Primecuts-This Week in the Journals

December 23, 2015

star-wars-the-force-awakens-movie-posterBy Pooja Gala, MD

Last week, world leaders convened in Paris to sign a landmark climate deal. 186 countries submitted plans to reduce greenhouse gas pollution to “hold the increase in the global average temperature to well below 2 degrees Celsius above pre-industrial levels” to avoid catastrophic storms, rising sea levels, and droughts [1]. Across the ocean, Janet Yellen announced an increase in federal interest rates for the first time in 7 years signaling the Fed’s confidence in the US economy [2]. Taking a break from US politics, millions of Americans across the country indulged in the politics between the First Order and the Resistance in Star Wars Episode VII: The Force Awakens. The movie became the first movie to break $100 million at the box office in one day [3].

In medical news, there is now a promising reversal agent for Factor Xa Inhibitors. The first Factor Xa Inhibitor was FDA approved in 2011 and studies repeatedly show the advantages of these drugs to Coumadin [4]. However, with no reversal agent currently on the market there is a reluctance to use these agents.

Is Andexanet alfa effective at reversing Factor Xa Inhibitors?

Andexanet alfa is a protein that binds the active site of factor Xa inhibitors with high affinity. The protein sequesters factor Xa inhibitors, reducing levels of anticoagulant activity. In the randomized, double-blinded, placebo-controlled ANNEXA-A (Apixaban) and ANNEXA-R (Rivaroxaban) studies, 101 healthy participants with an average age of 57.9 were placed on either Apixaban or Rivaroxaban and randomized to receive Andexanet or a matching placebo to reverse the effects of the Factor Xa inhibitor.

The primary outcome was percentage change in Factor Xa activity. In both studies Andexanet significantly reduced Anti-Factor Xa Activity within 2-5 minutes compared to placebo. For Apixaban, a mean reduction of 94±2% vs. 21±9%; P<0.001 was seen and for Rivaroxaban, 92±11% vs. 18±15%, P<0.001. All participants given full dose Andexanet had at least an 80 percent reversal (p<0.0001). No serious or severe adverse events or thrombotic events were reported. However, there was a transient elevation in D-Dimer and prothrombin fragments for up to 72 hours. Overall, Andexanet is an effective reversal agent for Factor Xa inhibitors. However, whether this agent reduces bleeding complications is yet to be determined and will require future studies. The significance of transiently elevated D-Dimer and prothrombin in a population with atrial fibrillation or thromboembolism also needs to be further evaluated. Of note, these studies were sponsored by Portola Pharmaceuticals with additional financial and scientific support from multiple other major pharmaceutical companies [5].

Should we be screening post-menopausal women for ovarian cancer?

In the US, ovarian cancer is rare, affecting 12.1 per 100,000 women per year and representing 1.3% of new cancer cases and 2.4% of all cancer deaths per year [6]. However, ovarian cancer has a poor prognosis with a 45.6% 5-year survival rate in the US and 40% 5-year survival rate in the UK and typically is asymptomatic until late in the disease course. Currently there is no screening test for ovarian cancer which led to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) study. 205,090 post-menopausal women aged 50-74 with no personal or family history of ovarian cancer were randomized to no screening, annual screening with serum CA125 (MMS), or annual screening with ultrasound (USS). CA125 was interpreted as normal, intermediate or elevated risk with those at intermediate risk receiving a repeat CA125 at 3 months and those at elevated risk receiving a repeat CA125 and ultrasound at 6 weeks. Ultrasound screening was interpreted as normal, unsatisfactory or abnormal with repeat ultrasound at 3 months in the unsatisfactory group and 6 weeks in the abnormal group. After approximately 11 years of screening, the number needed to screen (NNS) was 1 in 1990 for MMS and 1 in 2611 for USS to prevent 1 death from primary ovarian cancer [7]. In comparison, annual screening via mammography for breast cancer is estimated to have a NNS of 455 in ages 50-59 and 303 in ages 60-69 to prevent 1 death [8]. In the UKCTOCS study, there was no significant difference in mortality among patients that received no screening (0.034%), received MMS (.029%) or USS (.030%). The complication rates of false positive surgery were 3.1% in MMS and 3.5% in USS, comparable to the major complication rate of 2.9% reported for benign surgery nationally for gynecologic/oncology centers. Perhaps longer follow-up is needed to show a true mortality benefit in screening for ovarian cancer, but for now, new methods for early diagnosis, tools to assess risk and identify groups that would most benefit from screening and increased awareness are needed [7].

Can Zoster lead to an increase in cardiovascular events post-infection?

Recent studies are finding an association between herpes zoster and stroke [9]. A proposed mechanism includes VZV vasculopathy mediated by virus replication in arterial walls leading to inflammation and pathological arterial remodeling. This retrospective, self-controlled, case series study of Medicare beneficiaries shows a similar association between the virus and MIs, likely through a similar mechanism. In a population of 24,237 individuals with a median age of 80 and 90% with evidence of preexisting cardiovascular disease, the rate of myocardial infarctions (MIs) before a first diagnosis of zoster was compared to the rate post zoster infection. In the first week post-infection, the risk of MI increased 68% (p<0.005) compared to baseline, 25% in weeks 2-4, (p<0.005) and then the risk returned to the baseline risk for MIs in this population prior to being infected with zoster. There was a low vaccination rate in this population, and further studies are needed to see if vaccination can mitigate this association seen between an active zoster infection and cardiovascular risk [10].

Is a selective V1A receptor agonist superior to vasopressin in septic shock?

Currently, the Surviving Sepsis campaign guidelines recommend norepinephrine (NE) as a first line agent in septic shock and vasopressin (AVP) as an adjunctive therapy in volume and catecholamine refractory septic shock [11]. AVP is a mixed V1A/V2 receptor agonist. Activating V2 receptors can exacerbate septic shock by promoting microvascular thrombosis through the release of vWF, Factor VIII and causing fluid accumulation, vascular leakage and pulmonary edema through salt and fluid retention [12]. As an alternative, selepressin, a V1A specific receptor agonist is being tested in animal models of septic shock.

In this randomized, controlled ovine study, fecal peritonitis and septic shock were induced in 46 mechanically ventilated sheep. NE, AVP, or Selepressin were administered in models of “early” (10% reduction in MAP) or “late” (fluid refractory) septic shock. No antibiotics were given. Selepressin significantly increased median survival time (25.5 hours) in the early septic shock model, compared to NE (20.5 hours), AVP (23 hours), and placebo (19 hours) (p<0.01). A smaller increase was seen in the late septic shock model. In both models, selepressin resulted in a reduced cumulative fluid balance and lung edema, and in the early model resulted in better hemodynamic stabilization and preserved lung and renal function [13]. Whether this study has clinical significance for human patients receiving antibiotics remains unclear. However, the SEPSIS-ACT Trial, which is currently enrolling patients, should help answer this question. . This trial will compare selepressin to vasopressin in humans with septic shock requiring vasopressors [14].


A German study evaluated transcatheter-aortic valve replacement procedures since 2007 showing an increase in TAVRs performed and a trend towards improvement and decreased complications for both TAVRs and surgical aortic valve replacements. Given the higher risk patients receiving TAVRs, there are still significantly more complications with TAVRs compared to surgical aortic-valve replacements [15].

The standard of care for HIV patients starting on a new antiretroviral regimen includes the use of nucleoside reverse transcriptase inhibitors (NRTIs). The OPTIONS trial, a multicenter, open-label, prospective, randomized, controlled study showed that omitting NRTIs in new ART regimens for individuals who had failed PI-based regimens or had documented viral resistance is safe and equally as effective at suppressing HIV RNA levels [16].

In case reports, hematopoietic stem cell transplantation has been tried for patients with refractory Crohn disease. In a parallel-group, randomized clinical trial, 23 patients with refractory Crohn’s disease underwent HSCT. Unfortunately, compared to conventional therapy, there was no statistically significant improvement in sustained disease remission at 1 year and there were almost double the number of adverse events in patients undergoing HSCT versus standard therapy [17].

Finally, Nature debunks common science myths. This includes the myth that antioxidants are good, free radicals are bad and the myth that individuals learn best in their preferred learning style. The article concludes with some good news, the human population is NOT growing exponentially [18].

Pooja Gala, MD is a second year internal medicine resident at NYU Langone Medical Center

Peer Reviewed by Matthew Dallos, MD, Associate Editor, Clinical Correlations

1. NYTimes. The Road to a Paris Climate Deal. 12.14.15
2. NYTimes. A Quick Look at the Fed’s Interest Rate Increase.
3. MSN. Star Wars: The Force Awakens’ Topples Another Record With $100 Million-Plus Friday.
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6. National Cancer Institute. SEER Stat Fact Sheets: Ovary Cancer. <>
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13. He, Xinrong, et al. A selective V1A Receptor Agonist, Selepressin, is Superior to Arginine Vasopressin and to Norepinephrine in Ovine Septic Shock. Critical Care Medicine. 2016: 44 (23-31)
14. Ferring Pharmaceuticals. Selepressin Evaluation Programme for Sepsis-Induced Shock.
15. Reinohl J, et al. Effect of Availability of Transcatheter Aortic Valve Replacement on Clinical Practice. N Engl J Med. 2015; 373: 2438-2447
16. Dominique Farge, PhD et al. Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease. A Randomized Clinical Trial. JAMA, December 2015
17. Tashima KT, et al. HIV Salvage Therapy does not require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial. Ann Intern Med. 2015; 163 (12): 908-917
18. Scudellari, Megan. The science myths that will not diet. Nature. 2015; 528; 7582