By Joshua Rivers
Peer Reviewed
With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.
Benralizumab for the Prevention of COPD Exacerbations [1]
COPD in its most severe form requires triple therapy including glucocorticoids, long-acting beta agonists (LABA), and long-acting muscarinic antagonists (LAMA). It is thought that eosinophilic targets may represent an additional pathway for treatment. Benralizumab, used in treatment of severe eosinophilic asthma, is an interleukin-5-receptor alpha-directed cytolytic monoclonal antibody that directly reduces eosinophils via antibody-mediated cellular cytotoxicity.
Benralizumab has been shown in a phase 2 clinical trial to not significantly impact exacerbation frequency compared to placebo in COPD patients. In the GALATHEA and TERRANOVA trials, a subset of patients enrolled with eosinophil counts greater than or equal to 220 per cubic millimeter were given benralizumab.
Patients were randomly assigned to receive benralizumab (30 vs 100 mg in GALATHEA, 10 vs 30 vs 100 mg in TERRANOVA) every eight weeks vs placebo, with the primary endpoint being annualized exacerbation rate ratios after 56 weeks of treatment. The GALATHEA trial rate ratios were 0.96 in the 30 mg benralizumab group and 0.83 in the 100 mg group when compared to placebo. In the TERRANOVA trial, annualized exacerbation rate ratios were 0.85, 1.04, and 0.93 for 10mg, 30mg, and 100mg groups respectively when compared to placebo. After 56 weeks, none of the COPD exacerbation rate ratios reached significance in either trial.
These well designed randomized clinical trials were the second of their kind following the METREO and METREX trials using mepolizumab, another anti-interleukin-5 monoclonal antibody targeting eosinophils among COPD patients. All four of these clinical trials have failed to show significant benefit in reducing COPD exacerbations, suggesting that reducing eosinophilic activity may have no clinical benefit among COPD patients.
Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction [2]
Heart failure with preserved ejection fraction (HFpEF) has proven elusive for pharmacologic management. Among patients with reduced ejection fraction, Entresto (sacubitril-valsartan) showed a significant reduction in hospitalizations secondary to heart failure exacerbations, as well as death from cardiac causes, but there is not yet a similarly effective agent for HFpEF patients.
Over roughly a two-year period, 10,359 patients were screened at 848 centers in 43 countries for this study. 4,822 patients with New York Heart Association (NYHA) heart failure class II-IV, ejection fraction equal to or greater than 45%, proof of structural heart disease, and elevated BNP were randomized to Entresto vs valsartan alone. The primary outcome was a composite of heart failure hospitalizations and death from cardiovascular causes. 1,903 primary events took place over the two-year study period, with an event rate ratio of 0.87 (95% CI, 0.75-1.01; p=0.06) between the Entresto and valsartan group. The incidence of death due to cardiovascular cause, as well as all-cause mortality, was not statistically significant; hazard ratio was 0.95 (95% CI, 0.79-1.16) and 0.97 (95% CI, 0.84-1.13), respectively.
While Entresto appeared to not have any significant effects on HFpEF, in several post -hoc subgroup analyses from previous trials, there appeared to be a modest benefit in morbidity and mortality among those with lower but not frankly reduced ejection fraction (EF 40-55%), suggesting a need to study the impact of Entresto in this population.
Several studies have associated statins with reduced risk of hepatocellular carcinoma (HCC). Specifically, lipophilic statins (atorvastatin, simvastatin, fluvastatin, lovastatin) have shown some promise against hepatocarcinogenesis when compared to hydrophilic statins (pravastatin and rosuvastatin), but no formal prospective cohort study evaluated this until now. Mechanistically speaking, lipophilic statins have been shown to passively diffuse across cell membranes and exert antitumor effects including induction of G0/G1 cell cycle arrest, inhibition of Ras/Raf/Mek/ERK signaling, and trigger apoptosis.
From a Swedish registry of HBV and HCV patients, 6,554 lipophilic statin users, 1,780 hydrophilic statin users, and 8,334 non-statin users were propensity score-matched in a prospective cohort study. Primary outcomes were 10-year HCC incidence and 10-year mortality. Over the median follow-up period of eight years, 616 cases of HCC and 1803 deaths were reported. Lipophilic statin users, compared to non-statin users, had a significantly lower 10-year cumulative incidence of HCC with incidence of 3.3% and 8.1% respectively (adjusted hazard ratio 0.56; 95% CI 0.41-0.79). Hydrophilic statin users, compared to non-statin users, did not have a significantly lower 10-year cumulative incidence of HCC.
This study supports the use of lipophilic statins for HCC prevention, but further research is needed to characterize the populations that may have the greatest hepatoprotective benefit, as well as the role of both lipophilic and hydrophilic statins in these patients.
Vitamin D supplementation has been a mainstay of osteoporosis treatment and prevention. Studies have shown benefits of vitamin D supplementation in people with severe vitamin D deficiency (<30nmol/L), however, recent meta-analyses have suggested that vitamin D is not actually beneficial for osteoporosis. In addition, there is conflicting evidence for dose-specific benefits of vitamin D supplementation with osteoporosis risk reduction, with some studies suggesting that there is no added benefit for bone mineral density (BMD) with supplementation greater than 800 IU daily.
This single-center, double-blind randomized trial followed 311 patients for three years with a 1:1:1 randomization of patients to 400, 4000, and 10000 IU/day of Vit D PO. There were two primary outcomes: total volumetric BMD at the radius and tibia, assessed with high-resolution peripheral quantitative computed tomography (HR-pQCT), which is more sensitive than the classic DXA scan; and radius and tibial bone strength, measured via finite element analysis. At the end of the study, radial volumetric BMD was lower for the 4000 and 10,000 IU dosing groups at -3.9 mg HA/cm3 and -7.5 mg HA/cm3, respectively, compared to the 400 IU group. Tibial volumetric BMD followed a similar pattern with 4,000 and 10,000 IU dosing groups having -1.8 mg HA/cm3 and -4.1 mg HA/cm3, respectively, compared to the 400 IU group.
There was no statistically significant difference in bone strength for tibia or radius in healthy adults taking an increased dose of vitamin D, 4,000 and 10,000 IU compared to 400 IU daily. This study’s findings provides evidence against there being a benefit from high-dose vitamin D. Also, it’s evident the harmful implications of vitamin D supplementation need to be further determined as there is a negative association between increasing doses of vitamin D and BMD as assessed by HR-pQCT.
Minicuts
Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes [5]
Ticagrelor and prasugrel have both been used as antiplatelet therapies in acute coronary syndromes with planned invasive evaluation, but they have not been directly compared over the course of a year. A multicenter, randomized, open-label trial compared the incidence of death, MI, or stroke, and found that among 4000 patients, with about half on each med, prasugrel had significantly fewer events than ticagrelor.
Nabiximols for the Treatment of Cannabis Dependence [6]
To date there are no effective medications for treating cannabis dependence. This double-blind, randomized, clinical trial evaluated nabiximol versus placebo among 128 patients age 18-64. Over the 12-week follow-up period, the placebo group used cannabis significantly more days, mean [SD] of 53.1 [33.0] compared to 35.0 [32.4] days in the nabiximol group, with an estimated difference of 18.6 days (95% CI, 3.5-33.7; p = 0.02).
Biomarkers of systemic lupus erythematosus have been useful in identifying patients with SLE for decades, and now a novel group of markers called cell-bound complement activation products (CB-CAPs) are being considered. This study evaluated the utility of CB-CAPs as a predictor of SLE development and found CB-CAPs to be more prevalent in probable-SLE patients (patients not fully meeting ACR criteria, but suspected to develop SLE) than patients already diagnosed with SLE.
N95 Respirators vs Medical Masks for Preventing Influenza Among Health Care Personnel [8]
Several studies have shown conflicting results regarding the effectiveness of N95 masks in preventing viral respiratory infections. This randomized clinical trial evaluated N95 masks against regular medical masks among outpatient health care personnel. Out of 2371 total participants, 207 from the medical mask group and 193 from the N95 group developed influenza, demonstrating no significant difference with mask type.
Dr. Joshua Rivers is a resident physician at NYU Langone Health
Peer reviewed by Christian Torres, MD, chief resident, internal medicine, NYU School of Medicine
Image courtesy of Wikimedia Commons
References
[1] Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the Prevention of COPD Exacerbations. N Engl J Med. September 2019; 381:1023-1034. https://www.nejm.org/doi/full/10.1056/NEJMoa1905248?url
[2] Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. September 2019. doi: 10.1056/NEJMoa1908655 https://www.nejm.org/doi/full/10.1056/NEJMoa1908655?url
[3] Simon TG, Duberg A, Aleman S, et al. Lipophilic Statins and Risk for Hepatocellular Carcinoma and Death in Patients With Chronic Viral Hepatitis: Results From a Nationwide Swedish Population. Annals of Intern Med. September 2019. Doi:10.7326/M18-2753 2019;171(5):318-327 https://annals.org/aim/article-abstract/2748619/lipophilic-statins-risk-hepatocellular-carcinoma-death-patients-chronic-viral-hepatitis?doi=10.7326%2fM18-2753
[4] Burt LA, Billington EO, Rose MS, et al. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength A Randomized Clinical Trial. JAMA. 2019;322(8):736-745. Doi: 10.1001/jama.2019.11889. https://jamanetwork.com/journals/jama/article-abstract/2748796
[5] Schupke S, Neumann F, Menichelli M, et al. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N Engl J Med. September 2019. DOI: 10.1056/NEJMoa1908973. https://www.nejm.org/doi/full/10.1056/NEJMoa1908973?url
[6] Lintzeris N, Bhardwaj A, Mills L, et al. Nabiximols for the Treatment of Cannabis Dependence A Randomized Clinical Trial. JAMA Intern Med. 2019;179(9):1242-1253. doi:10.1001/jamainternmed.2019.1993. https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2737918
[7] Ramsely-Goldman R, Alexander RV, Massarotti EM, et al. Complement activation occurs in patients with probable systemic lupus erythematosus and may predict progression to ACR classified SLE. Arthritis and Rheumatology. August 2019. doi:10.1002/art.41093 https://doi.org/10.1002/art.41093
[8] Radonovich LJ, Simberkoff MS, Bessesen MT, et al. N95 Respirators vs Medical Masks for Preventing Influenza Among Health Care Personnel A Randomized Clinical Trial. JAMA. September 2019;322(9):824-833. doi:10.1001/jama.2019.11645 https://jamanetwork.com/journals/jama/article-abstract/2749214