Primecuts-This Week in the Journals

December 18, 2017

PrimeCuts 7 min read

By: Amanda Dowden, MD

This week, Alabama elected its first Democratic senate leader in 25 years, as democrat Doug Jones beat Republican Roy Moore in Alabama’s Senate Race. In local NYC news, in the wake of the opioid epidemic the Bronx opens a state supported outreach center for people and families struggling with substance abuse. Despite all that is going on in the news, there’s plenty of exciting, new medical literature to discuss, so let’s dive right in.

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

Venous thromboembolism (VTE) commonly occurs in cancer patients. The standard of care in these patients is low-molecular weight heparin (LMWH). However, in clinical practice around 30-60% of patients in different cohorts are not on LMWH for anticoagulation [1]. Reasons for the lack of compliance to guidelines include costs and reported inconvenience, with daily subcutaneous injections [2]. While there are several oral options for anticoagulation, there is limited data on the efficacy and safety of direct oral anticoagulants (DOACs) as compared to LMWH. Investigators in the Hokausai VTE Cancer trial, published recently in NEJM, sought to evaluate the role of edoxaban, a direct factor Xa inhibitor, in VTE [3].

The Hokausai VTE Cancer trial was an open-label, non-inferiority study, which randomized 1,050 patients to receive edoxaban or dalteparin (a LMWH) after 7 days of dalteparin. The composite primary outcome was recurrent VTE or major bleeding. This trial included adult patients with acute symptomatic VTE or incidentally discovered VTE with cancer diagnosed within 2 years prior to enrollment or active cancer.

Over the 12-month follow up, in respect to the composite primary outcome of recurrent venous thromboembolism or major bleeding, a fixed once-daily dose of oral edoxaban was found to be non-inferior to treatment with subcutaneous dalteparin (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for non inferiority; P=0.87 for superiority). The rate of recurrent venous thromboembolism was numerically lower with edoxaban than with dalteparin (7.9% and 11.3%, respectively; hazard ratio, 0.71; 95% CI, 0.48 to 1.06; P=0.09). However, the rate of major bleeding was significantly higher in the edoxaban group than with dalteparin, with 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (hazard ratio, 1.77 [95% CI, 1.03 to 3.04; P=0.04]). This difference is attributed to the increase in upper gastrointestinal bleeding, which was primarily seen in patients with gastrointestinal cancer.

One limitation to this study is dalteparin had a shorter median duration of treatment than with edoxaban, which may have influenced the relative efficacy of the two treatments. Nevertheless, these findings suggest that there may be a role for DOACs in the treatment of active VTEs in cancer patients.

Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial

Patients with diabetes need extensive control of their cardiovascular risk factors. Dyslipidemia is an important predictor of cardiovascular disease. While some studies show that extended statin use is associated with an increased risk of incident diabetes, statins remain the mainstay of treatment of dyslipidemia in diabetes [4]. Recently, research in cholesterol metabolism gave rise to a promising new drug, Evolocumab.   Evolocumab is a fully human monoclonal antibody directed against PCSK9, an enzyme that binds and degrades the Low-Density Lipoprotein (LDL) receptor found on the surface of hepatocytes [5]. By inhibiting PCSK9, higher quantities of LDL receptors are recycled and returned to the cell membrane, subsequently decreasing plasma LDL levels.

In this week’s Lancet: Diabetes & Endocrinology, investigators sought to evaluate the efficacy and safety of Evolocumab by diabetes status and the effect of Evolocumab on glycemia and risk of developing diabetes through a prespecified analysis of the FOURIER trial [6].

The FOURIER trial was a multinational, randomized, placebo-controlled trial in which 27,564 statin-treated participants with clinically evident atherosclerosis were randomized to Evolucumab versus placebo [6]. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. Additionally, the risk of new-onset diabetes was evaluated through serial monitoring of HbA1c and fasting plasma glucose at baseline and every 24 weeks.

Evolocumab significantly reduced cardiovascular outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios were 0.83 (95%, CI 0.75–0.93; p=0.0008) for the 40% of patients with diabetes and 0.87 (0.79–0.96; p=0.0052) for the remaining 60% of patients without diabetes. Additionally, Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1.05, 0.94–1.17), including in those with prediabetes (HR 1.00, 0.89–1.13).

Limitations of the study include a shorter follow-up time (median follow up of 2.2 years), as compared to the longer follow up time for studies that evaluated the risk of diabetes development with statins (4 years) [4]. Regardless, this study shows that Evolocumab is safe and effective to use in patients with or without diabetes, and that there was no increased risk in the development of diabetes during the study period. While these findings are significant, the prohibitive cost of PCSK-9 inhibitors will continue to limit their use in most patients.

Effect of Levothyroxine on Miscarriage Among Women with Normal Thyroid Function and Thyroid Autoimmunity Undergoing In Vitro Fertilization and Embryo Transfer: A Randomized Clinical Trial

The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm birth [7]. However, there is limited data to determine whether levothyroxine therapy improves the success of pregnancy.

An open-label, randomized clinical trial published this week in JAMA was done to evaluate the role of levothyroxine in pregnancy outcomes following assisted reproductive technology in antithyroperoxidase antibody positive, euthyroid women [8]. 600 anti-thyroperoxidase antibody positive women, who were undergoing IVF were randomized to receive levothyroxine or a placebo. The primary outcome was the miscarriage rate. The secondary outcomes were clinical intrauterine pregnancy rate and live-birth rate.

Results of this study showed that levothyroxine treatment did not reduce miscarriage rate (95% CI, −8.65% to 8.12%) or improve the live-birth rate (95% CI, −9.65% to 5.69%) compared with usual care. The limitations of this study are that it is a single center study and woman with   recurrent miscarriages and a known history of autoimmune diseases associated with miscarriage were excluded – and as such the generalizability of this study is limited. However, the results of this study are important. With no statistically significant difference in miscarriage rates or live births, these results do not support the routine use of levothyroxine in euthyroid patients who tested positive for anti-thyroperoxidase antibodies.

Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial

There is a strong link between weight and type 2 diabetes mellitus (T2DM) [9]. In a study published last week in The Lancet, investigators sought to evaluate whether effective weight management, delivered in the primary care setting, could produce sustained remission of type 2 diabetes [11].

The Diabetes Remission Clinical Trial (DiRECT) was an open-label, cluster-randomized trial which included 298 patients who had been diagnosed T2DM within the past 6 years from 49 primary care practices. The intervention group was taken off all anti-diabetic and antihypertensive medications and underwent a diet replacement phase with a low-calorie diet (825–853 kcal/day formula diet for 3–5 months), followed by a gradual food reintroduction (2–8 weeks). Additionally, the intervention group included structured support for long-term weight loss maintenance, such as cognitive behavioral therapy and individualized physical activity plans. The control group was best practice care under the current guidelines. The primary outcome was weight loss of 15 kg or more and remission of diabetes, defined as HbA1c of less than 6.5% off all antidiabetic medications.

At 12 months, the diabetes remission rate was 46% in the intervention group and 4% in the control group (odds ratio, 19.7; 95% confidence interval [CI], 7.8–49.8; p < 0.0001). Additionally, 24% of participants in the intervention group lost 15 kg or more compared to no participants in the control group (p<0.0001). This outlines the importance of intensive weight management within routine primary care in the remission of type 2 diabetes.

While this study boasts an impressively large sample size, only residents of Scotland and Tyneside of England were included, and as such the generalizability of the data is limited. Additionally, the myriad resources available to the intervention group does not reflect the reality of most practice environments. Regardless, the results of this study are important as this shows success in non-pharmacological approaches to diabetes.

MiniCuts:

1) Association between microcephaly, Zika virus infection, and other risk factors in Brazil: The final report of the first case-control study of 91 neonates evaluating Zika virus infection, vaccines, and larvicides as a potential cause of microcephaly confirmed the association of microcephaly and congenital Zika virus infection [12].

2)What role does Omega-6 fatty acid have in reducing the incidence of type 2 diabetes?: A pooled analysis of 39,740 adults from 20 prospective cohort studies found that linoleic acid has long-term benefits for the prevention of type 2 diabetes[13].

3) Does early antibiotic administration in the ambulance for sepsis reduce mortality? A randomized, controlled open-label trial in ten large regional ambulance services serving 34 secondary and tertiary care hospitals in the Netherlands found no significant differences in in-hospital, 28-day, or 90-day mortality among patients given early pre-hospital antibiotics compared to standard care [14].

Amanda Dowden, MD is a 2nd year internal medicine at NYU Langone Medical Center

Peer Reviewed by Daniel Taupin, MD Contributing Editor, Clinical Correlations

Picture Courtesy of I, Wildfeuer, CC BY-SA 3.0, Wikimedia Commons

References:

  1. Mahé I, Chidiac J, Helfer H, Noble S. Factors influencing adherence to clinical guidelines in the management of cancer associated thrombosis. J Thromb Haemost (2016) 14(11):2107–13.10.1111/jth.13483.
  2. Noble S, Prout H, Nelson A. Patients’ experiences of living with Cancer-associated thrombosis: the PELICAN study. Patient Prefer Adherence (2015) 9:337.10.2147/PPA.S79373.
  3. Raskob P, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. Published online Dec 12, 2017.
  4. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375: 735–42.
  5. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017; 376:1713-1722.
  6. Sabatine, Marc S et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial, The Lancet Diabetes & Endocrinology , Volume 5 , Issue 12, 941 – 950
  7. Thangaratinam S, Tan       A, Knox E, Kilby MD, Franklyn J, Coomarasamy A.       Association between thyroid autoantibodies and miscarriage and preterm birth. BMJ. 2011;342:d2616.
  8. Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y, Effect of Levothyroxine on Miscarriage Among Women With Normal Thyroid Function and Thyroid Autoimmunity Undergoing In Vitro Fertilization and Embryo Transfer A Randomized Clinical Trial. JAMA. 2017;318(22):2190–2198.
  9. Gerstein HC. Do lifestyle changes reduce serious outcomes in diabetes? N Engl J Med 2013;369:189–190.
  10. Kashyap SR, Gatmaitan P, Brethauer S, Schauer P. Bariatric surgery for type 2 diabetes: Weighing the impact for obese patients. Cleve Clin J Med. 2010;77:468–76.
  11. Lean ME, Leslie WS, Barnes AC, et al.Primary Care-Led Weight Management for Remission of Type 2 Diabetes (DiRECT): An Open-Label, Cluster-Randomised Trial. Lancet 2017;Dec 5.
  12. Araújo D., Velho T, Barreto Dhalia D, Kleber de Oliveira C, Cortez-Escalante W, JoseTorres J, Santiago Dimech L, George et al. Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. The Lancet Infectious Diseases. Published online Dec 11, 2017.
  13. Wu, Jason H Y et al. Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies. The Lancet Diabetes & Endocrinology, Volume 5 , Issue 12 , 965 – 974.
  14. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. N Alam, E Oskam, PM Stassen, et al. Lancet Respir Med (2017) published online Nov 28, 2017.