Primecuts – This Week In The Journals

By Derek Moriyama, MD

Peer Reviewed 

It is official. The members of the electoral college have cast their votes and Donald Trump will be the next President of the United States. As he continues to use twitter as a platform to inform the world of his beliefs, including a reference to the direction of our nuclear program [1], we are all left guessing how his Presidency will affect the future of our country and the world.

Aside from U.S. political news, there have been shocking news stories abroad this week as well. In Syria, we witnessed a forced evacuation of civilians and rebel fighters in East Aleppo [2], and in Germany, there was a recent Berlin Christmas market crash that killed 12 and wounded dozens [3]. In this week’s PrimeCuts, we hope to bring a little holiday cheer by highlighting scientific advances that aim to improve health and sustain life.

Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open label cluster-randomised trial [4] 

There is no doubt that the 2013 Ebola virus outbreak in west Africa shook the international community with a total of 28,652 suspected cases and total of 11,325 deaths reported by the CDC [5]. This week in the Lancet, Anna Maria-Henao-Restrepo, et al. gave their findings on the effectiveness of a new recombinant Ebola vaccine (rVSV-ZEBOV) in Guinea & Sierra Leone. The study was a cluster-randomized controlled study of people who were epidemiologically linked to subjects confirmed to have Ebola, defined as primary and secondary contacts of a confirmed Ebola case. A total of 4,160 eligible persons were consented and each cluster was randomized into immediate vaccination or 21 day delayed vaccination clusters. During the trial period there were 476 confirmed cases of Ebola virus disease in Guinea. Of the immediate vaccination clusters, no patients had symptoms of Ebola virus disease during the 84 day monitoring period versus 15 serologically confirmed cases in the delayed vaccination cohort. After these early findings, an independent safety board recommended randomization be stopped and additional patient placed in immediate vaccination nonrandomized clusters. None of these participants contracted the disease, giving the vaccine an estimated efficacy of 100% overall. There were minimal serious side effects reported. While the group did not look at the immunogenicity of the vaccine during the study, they will have complementary data from another study looking at immune response to vaccination in front-line workers. They are hopeful that the vaccine can help prevent future Ebola outbreaks.

Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences [6]

For years, the mainstay treatment for genital herpes simplex virus (HSV) has been the nucleoside analogues like acyclovir and the prodrugs valacyclovir and famciclovir. This week in JAMA, Anna Wald, et al. published research suggesting that the new helicase-primase complex inhibitor pritelivir may be a promising new treatment for HSV infection. The study was a randomized, double-blind, double-dummy crossover trial on 91 adults with recurrent HSV outbreaks. Subjects were randomized to either the pritelivir 100mg daily (after 400mg loading dose) or valacyclovir 500mg daily treatment arms for a 28-day period. This was followed by a 28-day wash-out period with subsequent crossing over of the treatment groups. Participants were instructed to swab their genitals four times per day while receiving treatment to detect viral shedding. The primary end point was a ratio of the number of genital swabs positive for HSV to the total number of swabs per participant between the treatment groups. Secondary end-points included frequency of genital lesions, HSV shedding, and quantity of HSV DNA detected on positive swabs. There was a lower incidence of swabs testing positive for HSV-2 in subjects using pritelivir 2.4% vs. 5.3% using valacyclovir (relative risk 42; 95% CI; 0.21 to 0 82; P=0.01).  Pritelivir also decreased overall genital shedding, frequency of pain, and number of genital lesions during the 28-day study periods. These findings suggest that the medication may not only decrease outbreaks but could limit viral transmission. The group was forced to stop the study early given FDA findings that monkeys experienced 39-week toxicity including skin related changes, alopecia, and anemia. These effects were not found in the groups participants. While, the findings suggest improvement in HSV treatment, more research is needed looking at long-term safety of this medication.

Comparison of Hospital Mortality and Readmission Rates for Medicare Patients Treated by Male vs Female Physicians? [7]

As the field of medicine continues to evolve, there has been an emergence of studies analyzing differences in how men and women practice medicine. Past studies have shown that women spend more time on preventative services and are more likely to achieve target doses of guide-line recommended medications than their male counterparts [8,9]. In the December 19, 2016 edition of JAMA internal medicine, new data suggests that elderly hospitalized patients treated by female physicians have lower mortality and readmissions compared with male physicians [9]. The retrospective study done by Yusuke Tsugawa et. al. looked at an enormous sample of Medicare patients from January 1, 2011 to December 31, 2014 who were admitted to multiple acute care hospitals throughout the United States. The goal of the study was to see if physician sex had an association with 30-day hospital mortality and readmission rates. The group looked at a total of 1,583,028 hospitalizations in analysis of 30-day mortality and 1,540,797 for examining 30-day readmissions. They used 3 regression models adjusted for patient characteristics, hospital fixed effect, and physician characteristics associated with physician sex. The result was a female physician mortality rate of 11.07% vs male rate of 11.49% (P <0.001; number needed to treat (NNT) of 223, to prevent 1 death). Women physicians also appeared to have a lower readmission rate of 15.02% compared with males 15.57% (P < 0.001; NNT=182, to prevent 1 readmission). These findings persisted across 8 common medical conditions as well as severity of illness. While the sample size is large, the effect size had a 0.43-percentage point difference and a relative risk reduction of 4%, which is arguably clinically meaningful. Future studies are warranted to investigate what sex-specific practice patterns contribute to the observed difference in patient outcomes.

Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI [10]

In recent years there has been data showing that the new oral anticoagulants (rivaroxaban, dabigatran, apixaban) have a favorable risk-benefit profile for stroke prevention in patients with atrial fibrillation [11]. In a recent edition of the New England Journal from December 22, 2016, Gibson, et al. published an international, multicenter, randomized, open-label trial (PIONEER AF-PCI) comparing triple therapy with warfarin, adenosine diphosphate platelet specific receptor inhibitors (P2Y₁₂ inhibitor), and aspirin to the use of rivaroxaban plus antiplatelet agents in atrial fibrillation patients who have undergone percutaneous coronary intervention (PCI) [10]. Patients with non-valvular atrial fibrillation who did not have severe renal failure, recent bleeding, or a history of ischemic stroke were eligible for enrollment and randomization. The participants were randomized to three treatment groups: (1) low dose rivaroxaban and P2Y₁₂ inhibitor; (2) very low dose rivaroxaban with P2Y₁₂ inhibitor and aspirin; or (3) warfarin with P2Y₁₂ inhibitor and aspirin. Both rivaroxaban treatment arms were found to have a lower risk of bleeding than triple therapy with warfarin post PCI.  The rate of significant bleeding in the warfarin treatment group was 26.7% compared to 16.8%  and 18% in the low dose rivaroxaban and very low dose rivaroxaban groups respectively (hazard ratio [HR]0.59; 95% confidence interval [CI], 0.47 to 0.76; P<0.001 and HR 0.63; 95% CI, 0.50 to 0.80; P<0.001 respectively). The rate of major adverse cardiovascular event (MACE) was similar across all study treatment groups (6% in the warfarin group compared with 6.5% in the low dose rivaroxaban and 5.6% in the very low dose rivaroxaban group); however, this study was not powered to detect non-inferiority or superiority for this outcome (p>0.05). As the authors point out, a study to determine superiority would require 40,784 participants which may not be feasible. The PIONEER AF-PCI trial adds the option of using rivaroxaban to the question of  “What is the Optimal antiplatElet and anticoagulation therapy with oral anticoagulation and coronary StenTing?” posed by the (WOEST) trial. [12] The PIONEER AF-PCI study is limited in that it did not compare the rivaroxaban treatment groups to warfarin therapy with P2Y₁₂ inhibitor alone, which is the suggested management strategy for most patients in the post-WOEST era. This important comparison will likely be the focus of future studies.

MINI CUTS

US spending on Personal Health Care and Public Health, 1996-2013; JAMA December 27, 2016

A look into personal and public health spending shows substantial increases over the study period with diabetes, heart disease, and low back and neck pain accounting for the diseases with the highest costs.

Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial; The Lancet December 22,2016

The addition of bortezomib to lenalidomide and dexamethasone improved overall survival in patients with newly diagnosed myeloma.

Factors Associated With and Prognostic Implications of Cardiac Troponin Elevation in Decompensated Heart Failure With Preserved Ejection Fraction JAMA Cardiology December 28, 2016 

New study illustrating that patients with acutely decompensated heart failure with preserved ejection fraction and elevated troponin level have worse in-hospital and post-discharge outcomes.

Derek Moriyama is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Kerrilynn Carney, MD Associate Editor, Clinical Correlations, Chief Resident, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

(1) https://twitter.com/realDonaldTrump/status/811977223326625792

(2) Domonoske, C. (2016, 12 23). The Two-way. Retrieved 12 23, 2016, from www.NPR.org: http://www.npr.org/sections/thetwo-way/2016/12/23/506713908/emptied-east-aleppo-now-regime-controlled-but-syrias-civil-war-rages-on

(3) Melissa Eddy, A. S. (2016, 12 19). Berlin Crash Is Suspected to Be a Terror Attack. Retrieved from New York Times: http://www.nytimes.com/2016/12/19/world/europe/berlin-christmas-market-truck-crash.html

(4) Henao-Restrepo AM, Camacho A, Longini IM, Watson CH, Edmunds WJ, Egger M., … Kieny MP (2016). Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). The Lancet. 2016. http://doi.org/10.1016/S0140-6736(16)32621-6

(5) https://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html

(6) Wald A, Timmler B, Magaret A, Warren T, Tyring S, Johnston C, … Ruebsamen-Schaeff H (2016). Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences. Jama, 316(23), 2495. http://doi.org/10.1001/jama.2016.18189

(7) Tsugawa Y, Jena AB, Figueroa JF, Orav EJ, Blumenthal DM, Jha AK (2016). Comparison of Hospital Mortality and Readmission Rates for Medicare Patients Treated by Male vs Female Physicians. JAMA Intern Med. Published online December 19, 2016. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2593255

(8) Baumhäkel M, Müller U, Böhm M (2009). Influence of gender of physicians and patients on guideline-recommended treatment of chronic heart failure in a cross-sectional study. European Journal of Heart Failure, 11: 299–303. doi:10.1093/eurjhf/hfn041             http://onlinelibrary.wiley.com/doi/10.1093/eurjhf/hfn041/full 

(9) Bertakis KD, Helms  LJ, Callahan  EJ, Azari R, Robbins JA (1995).  The influence of gender on physician practice style. Med Care. 1995;33(4):407-416.

https://www.ncbi.nlm.nih.gov/pubmed/?term=The+influence+of+gender+on+physician+practice+style.+Med+Care.+1995%3B33%284%29%3A407-416.

(10) Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, Fox KA. (2016). Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. New England Journal of Medicine, 375(25), 2423–2434. http://doi.org/10.1056/NEJMoa1611594

(11) Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Antman EM (2013). Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. The Lancet, 383(9921), 955–962. http://dx.doi.org/10.1016/S0140-6736(13)62343-0

(12) Dewilde WJM, Oirbans T, Verheugt FWA, Kelder JC, De Smet BJGL, Herrman P, Berg JM (2016). Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. The Lancet, 381(9872), 1107–1115. http://doi.org/10.1016/S0140-6736(12)62177-1

 

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