The most frequently reported TDF domain was “Environmental Context and Resources,” mentioned as factors in 63% of the studies examined. Primarily related to characteristics of the medication, this domain in patients with BPD includes side effects (sedation, weight gain, sexual dysfunction, and cognitive impairment) and the complexity of the treatment regimen. More complex regimens are typically associated with lower adherence; this is relevant in patients with BPD since lithium, the gold standard for long-term therapy in BPD, has a narrow therapeutic index and thus requires regular blood tests and dietary restrictions. A second TDF domain also mentioned in 63% of studies, “Beliefs about Consequences,” contains particularly important modifiable factors in patients with BPD. Beliefs about the necessity for pharmacologic treatment of the disorder and concerns about the medication’s effects were frequently reported causes of nonadherence. These beliefs could include any of the following:Medication is not needed to treat bipolar disorder.During periods of feeling well, without symptoms, a patient with BPD can discontinue medication.The patient is less productive while taking medication, reporting feeling “less like self.”With the understanding gained from mapping of these factors (both barriers to adherence and facilitators of adherence) to TDF domains, the study can allow clinicians to expand their adherence interventions to include talking to patients concerning their feelings about being medicated for the disease and their experiences with their treatment. (University of East Anglia. (2021). Why bipolar patients don’t take their meds.https://www.uea.ac.uk/news/-/article/why-bipolar-patients-don-t-take-their-meds; Prajapati, A. R., et al. (2021), Mapping modifiable determinants of medication adherence in bipolar disorder (BD) to the theoretical domains framework (TDF): A systematic review. Psychological Medicine, (51)7, 1082–1098. https://www.cambridge.org/core/journals/psychological-medicine/article/mapping-modifiable-determinants-of-medication-adherence-in-bipolar-disorder-bd-to-the-theoretical-domains-framework-tdf-a-systematic-review/EBFF00931816F6BF1A42C4916F034751)Released: June 2021© 2021 Wolters Kluwer  COVID-19 Vaccine Is Associated with Fewer Asymptomatic SARS-CoV2 Infections in a Single-Hospital StudyFindings from an observational study conducted at St. Jude Children’s Research Hospital offer early evidence that the mRNA COVID-19 vaccine protects against asymptomatic infections, according to a research letter that appeared in JAMA. Data was gathered from the program instituted by St. Jude to protect patients and employees from COVID-19. The hospital began routine testing of all employees in March of 2020, in which individuals were subjected to weekly nasal swabs to allow PCR testing for SARS-CoV2. Then, when the vaccine was made available in December 2020, the researchers followed all vaccine-eligible employees from December 17, 2020 to March 20, 2021.READ MORE...The study involved 5,217 St. Jude employees, of whom 3,052 (58.5%) received at least one dose and 2,776 (53.2%) received both doses of the Pfizer BioNTech mRNA vaccine. On follow-up, 236 of the employees included in the analysis tested positive for SARS-CoV2. Among individuals who received at least one vaccine dose, 51 tested positive during follow-up, of whom 29 were diagnosed through asymptomatic screening. Among unvaccinated individuals, 185 tested positive for the virus during follow-up, of whom 72 were diagnosed through asymptomatic screening. The study used incidence rate ratio (IRR), the ratio of confirmed COVID-19 cases per person days of follow-up in vaccinated compared with unvaccinated groups, as a measure of the association between vaccination and infection. The IRR was 0.21 for any SARS-CoV2 infection, 0.28 for positive infection results on asymptomatic screening, and 0.16 for symptomatic or known exposure cases. The IRR within the first 11 days after the first dose was 0.58 to 0.60 for all these outcomes. The IRR for positive virus results via asymptomatic screening from 12 days after the first dose until the second dose was 0.58, in the first 7 days after the second dose was 0.35, and for 7 days or longer after the second dose was 0.10.Even one dose of the vaccine reduced the risk of asymptomatic and symptomatic SARS-CoV2 infection by 79%. Analysis of asymptomatic infections found that vaccination had reduced that risk by 72%. Protection was even greater in employees who completed two doses; by a week or more after the second dose, vaccinated employees were 96% less likely than unvaccinated peers to become infected with SARS-CoV2, with asymptomatic infections being decreased by 90%. The data from this study is particularly valuable because of the broad asymptomatic testing, which enabled researchers to identify the many hidden cases of COVID-19 in the population.(Tang, L., et al. (2021). Asymptomatic and symptomatic SARS-CoV-2 infections after BNT162b2 vaccination in a routinely screened workforce. JAMA. https://jamanetwork.com/journals/jama/fullarticle/2779854; St Jude Children’s Research Hospital. News Releases. (2021). COVID-19 vaccine is associated with fewer asymptomatic SARS-CoV-2 infections.https://www.stjude.org/media-resources/news-releases/2021-medicine-science-news/covid-19-vaccine-is-associated-with-fewer-asymptomatic-sars-cov-2-infections.html)Released: June 2021© 2021 Wolters KluwerFinerenone Delays Atrial Fibrillation in Patients with CKD and DiabetesFinerenone, a nonsteroidal selective mineralocorticoid receptor antagonist, can be used as a therapeutic strategy to delay onset of atrial fibrillation and flutter in patients with chronic kidney disease (CKD) and type 2 diabetes. A new analysis of data from FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) presented at the American College of Cardiology’s 70th Annual Scientific Session examined the effects of finerenone on new-onset atrial fibrillation and flutter and the cardiorenal effects of the treatment in patients with a history of atrial fibrillation in the parent study. The primary endpoint in FIDELIO-DKD was a composite of kidney failure, renal death, and sustained decrease in GFR of 40% or more from baseline. This new analysis showed that patients taking finerenone derived these benefits regardless of atrial fibrillation history and also suggested that finerenone reduced the rate of new-onset atrial fibrillation.READ MORE...The study randomly assigned 5,674 patients with CKD and type 2 diabetes to finerenone or placebo and tracked outcomes for a median of 2.6 years. Finerenone significantly lowered risk of kidney events by 18% and risk of cardiac events by 14% compared to placebo. New-onset atrial fibrillation was reported in 82 patients (3.2%) in the finerenone arm of the trial compared with 117 patients (4.5%) in those taking placebo, a significant difference (hazard ratio, 0.71). The lower incidence of new-onset atrial fibrillation with finerenone treatment was notable at month 6 and continued throughout the trial, suggesting a sustained effect.Patients with CKD and type 2 diabetes mellitus are at increased risk of atrial fibrillation because these conditions can cause changes in the heart’s structure and electrical signaling, leading to fast and erratic heart rhythms. It’s thought that finerenone acts by blocking mineralocorticoid receptors and inhibits cardiac remodeling. Longer studies focusing specifically on new-onset atrial fibrillation are needed to confirm these findings. (Filippatos, G., et al. (2021). Finerenone reduces onset of atrial fibrillation in patients with chronic kidney disease and type 2 diabetes. J Am Coll Cardiol. Advance online publication. https://www.jacc.org/doi/pdf/10.1016/j.jacc.2021.04.079; AlphaGalileo. (2021). Finerenone may delay onset of atrial fibrillation in patients with chronic kidney disease, diabetes. American College of Cardiology 70th Annual Scientific Session. https://www.alphagalileo.org/en-gb/Item-Display/ItemId/208285?returnurl=https://www.alphagalileo.org/en-gb/Item-Display/ItemId/208285)Released: June 2021© 2021 Wolters KluwerMavacamten and Quality of Life in CardiomyopathyResults of a secondary analysis of a Phase III trial reported at the American College of Cardiology meeting and published in The Lancet demonstrate that the cardiac myosin inhibitor mavacamten improves results on quality of life measures in patients with hypertrophic obstructive cardiomyopathy.READ MORE...The researchers conducted a health status analysis of EXPLORER-HCM, a Phase III double-blind randomized controlled trial that involved 251 patients with symptomatic hypertrophic obstructive cardiomyopathy and left ventricular outflow tract gradient of at least 50 mm Hg at baseline. They were randomly assigned to mavacamten or placebo for 30 weeks, followed by an 8-week washout period. Primary findings from the trial, which were reported last year at the European Society of Cardiology, demonstrated that mavacamten use resulted in an increase in peak oxygen consumption and a reduction in New York Heart Association heart failure class. These results objectively showed improvement in patients’ functioning, but researchers sought to determine effect on quality of life, a more direct measure of how patients experience symptomatic improvement.Researchers administered the Kansas City Cardiomyopathy Questionnaire (KCCQ), a disease-specific measure of patients’ health status, at baseline, week 6, week 12, week 18, week 30, and week 38. Of 123 patients receiving mavacamten, 92 (75%) completed the questionnaire at baseline and week 30; 88 (69%) of the 128 assigned to placebo did. Changes from baseline to week 30 in KCCQ overall summary score and change in all subscales were analyzed.At 30 weeks, the improvement in KCCQ overall summary score was greater with mavacamten than with placebo: a 14.9-point change versus a 5.4-point change, for a difference of 9.1 points. Similar benefits were seen across all subscales of the KCCQ. In addition, a significantly larger percentage of patients receiving mavacamten reported a very large improvement (at least 20 points); 36% of patients in the mavacamten arm compared with 15% of those on placebo. These quality of life gains compare favorably with most treatments for heart failure. Overall, results of EXPLORER-HCM demonstrate that mavacamten may be used as primary therapy for hypertrophic obstructive cardiomyopathy, but more study is needed to compare it to the other agents that have been used to manage the disorder (for example, beta blockers, disopyramide, verapamil) and to determine which patients do better with which drugs. (MedPage Today. (2021). Mavacamten boosts quality of life in hypertrophic cardiomyopathy. https://www.medpagetoday.com/meetingcoverage/acc/92601; Spertus, J. A., et al. (in press). Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): Health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00763-7/fulltext)Released: June 2021© 2021 Wolters Kluwer
Drug News Abstracts - May 2021
Side Effects and COVID-19 Vaccine HesitancyVaccine hesitancy is increasingly a roadblock toward achieving herd immunity in many nations, including the United States. Reports of adverse effects, both common, such as fever and body aches, and rare but life-threatening, such as cerebral blood clots, have given fuel to these concerns. It’s tempting to refrain from discussing vaccine side effects with the public, but rebuilding trust in our health care institutions is important, and maintaining transparency around the costs and benefits of COVID-19 vaccinations can increase such trust.The reports of what is now termed vaccine-induced thrombotic thrombocytopenia (VITT) after vaccination with the viral vector vaccines produced by Astra Zeneca and Johnson & Johnson/Janssen, are contributing to this vaccine hesitancy. The FDA and the Centers for Disease Control, after six cases of cerebral venous sinus thrombosis combined with thrombocytopenia were reported in vaccinated people, ordered a pause in distribution of the J&J/Janssen vaccine in the United States. Ultimately, about 15 cases of VITT were identified, all occurring in women ages 18 to 48 within a median of 9 days after vaccination. Although the incidence is very low, its life-threatening nature made it imperative that clinicians learn how to recognize and treat it. These blood clots are thought to be related to the autoantibody platelet factor 4, which is responsible for heparin-induced thrombotic thrombocytopenia, and therefore cannot be treated by heparin or related anticoagulants. With this in mind, providers are encouraged to ask patients presenting with low platelet counts or with evidence of blood clots about recent vaccinations so they can manage the syndrome with IV immunoglobulins and other supportive care. Women, especially pregnant and postpartum women, should be encouraged to receive the mRNA vaccines.Other, non-life-threatening adverse events are also contributing to vaccine hesitancy. A recent article in the New York Times reported that up to 8% of vaccinated individuals are passing up the second dose because of reports of more severe reactions to the second dose. The challenge here is in educating the public that those reactions are actually a function of the vaccine working. It reflects the amnestic, or memory, response, as the body’s immune system remembers exposure to the spike protein of the SARS-CoV2 virus.Combatting vaccine hesitancy will require transparency by public health authorities to enable recognition and treatment of rare but life-threatening adverse reactions and clear communication of the risks and benefits of the vaccine versus infection with the actual virus. Although the common adverse effects—fever, headache, body aches—can be troublesome, they are brief, most occurring within the first few days after vaccination. But the viral infection carries a mortality rate of about 2%, and long-haul symptoms are estimated to occur in between 10% and 40% of infected individuals.(Lahey, T. (2021, April 13). Op-ed: J&J vax pause is actually good for COVID long game. MedPage Today. https://www.medpagetoday.com/infectiousdisease/covid19vaccine/92069; Walker, M. (2021, April 13). J&J COVID vaccine pause not an overreaction, officials say. Med Page Today. https://www.medpagetoday.com/infectiousdisease/covid19vaccine/92068; Marshall, S. & Salahi, L. (2021, May 5). Are side effects why many pass on COVID shots? [Audio podcast]. MedPage Today. https://www.medpagetoday.com/podcasts/trackthevax/92422)Released: May 2021© 2021 Wolters KluwerCOVID-19 Vaccines for Adults with Parkinson DiseaseThose with advanced Parkinson disease are at high risk of serious, life-threatening SARS-CoV2 disease, so the arrival of COVID-19 vaccines has created hope for them. Although the risk of infection with the virus is not higher for patients with Parkinson disease, the risk of experiencing severe respiratory disease and long-term sequelae does appear to be elevated among those who do become infected, especially among those with more advanced Parkinson disease. Motor and nonmotor symptoms of Parkinson disease can worsen as a result of COVID-19, and the risk of death from COVID-19 also appears to be higher than in the general population.Concerns, however, have been expressed by patients, their families, and clinicians about the safety and efficacy of the vaccine in those with Parkinson disease. In particular, concerns have been raised about the effects of the COVID vaccine on the disease process and on dopaminergic medications.An article in the Journal of Parkinson Disease sought to lay out recommendations from the International Parkinson and Movement Disorder Society (IPDMS). The IPDMS made the following points:The vaccines currently available under the Emergency Use Authorization, both mRNA and viral vector vaccines, produce immunization through mechanisms not known to interact with the neurodegenerative process in Parkinson disease.Reported data on those vaccines shows no difference in the types or incidence of side effects in persons with Parkinson disease compared to the general population.COVID-19 vaccines are not known to interfere with current Parkinson disease therapies.The authors of the article recommend that patients with Parkinson disease receive the vaccine, unless they have specific contraindications, among them being frail and elderly or terminally ill patients living in long-term care facilities. They also encourage patients with Parkinson disease to discuss the vaccination with their physicians and encourage clinicians to stay up-to-date with published reports on the vaccine rollout. (Bloem, B. R., et al. (2021). COVID-19 vaccination for persons with Parkinson’s disease: Light at the end of the tunnel? J Parkinson Dis; 11(1): 3-8. https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd212573)Released: May 2021© 2021 Wolters KluwerChoosing the Best Epilepsy Drugs for Newly Diagnosed PatientsThe Phase IV open-label Standard New Epileptic Drug (SANAD II) studies compared newer therapies such as levetiracetam and zonisamide to older antiseizure medications such as valproate to determine the noninferiority of the new drugs to standard therapy. Published in The Lancet, SANAD II consisted of two pragmatic, open-label, randomized trials: one that compared the long-term clinical effectiveness of valproate and levetiracetam as treatment of generalized seizures (the second compared lamotrigine, levetiracetam, and zonisamide to determine if the newer drugs are appropriate first-line therapies for focal epilepsy).The generalized epilepsy study recruited patients from 69 adult and pediatric neurology services in the UK. The median age was 13.9 years, and 65% of those enrolled were male; 397 patients had generalized epilepsy and 123 unclassified epilepsy. The studies were designed as noninferiority trials and, in new patients with generalized epilepsy, levetiracetam didn’t meet the noninferiority criteria compared with valproate in time to 12-month remissions from seizures on intent-to-treat analysis, with a hazard ratio (HR) of 1.19; on per protocol analysis, valproate was found to be clearly superior (HR, 1.68). Valproate was also superior to levetiracetam for time to treatment failure (HR, 0.65) and time to first subsequent seizures (HR, 0.82). At 2 years, there was a 15% difference in the treatment failure rate for levetiracetam compared with valproate. Valproate was also superior in cost-effectiveness, based on differences in costs and quality-adjusted life-years.These findings have an important clinical consequence. Valproate has long been a first-line treatment for newly diagnosed generalized epilepsy, but the FDA has warned against its use in women of childbearing age due to the known risk of birth defects. Levetiracetam has increasingly been prescribed for these women, so these findings present a dilemma for them. Each woman and her clinicians need to weigh the reality of the teratogenic effects of valproate against the lower effectiveness of levetiracetam. (George, J. (2021, April 12). Epilepsy drugs for newly diagnosed patients: What's best? MedPage Today. https://www.medpagetoday.com/neurology/seizures/92051; Cross, J. H. & Tomson, T. (2021). Newer versus older antiseizure medications: further forward? The Lancet. 397(10282): 1327-1329. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00435-9/fulltext; Marson, A., et al. (2021). The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: An open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. The Lancet; 397(10282): 1375-1386. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00246-4/fulltext; Marson, A., et al. (2021). The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. The Lancet; 397(10282): 1363-1374. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00247-6/fulltext)Released: May 2021© 2021 Wolters KluwerAddition of Nivolumab to Chemotherapy Improves Response in Operable Lung CancerAdding the anti-PS-1 monoclonal antibody nivolumab to standard platinum-based chemotherapy before surgery increased the pathological complete response (pCR) rate in patients with operable lung cancer. These results of the Checkmate-816 trial were reported at the American Association for Cancer Research (AACR) annual meeting, held virtually from Philadelphia.The multicenter, Phase III trial enrolled 358 patients with newly diagnosed, stages Ib to IIIa non–small-cell lung cancer (NSCLC) and no known EGFR or ALK alterations. The study evaluated two combination strategies: fixed-dose nivolumab and platinum-based chemotherapy and weight-adjusted nivolumab and ipilimumab, and compared them to chemotherapy alone. However, the presentation at the AACR meeting discussed only the data for the nivolumab-chemotherapy arm. Patients underwent surgery within 6 weeks, after restaging based on radiologic findings; after surgery, patients could receive chemotherapy with or without radiotherapy.The primary endpoint, pCR, was defined as no residual viable tumor when the resected lung specimen and the sampled lymph nodes were examined after surgery. Adding nivolumab to chemotherapy produced an improvement in pCR, to 24% of patients, compared with 2.2% in the chemotherapy arm alone. Combination therapy also improved the major pathologic response rate, which is defined as 10% or less residual viable tumor cells in the lung and lymph nodes, to 36.9%, compared with 8.9% in the chemotherapy alone arm. Presurgical objective response rate was 54% with nivolumab combination vs. 37% with chemotherapy alone. The addition of nivolumab maintained a tolerable safety profile, and the rates of adverse events leading to surgery delay or cancellation were low: 83% of those in the nivolumab combination arm underwent surgery, as did 75% of those treated with chemotherapy alone. Surgery was delayed in 21% of nivolumab patients and 18% of chemotherapy patients.These findings, along with data from several retrospective studies that show a clear trend toward improved survival in those patients who achieve pCR, are encouraging. The study is ongoing, so results for event-free survival are still to come.(Bankhead, C. (2021, April 11). A win for nivolumab as preoperative therapy for lung cancer. MedPage Today. https://www.medpagetoday.com/meetingcoverage/aacr/92038; AACR. News Release. (2021, April 10). Neoadjuvant nivolumab plus chemotherapy increased pathological complete response rate in CheckMate-816 lung cancer trial. https://www.aacr.org/about-the-aacr/newsroom/news-releases/neoadjuvant-nivolumab-plus-chemotherapy-increased-pathological-complete-response-rate-in-checkmate-816-lung-cancer-trial/)Released: May 2021© 2021 Wolters Kluwer