Primecuts – This Week In The Journals

October 4, 2016

PrimeCuts 9 min read

EhealthTree-2By Ian Henderson, MD

Peer Reviewed

This past week Donald Trump and Hilary Clinton took part in the first presidential debate of the 2016 elections. Held at Hofstra University in Long Island, NY, the debate was met with much anticipation and many questions. In between the sniffles, shimmies, microphone malfunctions, fact checking, and high volume interruptions the candidates discussed several pressing issues including the country’s economic future, race relations, and national security. While at first many were hesitant to declare a winner, a Washington Post-ABC poll released October 2nd showed 53% of Americans felt Hilary Clinton won the debate1. From the future of the country to the future of medicine, we turn to prime cuts for the latest in medical research.

The effect testosterone replacement therapy on the risk of venous thromboembolism

In the past 5 to 10 years, improved awareness and understanding of age related hypogonadism combined with an older adult population has led increased use of testosterone replacement therapy(TRT). From 2010-2013 the number of patients on TRT in the US rose from 1.2 million to 2.2 million2. As TRT use has become more widespread, concerns over potential side effects including venous thromboembolism (VTE), have grown. In 2014, the FDA issued a warning about the possible association of TRT and VTE3.  Despite this warning, no well-designed studies have look at the risk of VTE associated with TRT.

This week in Chest, Sharma, et al. published a retrospective study addressing the risk of VTE with TRT4. The study included 71,407 patients with 2 documented serum total testosterone (sTT) levels below the lower limit of normal from Veteran Affairs hospitals across the nation. Patients were excluded if they had a history of previous DVT/PE, history of hypercoaguable state, diagnosis of any type of cancer, were on anticoagulation, had a normalized sTT level prior to initiation of therapy, or had received TRT without baseline sTT testing. The patients were analyzed in the 3 groups: those on TRT with a normalized sTT, those on TRT with continued low sTT, and those with low sTT not on TRT. The primary outcome was the incidence of DVT/PE. The primary outcome occurred at the same rate for all 3 groups. In multivariate analysis, treatment with TRT to therapeutic levels compared to no treatment was not associated with increased risk of DVT/PE (HR 1.1; 95% CI 0.78-1.54, p=.6). Patients in the TRT group were followed for an average of 6 years.

In the largest study to date to evaluate the risk of VTE with TRT, Sharma, et al. demonstrated that TRT in low to moderate risk patients is not associated with an increased risk of VTE events. Due to its retrospective design, the study’s results are subject to unmeasured effects of confounders. The authors attempted to combat this with the use of multivariate analysis, but it is impossible to account for all possible confounding variables. Also by excluding patients with thrombophilia, history of DVT/PE, and cancer, the study was unable to comment on VTE in the highest risk and key population. Finally the trial did not examine the effects of supratherapeutic testosterone levels on VTE risk. As result, it is unknown if TRT given without monitored sTT levels could still confer an increase VTE risk. While this study can reassure physicians that TRT is likely not associated with increased risk of VTE, further studies with prospective design and including higher risk patients are needed to more definitively elucidate the thrombogenic risk of TRT.

Primary prevention ICD implantation for non-ischemic cardiomyopathy

Over the past 20 years, medical care of systolic heart failure (HFrEF) has advanced significantly with the wide spread use of neuro-hormonal blockade medications, ICDs, and cardiac resynchronization therapy (CRT) leading to significant increases in survival. ICD implantation specifically has been shown to be associated with large reductions in the rate of sudden cardiac death (SCD) and overall mortality, but these studies were done in patients with ischemic cardiomyopathy (ICM)5. The evidence for the benefit for ICD implantation in non-ischemic cardiomyopathy(NICM) comes mainly from subgroup analysis and no single study has demonstrated a convincing effect of ICD therapy on total mortality.

In this week’s NEJM, Købler, et al. published a randomized controlled study designed to assess the mortality benefit derived from ICD implantation in patients with NICM6. The study enrolled 1215 patients with symptomatic (NYHA Classs II-IV) systolic heart failure (EF <35%) not caused by CAD with elevated NT-proBNP (>200pg/mL) despite adequate medical therapy. The patients were randomized to ICD implantation plus usual clinical care or to usual clinical care alone. Usual clinical care included beta-blockers and ace-i/arb in over 90% of patients, mineralocorticoid antagonist in over 50% of patients, and CRT in about 50% of the patients. The primary outcome of the trial was death from any cause. Secondary outcomes were sudden cardiac death and cardiovascular death. After a median follow up of 67.6 months, ICD implantation as compared to usual medical care was not associated with a reduced risk of overall mortality (HR 0.87, 95% CI 0.68-1.12; P=0.28).  ICD implantation was associated with a reduced risk of SCD death (HR 0.50, 95% 0.31-0.82; P=0.005). These results held true across all subgroups except in patients less than 59 years old and those with NT-proBNP less than 1177 pg/ml. In these two subgroups, ICD implantation was associated with reduced risk of overall mortality compared to usual medical care.

In this large scale randomized controlled trial, Købler, et al. demonstrated that ICD implantation in patient with HFrEF from NICM did not provide an overall survival benefit. These results differ significantly from findings of past studies, which showed large overall survival benefits with ICD implantation. This difference can be explained 2 ways. First, as stated earlier, previous studies had mainly included patients with ICM. Perhaps patients with NICM are at lower risk of SCD given the lack of myocardial scar from past infarctions and therefore do not gain as much of a survival benefit from ICDs. This underscores the point that heart failure from ischemic causes is truly a different disease from heart failure from non-ischemic causes. Second, the previous trials were done when current medical therapies were not as widely used and interventions such as CRT and mineralocorticoid antagonist therapy were not standard of care. As a result, the question is raised: is the benefit of ICD implantation today really as large as it was in the past given the advances in current medical therapy? This study shows that patients with HFrEF from NICM may not benefit from ICD implantation in addition to standard medical care, unless the patient is less the 59 or has a NT-proBNP less than 1177 pg/ml, though these sub-groups should be more directly studied. Further studies are needed to better understand the benefit of ICD implantation in ICM in the era of modern medical therapy.

Comparison of a once daily LABA-Inhaled Corticosteroid to standard care in COPD

Current guidelines for medical management of COPD are based off of safety and efficacy trials done in the process of getting FDA approval for a new medication7. These trials are conducted in a highly controlled and monitored environment enrolling with carefully selected patient populations. As a result, the studies are difficult to apply broadly to all patients and are not an ideal basis for guidelines.

In order to have more generalizable data Vestbo, et al. designed a controlled effectiveness study, published in the NEJM this week8, that looked at a new inhaled corticosteroid (ICS) and long acting beta agonist (LABA) combination as it compared to usual care. The trial was conducted in 75 general practices and enrolled patients over 40 with the diagnosis of COPD and at least 1 exacerbation, defined as any worsening of respiratory symptoms that led to treatment with antibiotic agents or systemic glucocorticoids (or both), to hospital admission, or to scheduled or unscheduled hospital visits, within the past year. Patients were randomized to usual care or to treatment with once daily fluticasone furate and vilanterol plus continuation of a long acting muscarinic antagonist (LAMA) if they were previously taking it. Usual care consisted of a regular maintenance inhaler therapy with at least one long acting bronchodialtor defined as a LABA or LAMA. Treatment in the usual care group ranged from LAMA or LABA monotherapy all the way to triple (ICS, LABA, LAMA) therapy. The primary outcome was rate of moderate to severe exacerbation at 1 year. Treatment with fluticasone furoate–vilanterol was associated with a reduced rate of moderate or severe exacerbations (RRR of 8.4%, 95% CI 1.1- 15.2, P=0.02).

By conducting the trial in the patient’s general practice and comparing the study treatment to a real life variable control group, this study provides more broadly applicable and practical data compared to previous COPD trials. When compared with the safety and efficacy trials for fluticasone furoate–vilanterol, the importance of the design difference becomes even clearer. In a controlled trial comparing the efficacy of fluticasone propionate-salmeterol and fluticasone furoate–vilanterol there was no difference in treatment efficacy. These results suggest that use of either medication would result in similar outcomes, but the present trial discussed above, which was conducted in a more real world fashion, suggests that treatment with fluticasone furoate-vilanterol leads to improved outcomes. While these results are encouraging, they must be viewed with critical eye as there is no way to tell if the improved outcomes with fluticasone furoate-vilanterol are due to trial design, increased medication compliance with once daily dosing, or a true intrinsic property of the medication.

Short versus Long antibiotic course for treatment of CAP

The Infectious Disease Society of America (IDSA) and American Thoracic Society (ATS) published guidelines in 2007 on the treatment of community acquired pneumonia (CAP). These guidelines, based mainly off of expert opinion, recommend treating all patients with antibiotics for 5 days and then clinically reassessing the need for longer antibiotic treatment9. Despite these guidelines, most clinicians treat CAP for a set standard duration, normally of 7 to 10 days, without clinical reassessment.

In this week’s issue of JAMA Internal Medicine, a randomized controlled trial testing the clinical effectiveness of these guidelines was published10. In this study, Uranga et al. randomized 312 patients hospitalized with the diagnosis of CAP who completed 5 days of antibiotic treatment to clinical reassessment or a treatment duration determined by the treating physician. Patients in the clinical reassessment group had their antibiotics discontinued if they had been afebrile for 48 hours and had no more than one of the following clinical characteristics, SBP <90, HR >100, RR>24, O2sat <90%, or PaO2 <60 mm Hg. The primary outcomes were clinical success rate at day 10 and day 30 as defined by resolution or improvement in signs and symptoms of CAP without further antibiotics and CAP-related symptoms at day 10 measured with a CAP symptom questionnaire. Compared to physician determined treatment duration, clinical reassessment based therapy was not associated with lower clinical success rate at day 10 or day 30 (Day 10 treatment success 48.6% for control vs 56.3 for intervention, P=.18). Treatment based off of clinical reassessment was associated with shorter duration of antibiotic therapy compared to physician determined treatment duration, a mean of 5 vs 10 days of antibiotic therapy.

This study is the first randomized control trial to look at different lengths of antibiotic treatment courses for CAP. The trial resoundingly supports the use of the IDSA/ATS guidelines for CAP. This supportive data should lead to more widespread use and acceptance of these guidelines as they are now backed by more than expert opinion. Moreover, this study raises a larger more intriguing question of can other infections be treated safely with shorter courses of antibiotics? This question requires further study with randomized controlled trials like the one discussed above before physicians can definitively start using shorter courses of antibiotics for all infections.

Mini Cuts:

A study in Chest this week, demonstrated the diagnosis of hypertension was associated with having undiagnosed OSA during rapid eye movement (REM) sleep11. Further demonstrating the incompletely understand relationship between hypertension and OSA.

While antibiotics, specifically azithromycin, are a pillar of management for COPD exacerbations, there role in asthma exacerbations is less clear. A study in JAMA Internal Medicine this week showed no benefit of azithromycin compared to placebo when added to standard of care in patients with asthma exacerbations12.

An article in JACC this week explored the relationship of abdominal and visceral fat volume and quality to common cardiovascular disease risk factors such as hypertension, hypertriglyceridemia, and the metabolic syndrome13.

A meta-analysis, published this week in JAMA, found that endovascular thrombectomy plus medical therapy resulted in lower degrees of disability at 30 days compared to medical therapy alone14. Interestingly this benefit was time sensitive and there was significant benefit derived from endovascular therapy when performed beyond 7.3 hours of symptom onset.

Dr. Ian Henderson is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by David Kudlowitz, MD, Chief Resident, Internal Medicine, NYU School of Medicine

Image courtesy of Wikimedia Commons

References:

  1. Clement S, Guskin E. “53 percent of people in new WaPo-ABC poll say Hillary Clinton won the debate.” Washington Post. 2 October 2016. https://www.washingtonpost.com/news/the-fix/wp/2016/10/02/poll-clinton-wins-debate-with-more-saying-trump-got-facts-wrong/
  2. Mohamoud MA, Chai G, Staffa J. Drug use review. In: Joint Meeting for Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSARM AC). Silver Spring, MD: US Food and Drug Administration; 2014. http://www.fda.gov/downloads/%20AdvisoryCommittees/Committees%20MeetingMaterials/Drugs/Reproductive%20HealthDrugsAdvisoryCommittee/UCM412536.pdf Published September 17, 2014.
  3. US Food and Drug Administration. FDA Adding General Warning to Testosterone Products About Potential for Venous Blood Clots. Silver Spring, MD: US Food and Drug Administration; 2014. http://www.fda.gov/Drugs/DrugSafety/ucm401746.htm Published December 10, 2014.
  4. Sharma R, Oni OA, Chen G, et al. Association Between Testosterone Replacement Therapy and the Incidence of DVT and Pulmonary Embolism A Retrospective Cohort Study of the Veterans Administration Database. Chest. 2016; 150(3):563-571. http://journal.publications.chestnet.org/article.aspx?articleID=2524110
  5. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933-40 http://www.nejm.org/doi/full/10.1056/NEJM199612263352601#t=article
  6. 6. Købler, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure N Engl J Med 2016; 375:1221-1230. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1608029?query=featured_home
  7. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013; 187: 347-65. http://www.atsjournals.org/doi/abs/10.1164/rccm.201204-0596PP?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed#.V_G5TugrJhE
  8. Vestbo, et al. Effectiveness of Fluticasone Furoate– Vilanterol for COPD in Clinical Practice. N Engl J Med 2016;375:1253-60. http://www.nejm.org/doi/full/10.1056/NEJMoa1608033?query=featured_home
  9. MandellLA,WunderinkRG,AnzuetoA,et al; InfectiousDiseasesSocietyofAmerica;American ThoracicSociety.InfectiousDiseasesSocietyof America/AmericanThoracicSocietyconsensus guidelinesonthemanagementof community-acquiredpneumoniainadults.Clin InfectDis.2007;44(suppl2):S27-S72. http://cid.oxfordjournals.org/content/44/Supplement_2/S27.full.pdf+htm
  10. Uranga A, España PP, Bilbao A, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial.JAMA Intern Med.2016;176(9):1257-1265. http://archinte.jamanetwork.com/article.aspx?articleid=2536189
  11. Appleton SL, Vakulin A, Martin SA, et al. Hypertension Is Associated With Undiagnosed Osa During Rapid Eye Movement Sleep. Chest. 2016;150(3):495-505. http://journal.publications.chestnet.org/article.aspx?articleID=2506756
  12.  Johnston SL, Szigeti M, Cross M, et al. Azithromycin for Acute Exacerbations of Asthma: The AZALEA Randomized Clinical Trial. JAMA Intern Med. Published online September 19, 2016. http://archinte.jamanetwork.com/article.aspx?articleid=2553295
  13. Lee JJ, Pedley A, Hoffmann U, Massaro JM, Fox CS. Association of Changes in Abdominal Fat Quantity and Quality With Incident Cardiovascular Disease Risk Factors. J Am Coll Cardiol. 2016;68(14):1509-1521 https://content.onlinejacc.org/article.aspx?articleID=2555924
  14. Saver JL, Goyal M, van der Lugt A, et al. Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis. JAMA.2016;316(12):1279-1288. http://jama.jamanetwork.com/article.aspx?articleid=2556124