By Gregory Rubinfeld, MD
Peer Reviewed
Manhattan enjoyed its first snow of the season and in its wake New Yorkers trudge carefully through the slick and slush covered streets[1]. On a somber note, tragedy grips the west coast as wildfires in Southern California continue to spread forcing hundreds of thousands to evacuate their homes[2]. Our thoughts go out to those suffering from this disaster as we turn towards this week’s medical news.
Catheter Directed Thrombolysis Does Not Reduce the Incidence of the Post Thrombotic Syndrome Following DVT
The post thrombotic syndrome is among the most common long-term sequelae of patients with deep vein thrombosis (DVT). Post thrombotic syndrome (PTS) typically causes chronic, pain, swelling, and ulceration of the involved extremity, and can lead to major disability [3]. Approximately half of patients with a proximal DVT will suffer from PTS within 2 years [4]. The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) sought to determine if catheter directed thrombolysis was an effective means for preventing PTS [5].
The ATTRACT trial was a randomized, multicenter, open-label, assessor-blinded, study that randomized 692 patients with acute proximal DVT to receive anticoagulation alone or anticoagulation plus catheter directed thrombolysis. Patients were followed for 24 months to assess for the primary efficacy endpoint of PTS development. A diagnosis of PTS was made if patients had a Villalta score (a scale used to assess for PTS based on symptoms and physical exam findings) of 5 or higher. Patient were excluded from the trial if they had established PTS, were at high bleeding risk, had cancer, or had symptoms from their DVT for over 14 days.
Over the 24 month follow up period there was no significant difference in the primary efficacy endpoint, with PTS noted in 47% of patients in the catheter directed thrombolysis group and 48% in the anticoagulation only group (risk ratio 0.96; 95% CI 0.82 to 1.11; P=0.56). However, there was a statistically significant decrease in the development of moderate to severe PTS (Villalta score of 10 or higher) in the catheter group (risk ratio 0.73, CI 0.54 to 0.98; P=0.04). Perhaps notable was the difference in major bleeding within 10 days of the intervention, with 1.7% of the patients in the catheter group developing a nonfatal major bleed, compared to 0.3% of patients in the anticoagulation only group (P=0.049).
The key limitations of this study include the small sample size and imperfect follow up. With regards to the latter, 80 patients from the study had no PTS assessment, two thirds of who came from the anticoagulation only group. Despite these limitations, the lack of efficacy and increased risk of bleeding demonstrated in the experimental group provide compelling reasons to avoid catheter directed thrombolysis for the prevention of PTS in patients with acute proximal DVT.
Increased Risk of Breast Cancer Associated with Hormonal Contraceptive Use
Prior studies have demonstrated an association between oral contraceptive use and an increased risk of developing breast cancer. However, many of these studies were conducted with combined hormonal contraceptives that contained higher doses of estrogen than those that are currently in use [6]. It has therefore been a challenge to delineate the specific risk of developing breast cancer associated with contemporary hormonal contraceptives. A nationwide prospective cohort study followed 1.8 million women for 10.9 years to assess new diagnoses of breast cancer among current, former, and never users of hormonal contraception [7]. All women in Denmark between the ages of 15 and 49 were included, with the exception of those who had history of cancer, venous thromboembolism, or treatment for infertility. Data on different types of hormonal contraceptives used, duration of use, and time since last used were analyzed as well.
Women who ever used hormonal contraception were more likely to develop breast cancer than those who never used (RR 1.20; 95% CI 1.14 to 1.26). Parsing this out a little further, we see that the increased risk of developing breast cancer compounds with duration of use, as the relative risk of 1.09 with less than 1 year of use increases to 1.18 with 1 to 5 years of use, which further increases to 1.24 with 5 to 10 years of use, which increases even further to 1.38 with more than 10 years of use (P=0.002). In women who used hormonal contraception for over 5 years, the increased risk of developing breast cancer persisted for at least 5 years after discontinuation. Of note there was a relatively lower incidence in breast cancer among users of the progestin only implant and depot medroxyprogesterone acetate. The absolute increase in the incidence of breast cancer in women who ever used hormonal contraception compared to never users was 13 per 100,000 person-years (95% CI 10 to 16).
While this study boasts an impressively large sample size, only residents of Denmark were included, and as such the generalizability of the data is limited. That being said, the reported upswing in the incidence of breast cancer with hormonal contraception use is striking, particularly the clear incremental increase in risk with duration of use. It may also be worth mentioning that the aforementioned 20% higher risk of developing breast cancer translated to only 1 extra breast cancer diagnosis for every 7690 women using hormonal contraception for 1 year. This small (but not insignificant) risk should be considered against the benefits of hormonal contraception, which include reduction in the risks of developing endometrial and ovarian cancers. In fact some suggestion has been made that there is a net reduction in the total risk of cancer with 5 or more years of oral contraceptive use [8].
National Burden of Readmissions Following Revascularization for Peripheral Arterial Disease
More than 200 million people suffer from peripheral arterial disease (PAD), with approximately 8.5 million people affected in the United States [9]. Limited data suggest that there is a high rate of readmission following revascularization for PAD.
In the latest issue of Annals of Internal Medicine Secemsky et al. set out to further explore the national burden of these readmissions [10]. They conducted a nationwide retrospective cohort study using data from the 2014 Nationwide Readmissions Database accounting for nearly half of all U.S. hospitlizations. 61,969 hospitalizations in which a peripheral arterial revascularization (either endovascular or surgical) was performed were analyzed to assess for a primary outcome of thirty-day non-elective readmission, as well as the cause and cost of the readmission. Of the 61,969 patients studied 10,924 (17.6%) had a readmission within 30 days. 503 (4.6%) patients died during this readmission. The most common cause of readmission was complication from the revascularization procedure, more than half of which was due to infections associated with the revascularization. The nationally weighted cost of all readmissions amounted to over 400 million dollars.
This study relied on billing codes for most of its data, thus the possibility of misclassification of diagnoses ought to limit one’s interpretation of these results. Nevertheless, the finding that 1 in every 6 patients undergoing peripheral revascularization was readmitted within 30 days calls attention to a vulnerable population. Strategies aimed at preventing these readmissions, such as routine early follow up after discharge, may prove beneficial.
Gene Therapy for Treatment of Hemophilia B
Hemophilia B is an X-linked disorder characterized by deficient or dysfunctional factor IX. The classic manifestation of spontaneous hemarthrosis typically occurs in patients with a factor IX coagulant activity level of less than 5% of normal [11]. The current standard of care involves routine transfusion of exogenous factors to prevent bleeding. Achieving sustained levels of clotting factor activity with a single therapeutic intervention would mark a tremendous step forward in the treatment of hemophilia.
This week the New England Journal of Medicine showcases a study by George et al. that heralds a remarkable advancement towards this goal [12]. The study was an open-label, nonrandomized, multicenter, phase 1-2a trial that investigated the safety and efficacy of a one-time infusion of a single-stranded adeno-associated viral vector. The vector consisted of a bioengineered capsid, a liver-specific promoter, and a factor IX Padua transgene. The novel therapy was given to 10 men with hemophilia B and factor IX activity less than 2% of normal. The mean follow up time was 49 weeks. The factor IX activity stimulated by the vector demonstrated a sustained increase with a mean steady state level of 33.7%. This translated into a marked reduction in annual bleeding rates as well, with a mean of 0.4 bleeding events per year after vector administration, decreased from 11.1 events per year prior to the intervention (P=0.02). The mean number of annual factor IX infusions decreased as well from 67.5 pre-vector therapy to 1.2 post-vector therapy (P=0.004). The only observed adverse event attributed to the therapy was an asymptomatic transient elevation in liver enzyme levels in 2 patients, both of which resolved after short courses of prednisone.
The salient limitations of this study include its small sample size and short follow up. Further study is needed to elucidate the long-term safety and efficacy of vector therapy for hemophilia B. However, this study stands as an exciting advancement in the management of hemophilia, with the demonstration of sustained factory IX activity and near resolution of bleeding and factor use after a single administration of the vector.
Mini-cuts
An observational study including 27 million U.S. births demonstrated that statewide mandatory newborn screening for critical congenital heart disease was associated with a significant decrease in infant cardiac deaths [13].
Are substitute physicians just as good? A retrospective cohort analysis of 1.8 million hospitalized Medicare beneficiaries found no significant difference in 30-day mortality among patients treated by locum tenens physicians compared to non-locum tenens physicians [14].
Can we reduce the incidence of syphilis and chlamydia in at risk populations? An open-label randomized controlled trial showed that post exposure prophylaxis with doxycycline reduced the incidence of bacterial sexually transmitted infections in high-risk men who have sex with men [15].
Dr. Gregory Rubinfeld, is a 1st year Internal Medicine Resident at NYU Langone Health
Peer reviewed by Dr. Ian Henderson, Contributing Editor, Clinical Correlations and Chief Resident in Internal Medicine, NYU Langone Health.
Image courtesy of Wikimedia Commons
References:
- Connelly, E. First snowfall of the season blankets NYC. New York Post. December 9, 2017.
- Medina, J. Five Days of Smoke and Fire in Southern California. New York Times. December, 8 2017.
- Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost 2008;6:1105-1112.
- Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the post thrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008;149:698-707.
- Vedantham S et al. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 2017 Dec 7; 377:2240.
- Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713-1727.
- Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med 2017;377:2228-2239.
- Bassuk SS, Manson JE. Oral contraceptives and menopausal hormone therapy: relative and attributable risks of cardiovascular disease, cancer, and other health outcomes. Ann Epidemiol 2015;25:193-200.
- Fowkes FG, Rudan D, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. 2013; 382: 1329-40.
- Secemsky EA, Schermerhorn M, et al. Readmission After Revascularization Procedures for Peripheral Arterial Disease. Annals of Internal Medicine. 2017; DOI: 7326/M17-1058.
- Mannucci PM, Tuddenham EGD. The hemophilias — from royal genes to gene therapy. N Engl J Med 2001;344:1773-1779.
- George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med 2017;377:2215-2227.
- Abouk R, Grosse SD, Ailes EC, Oster ME. Association of US state implementation of newborn screening policies for critical congenital heart disease with early infant cardiac deaths. JAMA. doi:1001/jama.2017.17627.
- Blumenthal DM, et al. Association between treatment by locum tenens internal medicine physicians and 30-day mortality among hospitalized medicare beneficiaries. JAMA 2017; DOI: 10.1001/jama.2017.17925.
- Molina, JM, Charreau, I, Chidiac, C et al. Post-exposure prophylaxis with doxycycline to prevent sexually transmitted infections in men who have sex with men: an open-label randomised substudy of the ANRS IPERGAY trial. Lancet Infect Dis. 2017; (published online Dec 8.) http://dx.doi.org/10.1016/S1473-3099(17)30725-9