PrimeCuts

Primecuts – This Week In The Journals

May 31, 2016

Red_crabsBy Jung-Eun Ha, MD

Peer Reviewed

These past few weeks have seen some very interesting news items. The first genitourinary reconstructive (penile) transplant in the US was performed by surgeons at Massachusetts General Hospital earlier this month.[1] The patient lost his organ to penile cancer in 2012 and has thus far had an uneventful post-operative course, including the resumption of normal urination. This surgery follows two earlier penile transplants performed abroad. The first transplant was in China in 2005, but the transplant had to be removed 2 weeks later due to psychological distress for the patient and family. In 2014, a South African patient underwent a transplant and was able to successfully father a daughter the following year.

On May 13, Pfizer announced that it would strictly regulate that certain of its medications not be used in executions.[2] These medications include sedatives like midazolam, propofol, and hydromorphone, paralytics such as pancuronium bromide, rocuronium, and vecuronium bromide, and potassium chloride. This move is seen as a win for those who oppose capital punishment. The 20-plus states that use more than one drug for execution will now likely find it harder to secure the necessary medications, though there are 6 other states that use only one drug, phenobarbital, which is not regulated by Pfizer. To get around such regulations, some states have increasingly been using compounding pharmacies. Some have also passed laws allowing non-pharmacological methods of execution such as firing squad, gas chamber, or electric chair.

Finally, in non-medical news, the beaches of Southern California have been covered with tiny red crabs for a second straight year.[3] Known as tuna crabs as they are favored by some tuna species, they have been found to be carried from their natural habitats in Mexican waters to California likely due to the El Nino system. Unfortunately they are not edible for humans as their diet mainly consists of toxin-producing planktons.

Now let’s turn to the most interesting recently-released articles in medicine.

Indacaterol and glycopyrronium vs. salmeterol and fluticasone in reducing COPD exacerbations.

Recent guidelines recommend using long-acting beta-agonists (LABA) plus inhaled glucocorticoids or long acting muscarinic antagonist (LAMA) to reduce COPD exacerbations. The year-long randomized, double blind, multicenter, noninferiority FLAME study published in NEJM was conducted to answer which combinations might work better.[4] 1680 patients received the LABA indacaterol and the LAMA glycopyrronium, and 1682 patients received the LABA salmeterol and the glucocorticoid fluticasone. Patients who received indacaterol and glycopyrronium had 11% less annual COPD exacerbations compared to those who received salmeterol and fluticasone (p=0.003), and a longer time to the first exacerbation as well (71 days vs. 51 days, p<0.001). As previous studies[5] have shown that use of a LABA plus glucocorticoids had a stronger effect on patients with higher eosinophil counts, patients were further divided into groups with eosinophil counts lower than and equal/greater than 2%. Incidence of adverse effects and deaths were similar between the two treatment groups although incidence of pneumonia was 3.2% in the LABA plus LAMA group and 4.8% in the LABA plus glucocorticoids group. The study might have favored the LABA plus LAMA regimen as this used once-daily dosing, whereas dosing was twice-daily for the LABA plus glucocorticoid regimen. The study also used electronic flags for the outcome variable of COPD exacerbation, including all severities of exacerbations, which would have pushed the result towards noninferiority. The study is the last of the IGNITE study series sponsored by Novartis, which evaluates indacaterol and glycopyrronium.

Ticagrelor vs. aspirin after ischemic stroke or transient ischemic attack.

After ischemic strokes and transient ischemic attacks (TIAs), the risk of subsequent ischemic attacks is high within the first 90 days. Aspirin is commonly used for prevention in these settings, but even on aspirin, the recurrent stroke rate is about 10 to 15% during the first 90 days. Aspirin also leads to an increased risk of GI bleeding. Ticagrelor is an antiplatelet that directly binds the P2Y12 receptor on platelets and is hypothesized to be more effective and selective than aspirin. Recently the NEJM published the results of the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial,[6] a multicenter, double-blind, parallel-group trial that randomized patients with non-cardioembolic ischemic stroke or TIA into ticagrelor or aspirin monotherapy within 24 hours after symptom onset, provided that they did not receive thrombolytic therapy. The primary composite end points, which included stroke, myocardial infarction, or death, occurred in 6.7% of patients who received ticagrelor vs. 7.5% of patients who received aspirin (p=0.07). The main secondary end point of ischemic stroke occurred in 5.8% of the ticagrelor group vs. 6.7% of the aspirin group (p=0.046). The major bleeding at any location occurred in 0.5% in the ticagrelor group vs. 0.6% in the aspirin group (NS), while intracranial bleeds occurred in 0.2% in the ticagrelor group vs 0.3% in the aspirin group. Early treatment termination occurred in 17.5% of participants in the ticagrelor group vs 14.7% of those in the aspirin group, mainly due to the side effect of dyspnea (6.2% vs 1.4%). The study was limited as patients at highest risk for stroke were mostly excluded, as they would have undergone further interventions and were likely already receiving more than multiple drug therapy. The study also excluded those who received thrombolytics, thereby further limiting generalizability. More studies need to be done to find a better agent to prevent recurrent ischemic events in larger patient populations.

Antacid therapy in idiopathic pulmonary fibrosis (IPF).

The incidence of gastroesophageal reflux disease (GERD) in patients with IPF is higher than in the general population. This may be due to the increased recoil of the fibrotic lung that could dilate the lower esophageal sphincter. GERD may also exacerbate IPF from chronic micro-aspiration and associated inflammation. Based on retrospective studies that showed slowed progression of IPF in patients who received antacids, such treatment is now recommended in the IPF treatment guidelines.

In this post-hoc analysis of 624 patients with IPF in three large controlled trials published in the Lancet,[7] randomized antacid therapy did not yield clinically significant improvements in outcomes after 52 weeks. In the Kaplan-Meier analysis, patients who received antacid treatment had similar disease progression at 1 year compared with placebo (37.8% vs. 40.5%; p=0.40). The rates of all-cause mortality and IPF-related mortality were similar between the treatment and control groups. Adverse gastrointestinal effects were similar between the two groups as well after stratifying by baseline FVC. On the other hand, in patients with FVC less than 70%, infections (including pneumonia) were significantly higher with antacid therapy than with no antacid therapy (74% vs. 62%; p=0.017). The difference from previous studies may be due to exclusion of patients with advanced diseases and those who are listed for potential transplantation. The study also had a relatively small sample size and was underpowered to detect any meaningful subtle differences. On the other hand, previous retrospective analyses may have been affected by lead-time bias, leading to slower disease progression with antacid therapy. Given these results, individualized approach to IPF treatment may be ever more necessary.

Association between environmental toxins and ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of motor neurons, and some hypothesize that toxic exposures in addition to genetic susceptibility may lead to this condition. A case control study[8] published in JAMA Neurology evaluated 156 cases and 128 controls in Michigan from 2011 to 2014. In addition to survey data of self-reported exposures to occupational and residential toxins, the study also measured serum concentration of 122 pollutants, more than any other previous studies looking at this issue. Exposure window was also considered, such as within the last 10 years, between 10 to 30 years, more than 30 years prior, or at least once in the past. The study found that reported exposure to toxins was significantly associated with ALS (OR=5.09, p=0.002). Military service with likely exposures to chemicals was also associated with ALS. Multivariable analysis of the serum concentration of pollutants showed that 2 OCPs (organochlorine pesticides), 2 PCBs (polychlorinated biphenyls), and 1 BFR (brominated flame retardant) were all significantly associated with development of ALS. There was modest concordance between survey data and measured data giving confidence to the previous survey data. These results suggest that controlling modifiable risk factors for ALS may translate into reductions in incidence of ALS.

Mini cuts:

A cohort study looked at late mortality (from 1 month to 2 years after admission) for sepsis in Medicare populations.[9] Compared with adults not in the hospital, patients with sepsis had a 22% absolute increase in late mortality. Compared with patients admitted to the hospital with non-sepsis infections or sterile inflammatory conditions, patients with sepsis had a 10% increase in late mortality.

1% relative reductions in smoking prevalence and mean packs-smoked are associated with 0.118% (p < 0.001) and 0.108% (p < 0.001) reductions in per capita healthcare expenditures, respectively.[10] A 10% relative reduction in smoking in every state is predicted to result in a $63 billion reduction in healthcare expenditures in the following year.

The American Community Survey (ACS) data were evaluated for the insurance and Indian Health Service (IHS) coverage among Native Americans one year after the Affordable Care Act (ACA) was mandated.[11] The ACA was associated with significant coverage increases for Native Americans, primarily in Medicaid expansion states, where Medicaid expansion is likely supplementing rather than replacing IHS.

Physician and surrogate decision makers were found to have incongruous views regarding prognosis in 53% of ICU cases.[12] In 28% of cases this was due to misunderstandings by surrogates and differences in beliefs. Surrogates had more optimistic beliefs than physicians, including religious beliefs and beliefs that the patient has unique strengths unbeknownst to the physician, out of their need to maintain hope for the patient.

Dr. Jung-Eun Ha is an  intern at NYU Langone Medical Center

Peer reviewed by Anish B. Parikh, MD, Chief Resident, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Comons

References

[1] Massachusetts General Hospital. First Genitourinary Vascularized Composite Allograft (Penile) Transplant in the Nation Performed at Massachusetts General Hospital http://www.massgeneral.org/News/pressrelease.aspx?id=1937 May 16, 2016. Accessed on May 18, 2016

[2] Eckholm E. Pfizer Blocks the Use of Its Drugs in Executions. The New York Times.  http://www.nytimes.com/2016/05/14/us/pfizer-execution-drugs-lethal-injection.html May 13, 2016. Accessed on May 18, 2016

[3] Reuters. Tiny red crabs are back on California beaches. Scientists blame El Niño. The Washington Post. https://www.washingtonpost.com/lifestyle/kidspost/tiny-red-crabs-are-back-on-california-beaches-scientists-blame-el-nino/2016/05/17/0688e2c6-1c46-11e6-b6e0-c53b7ef63b45_story.html May 17, 2016. Accessed on May 18, 2016.

[4] Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers T, et al. Indacaterol–Glycopyrronium versus Salmeterol–Fluticasone for COPD. NEJM. Published Online: May 15, 2016 (DOI: 10.1056/NEJMoa1516385). http://www.nejm.org/doi/full/10.1056/NEJMoa1516385

[5] Pavord ID, Lettis S, Locantore N, et al. Blood eosinophils and inhaled corticosteroid/ long-acting β-2 agonist efficacy in COPD. Thorax 2016; 71: 118-25. http://thorax.bmj.com/content/71/2/118.full.pdf

[6] Johsnton SC, Amarenco P, Albers GW, Denison H, Easton D, Evans SR, et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. NEJM. Published Online: May 10, 2016 (doi: 10.1056/NEJMoa1603060). http://www.nejm.org/doi/full/10.1056/NEJMoa1603060

[7] Keruter M, Wuyts W, Renzoni E, Koschel D, Maher TM, Kolb M, et al. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. Lancet. 2016; 4(5):381-389. http://thelancet.com/journals/lanres/article/PIIS2213-2600(16)00067-9/fulltext

[8] Su F-C, Goutman SA, Chernyak S, Mukherjee B, Callaghan BC, Batterman S, Feldman EL. Association of Environmental Toxins With Amyotrophic Lateral Sclerosis. JAMA Neurol. Published Online May 9, 2016 (doi:10.1001/jamaneurol.2016.0594). http://archneur.jamanetwork.com/article.aspx?articleid=2519875

[9] Prescott HC, Osterholzer JJ, Langa KM, Angus DC, Iwashyna TJ. Late mortality after sepsis: propensity matched cohort study. BMJ. 2016; 353: i2375. Published Online: May 17, 2016 (http://dx.doi.org/10.1136/bmj.i2375). http://www.bmj.com/content/bmj/353/bmj.i2375.full.pdf

[10] Lightwood J, Glantz SA. Smoking Behavior and Healthcare Expenditure in the United States, 1992–2009: Panel Data Estimates. PLoS Med. 2016;13(5): e1002020. Published Online: May 10,2016 (doi:10.1371/journal.pmed.1002020)

http://journals.plos.org/plosmedicine/article/asset?id=10.1371%2Fjournal.pmed.1002020.PDF

[11] Frean M, Shelder S, Rosenthal MB, Sequist TD, Sommers BD. Health Reform and Coverage Changes Among Native Americans. JAMA Intern Med. Published online May 16, 2016. (doi:10.1001/jamainternmed.2016.1695) http://archinte.jamanetwork.com/article.aspx?articleid=2521825

[12] White DB, Ernecoff N, Buddadhumaruk P, Hong S, Weissfeld L, Curtis JR, Luce JM, Lo B. Prevalence of and Factors Related to Discordance About Prognosis Between Physicians and Surrogate Decision Makers of Critically Ill Patients. JAMA. 2016;315(19):2086-2094. http://jama.jamanetwork.com/article.aspx?articleid=2521967

Primecuts – This Week In The Journals

May 23, 2016

1280px-Flip_flops_-_just_pick_one_upBy Priya Patel, MD

Peer Reviewed

This last week, ISIS had a number of terrorist attacks, confirming a shift from traditional battlefield tactics back to targeted attacks seen prior to 2014. They confirmed their role in the bombings at a gas plant in Baghdad which killed 10 and injured 24 [1]. Just days prior to this, 66 were killed in a bombing in a Baghdad food market and 87 others were injured [2].

In the U.S., even more attention has been turned towards likely Republican candidate Donald Trump as the presidential primaries are coming to an end. The New York Times sparked a nationwide exploration into his past relationships with women in his professional and private life when they wrote an in-depth exposé on these relationships over the past 40 years, characterized by “unwelcome romantic advances, unending commentary on the female form, a shrewd reliance on ambitious women, and unsettling workplace conduct.” [3]

Now, moving on to the latest news in medicine. 

Tocilizumab, the next new treatment for giant cell arteritis. 

Tocilizumab, a monoclonal antibody that acts against the interleukin-6 receptor, was looked at as a novel therapy for giant cell arteritis (GCA) in a recent paper published in the Lancet. IL-6 induces acute phase responses and has been implicated in the pathogenesis of GCA. IL-6 concentrations have been shown to be higher in all layers of medium and large-sized vessels in patients with GCA, and these levels may increase during flares and decrease with treatment with steroids [4]. Villeger et al. conducted the first randomized, placebo-controlled trial to study the efficacy and safety of tocilizumab in patients with newly diagnosed or recurrent GCA [5]. A total of 30 patients were randomly assigned in a 2:1 fashion to either treatment of intravenous tocilizumab every 4 weeks for 1 year + oral prednisolone with tapering, or placebo + oral prednisolone with tapering. The primary endpoint of remission at 12 weeks of treatment (meaning normal ESR and CRP and the absence of symptoms on low dose prednisolone of 0.1mg/kg/day) occurred in 85% of the intervention group compared to 40% of the placebo group (risk difference 45%, 95% CI 11–79; p=0.0301).  Additionally, 85% of patients in the intervention group maintained remission at the end of the year compared to just 20% in the placebo group (risk difference 65%, 95% CI 36–94; p=0.0010). While the standard therapy, steroids, is widely accepted, the side effects of long-term corticosteroid use are well-known and include osteoporosis, joint necrosis, and adrenal insufficiency [6]. Tocilizumab could be a great alternative to avoid these side effects and help patients maintain remission if future studies confirm these findings.

Does cardiac index really influence renal function in heart failure patients? 

Decreased renal function in hospitalized heart failure patients has long been attributed to a low cardiac index (CI). However, recent studies have challenged this idea by demonstrating a lack of correlation between cardiac output and renal function. Several recent studies have even showed paradoxical correlations between cardiac output and renal function. The ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial was a randomized trial evaluating the use of pulmonary artery catheterization in patients hospitalized with heart failure [7]. Hanberg et al. analyzed data from this large trial, including patients either randomized to the PAC arm of the ESCAPE trial, or enrolled in the PAC registry of the ESCAPE trial, to study the relationship between CI and renal function in patients with decompensated heart failure [8]. Of note, patients included were mostly white males in their 50s-60s. The authors did not find statistically significant associations supporting the idea that low cardiac output is an important drive for renal dysfunction in this population.  Further breakdown of these patients into those with co-morbidities such as diabetes and hypertension, those with EF >40%, and those receiving classic heart failure medications such as loop diuretics, beta-blockers and ace inhibitors still did not show a relationship between CI and renal function. One of the major limitations of this study is the limitation of evaluating kidney function via creatinine and estimated GFR.  Also, the etiology of kidney disease in these patients at baseline is unknown. Nonetheless, the lack of relationship found between cardiac and kidney function supports the concept that decreased renal function in patients hospitalized with heart failure may not be attributed to a low CI. Instead there may be other factors that directly influence renal function, such as neurohormonal systems.

Mortality benefit of statins sustained through extended follow-up. 

Statins have become standard treatment in those with cardiovascular disease. However, there is controversy over longer term use of statins, particularly due to concern for increased cancer incidence [9, 10]. In an extended follow-up of the LIPID study, researchers evaluated all-cause mortality, cause-specific mortality and new cancer diagnoses in the 7721 of the original 9014 patients evaluated in the LIPID study [11,12]. The original LIPID study was a double-blind, randomized trial of 9014 patients with coronary artery disease treated with pravastatin 40mg daily versus placebo over 6 years looking at mortality from CAD [11]. Initially after the 6-year double-blind period, the study showed a statistically significant decrease in all-cause, cardiovascular and coronary heart disease-related mortality in the pravastatin group. Given the mortality benefit in the LIPID trial, all participants (regardless of original randomization group) were offered statin therapy, and 88% of those in the statin group and 86% of those in the placebo group were started on a statin. During extended follow-up over 10 years, patients who had been assigned pravastatin maintained a significantly lower risk of death from CHD, from cardiovascular disease, and from any cause [12]. There were no significant differences in mortality from cancer or in the incidence of organ-specific cancers between the groups. Overall, this study further validates the efficacy of statins and does not support an association of long-term statin use with cancer.

Amiodarone and Lidocaine could play a role in out-of-hospital cardiac arrest. 

Antiarrhythmic agents including lidocaine and amiodarone are frequent drugs of choice in the setting of shock-refractory ventricular fibrillation or pulseless ventricular tachycardia in patients presenting with cardiac arrest in the field. Earlier studies have shown that patients who received amiodarone in this setting were more likely to have return to spontaneous circulation and survive to be admitted to the hospital. In a recent study, Kudenchuk et al. explored the effects of survival and neurologic outcome in 3026 patients with out of hospital cardiac arrest with ventricular fibrillations or pulseless ventricular tachycardia unresponsive to defibrillation at ten different North American sites [13]. Participants were randomized to receive amiodarone, lidocaine or placebo after failing standard of care treatment of defibrillation.  In the per-protocol analysis, 24.4% of patients in the amiodarone group survived to hospital discharge, compared to 23.7% of patients in the lidocaine group, and 21.0% of patients who received placebo. The absolute risk difference for the primary comparison of amiodarone versus placebo was 3.2 percentage points (95% CI,-0.4 to 7.0; p=0.08). The rates of survival with a favorable neurologic outcome were similar in all of the groups. Of note, there was heterogeneity of treatment effect with respect to whether or not the arrest was witnessed (p=0.05). There was a statistically significant difference between the survival rates of patients who received amiodarone versus placebo, and for lidocaine versus placebo, but not for amiodarone versus lidocaine. This may indicate that amiodarone and lidocaine are both effective medications for refractory pulseless ventricular tachycardia and ventricular fibrillation after cardiac arrest, but the timing of the treatment is key.

Mini-cuts:

An adjusted one-dose administration of the oral cholera vaccine prequalified by the WHO, rather than the standard two dose regimen, was protective in residents of Dhaka, Bangladesh, a highly endemic area [14].

NYU’s own investigators led by Dr. Bangalore explored the benefit of coronary artery bypass graft (CABG) vs percutaneous coronary intervention (PCI) in patients with multi-vessel coronary disease and systolic dysfunction and found that both groups had similar primary outcomes of long-term survival. PCI was associated with higher risk of associated with risk of MI and repeat revascularization, and CABG was associated with higher risk of stroke [15].

A recent article in Chest performed a large cohort analysis of patients with fibrotic interstitial lung disease hospitalized at one institution over 3 years with acute respiratory worsening for any reason and found that they had a statistically significant increase in in-hospital and post-discharge mortality [16].

Dr. Priya Patel is a resident at NYU Langone Medical Center 

Peer reviewed by Karin Katz, M.D., Chief Resident, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References: 

  1. http://www.cnn.com/2016/05/15/middleeast/iraq-violence-isis/index.html
  2. http://www.nytimes.com/2016/05/12/world/middleeast/baghdad-market-bomb-isis.html 
  3. http://www.nytimes.com/2016/05/15/us/politics/donald-trump-women.html?_r=0 
  4. Emilie D, Liozon E, Crevon MC, et al. Production of interleukin 6 by granulomas of giant cell arteritis.Human Immunology. 1994;39(1):17–24.
  5. Villiger PM et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016 Mar 4.  http://www.sciencedirect.com/science/article/pii/S0140673616005602
  6. Buchman A. L. Side effects of corticosteroid therapy: Inflammatory bowel disease. J. Clin. Gastroenterol. 33, 289–294 (2001). http://journals.lww.com/jcge/Abstract/2001/10000/Side_Effects_of_Corticosteroid_Therapy.6.aspx
  7. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005;294:1625–33.
  8. Hanberg JS et al. Reduced Cardiac Index Is Not the Dominant Driver of Renal Dysfunction in Heart Failure. Journal of the American College of Cardiology, 2016; 67(19)2199-2208. http://m.amedeo.com/27173030
  9. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278. doi:10.1016/S0140-6736(05)67394-1 http://www.ctsu.ox.ac.uk/research/meta-trials/ctt/ctt-website
  10. Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G. Statins and the risk of colorectal cancer. N Engl J Med. 2005;352:2184–2192.
  11. LIPID Study Group, Tonkin A, Simes RJ. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1347–1357
  12. Hague WE et al. Long-Term Effectiveness and Safety of Pravastatin in Patients With Coronary Heart Disease: Sixteen Years of Follow-Up of the LIPID Study. Circulation. 2016; 133:1851-1860.  http://www.mdlinx.com/cardiology/medical-news-article/2016/05/11/coronary-heart-disease-cardiovascular-diseases-cholesterol/6667461/
  13. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. N Engl J Med 2016;374:1711-1722. http://www.nejm.org/doi/full/10.1056/NEJMoa1514204
  14. Qadri F et al. Efficacy of a single-dose, inactivated oral cholera vaccine in Bangladesh. N Engl J Med 2016 May 5; 374:1723.
  15. Bangalore, Sripal; Guo, Yu; Samadashvili, Zaza; Blecker, Saul; Hannan, Edward L. Revascularization in Patients with Multivessel Coronary Artery Disease and Severe Left Ventricular Systolic Dysfunction: Everolimus Eluting Stents vs. Coronary Artery Bypass Graft Surgery. Circulation. 2016 May 5;:?-? (2101292) http://circ.ahajournals.org/content/early/2016/05/04/CIRCULATIONAHA.115.021168.short?rss=1
  16. Moua T, Westerly BD, Dulohery MM, Daniels CE, Ryu JH, Lim KG. Patients With Fibrotic Interstitial Lung Disease Hospitalized For Acute Respiratory Worsening: A Large Cohort Analysis. Chest. 2016;149(5):1205-1214. http://journal.publications.chestnet.org/article.aspx?articleid=2481791

 

 

Primecuts – This Week In The Journals

May 11, 2016

1280px-2006-12-09_Chipanzees_D_BruyereBy Tania Ruiz-Maya, MD

Peer Reviewed

This past week there was great news for all animal advocates and conservationists when the world’s largest chimpanzee research facility, Louisiana’s New Iberia Research Center (NIRC), announced that it will release all 220 of its chimps to a sanctuary in what it is calling the largest resettlement of chimpanzees from a U.S. research center [1]. The transfer to Project Chimps, a 95-hectare sanctuary in the mountains of northern Georgia, will be completed in the next 3 to 5 years. In sports news, Golden State Warriors guard Stephen Curry became the first unanimous NBA Most Valuable Player, winning the award for a second straight season. Curry joins Tom Brady (2010 NFL MVP) and Wayne Gretzky (1982 Hart Trophy winner) as the only unanimous MVP’s in their respective leagues [2]. The fire that has already prompted the evacuation of 88,000 people from the city of Fort McMurray was on its way to doubling in size after 1 week. This is expected to be the costliest natural disaster in Canada’s history [3]. And now on to updates in the medicine world.

Ventilator associated pneumonia can be identified earlier with lung ultrasound

Bedside ultrasound is emerging as a minimally invasive, low cost clinical tool that can help physicians make quick and accurate diagnoses. A new multicenter prospective study published in Chest assessed whether lung ultrasound (LUS) could improve the early diagnosis of ventilator-associated pneumonia. (VAP) [4]. The study enrolled patients with suspected VAP at 3 different ICUs in France, Italy and Canada. Suspicion of VAP was based on mechanical ventilation ≥ 48hrs, a new or evolving infiltrate on chest x-ray, and two or more clinical signs or symptoms of pneumonia (temperature ≥ 38.5C or < 36.5C  leukocytosis >/ml or leukopenia <4./ml, purulent tracheal secretions, PaO2/FiO2 < 300mmHg). Patients with ongoing pneumonia or contraindication for fiber-bronchoscopy were excluded.

LUS findings including subpleural consolidation, lobar consolidation and dynamic air bronchogram were aggregated into the ventilator-associated pneumonia lung ultrasound score (VPLUS). VAP diagnosis was confirmed by positive results on BAL (≥1 microorganism with a concentration ≥ 104 CFU/mL) or simultaneous presence of all clinical criteria with negative result on BAL if antibiotics had been modified/introduced in the previous 48 hours.

In this study, LUS was a reliable tool for early VAP diagnosis at the bedside, showing that subpleural consolidation and a dynamic arborescent/linear air bronchogram had a positive predictive value of 86% with a positive likelihood ratio of 2.8. Two dynamic linear/arborescent air bronchograms produced a positive predictive value of 94% with a positive likelihood ratio of 7.1. A VPLUS score ≥ 2 had 69% specificity and 71% sensitivity. Endotracheal aspirate (EA) data was also integrated with VPLUS to assess whether combining these tests could improve the diagnostic accuracy (VPLUS-EAgram). A VPLUS-EAgram score ≥ 3 had 77% specificity and 78% sensitivity. Both performed better than the clinical pulmonary infection score (CPIS), which integrates various signs and symptoms of pneumonia and has been used in the diagnosis of VAP.

From this study, it appears that if used consistently, LUS could be a relatively sensitive and specific, noninvasive method to improve early detection of VAP. However, LUS is operator dependent and LUS findings may be difficult to interpret in patients with differences in body habitus. Additionally, VAP is a difficult diagnosis to confirm. BAL and the clinical diagnostic criteria used in the study have their own limitations. Also, the study included patients with relatively high pre-test probability of pneumonia. Whether ultrasound can be used for patients in which suspicion for pneumonia is lower remains unclear. Lastly further studies will be needed to test whether early diagnosis with ultrasound has meaningful impact on clinical outcomes.

Prevention of late MI after coronary stenting in diabetic patients with double antiplatelet therapy 

Patients with diabetes mellitus (DM) who undergo coronary stenting have higher rates of death and myocardial infarction (MI) than patients without DM [5]. Therefore, whether continued dual antiplatelet therapy after 1 year can improve outcomes after coronary stenting in diabetics remains unclear. A new study published in Circulation looked at the effects of continued thienopyridine therapy among patients with DM participating in the Dual Antiplatelet Therapy (DAPT) Study using a prespecified analysis [6]. In this study, 11,648 patients with coronary stents who had received 12 months of thienopyridine plus aspirin were randomly assigned to continued thienopyridine or placebo for 18 more months. Aspirin was continued in both groups. As expected, diabetics were at increased risk of death, MI or stroke compared to non-diabetics.  When diabetics were continued on dual antiplatelet therapy for an additional 18 months there was a significantly decreased rate of stent thrombosis (0.5% vs. 1.1%, P=0.06) and MI (3.5% vs. 4.8%, P=0.058). The NNT to prevent stent thrombosis was 167 and it was 77 to prevent MI. Bleeding rates were not significantly higher between the 2 groups, although the study was not powered to detect this difference. From this study, it seems reasonable to continue diabetics on thienopyridine beyond 1 year after coronary stenting. One of the limitations of the study is that the subgroups of patients with and without DM were not powered for comparison between randomized treatment arms. Further studies are needed to identify the optimal duration of dual antiplatelet therapy after coronary stenting in patients with DM and its mortality benefit vs. risk of bleeding. 

Ablation versus Escalation of Antiarrhythmic Drugs for ventricular tachycardia 

Up to 15% of patients with ICDs are initially treated with a concomitant antiarrhythmic drug and up to 38% receive an appropriate shock for ventricular arrhythmia within 5 years [7]. The Ventricular Tachycardia Ablation versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease (VANISH) trial was a multicenter, randomized control trial that compared catheter ablation with escalated antiarrythmic drugs (AAD) therapy in patients with ischemic cardiomyopathy and an ICD who had ventricular tachycardia (VT) despite first line ADD therapy [7]. This study enrolled patients with an episode of VT during treatment with amiodarone or another class I or class III AAD within the previous 6 months.

Patients were randomly assigned to receive either catheter ablation with continuation of baseline AAD or escalated AAD therapy. During a mean (±SD) of 27.9±17.1 months of follow-up, ventricular arrhythmias occurred significantly less frequently in the ablation group (59.1% versus 68.5%). The NNT to prevent a ventricular arrhythmia was 11 for ablation instead of additional antiarrhythmics.

The rate of the composite outcome of death at any time or VT storm or appropriate ICD shock after 30 days was lower in patients who underwent ablation compared to patients that received escalated AAD therapy. There was no significant difference in mortality between the groups. Treatment associated adverse events were also more frequent in the escalated therapy group (51 vs 22 P=0.25) and occurred in more patients (39 vs 20 P=0.003).

Similar to previous ablation studies [8,9], this data suggests that catheter ablation should be preferred over escalation of AAD therapy for the reduction of recurrent VT in this population.

Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease (COPD) after withdrawal of inhaled corticosteroids

Can eosinophil counts predict COPD exacerbations after withdrawal of inhaled glucocorticoids? Post-hoc analysis of the WISDOM trial published this week shows that patients with higher blood eosinophil counts at screening were more likely to develop exacerbations after inhaled corticosteroids (ICS) treatment was withdrawn, suggesting an effect size related to eosinophil counts [10]. Patients were separated into parallel groups that received tiotropium, salmeterol and fluticasone daily for 6 weeks and were then randomly assigned to receive either continued or reduced ICS over 12 weeks. The rates of exacerbations after ICS withdrawal were compared in both groups as well as time to exacerbation outcomes on the basis of blood eosinophil subgroups.

This is the first analysis to investigate eosinophil subgroups in the presence of a long acting muscarinic antagonist (LAMA) plus a long acting beta2 agonist (LABA). This is of particular interest for clinicians since most patients with exacerbations are on these therapies in addition to ICS. The mechanism underlying the association between blood eosinophils and ICS response remains unclear. According to this study, any association between blood eosinophil counts and exacerbation rate is only seen when the baseline eosinophil count is greater than 4% or 300 cells per μL. The positive signal seen when a lower cutoff is used reflects the effect of withdrawal of ICS on those with higher eosinophil counts. These findings need to be confirmed in appropriately stratified prospective clinical trials. In the meantime, there is a plausible argument that long-acting bronchodilator use is at least as effective as ICS/LABA in preventing exacerbations in patients with severe COPD on maintenance treatment with a LABA and a LAMA [10]. 

Mini cuts: 

Impact of timing of Metoprolol during STEMI on infarct size and ventricular function.

IV administration of metoprolol before primary angioplasty reduces infarct size in patients with STEMI, and earlier administration is associated with smaller infarct size and higher residual LVEF [11].

Phase 1 trials of rVSV Ebola vaccine in Africa and Europe.

The replication-competent recombinant vesicular stomatitis virus (rVSV)–based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa [12].

Physical Fitness Among Swedish Military Conscripts and Long-Term Risk for Type 2 Diabetes Mellitus: A Cohort Study

Low aerobic capacity and muscle strength at age 18 years were associated with increased long-term risk for type 2 DM, even among those with normal body mass index [13].

Dr. Tania Ruiz-Maya is a resident at NYU Langone Medical Center

Peer reviewed by Matthew Dallos, MD, Chief Resident, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References: 

  1. http://1.http://www.sciencemag.org/news/2016/05/world-s-largest-chimpanzee-research-facility-release-its-chimps
  2. http://2.http://espn.go.com/nba/story/_/id/15499690/stephen-curry-golden-state-warriors-first-unanimous-most-valuable-player
  3. http://www.businessinsider.com/alberta-irefighters-are-using-drones-2016-5
  4. Mongodi S, Via G, Girard M, et al. Lung Ultrasound For Early Diagnosis Of Ventilator-Associated Pneumonia. Chest. 2016;149(4):969-980   http://www.sciencedirect.com/science/article/pii/S0012369215003402
  5. Ritsinger V, Saleh N, Lagerqvist et al High event rate after a first percutaneous coronary intervention in patients with diabetes mellitus: results from the Swedish coronary angiography and angioplasty registry. Circulation Cardiovascular Interventional. 2015;8:e002328. http://circinterventions.ahajournals.org/content/8/6/e002328.figures-only
  6. Meredith I, Tanguay JF, Kereiakes D, et al. Diabetes Mellitus and Prevention of Late Myocardial Infarction After Coronary Stenting in the Randomized Dual Antiplatelet Therapy Study. Circulation 2016;133:1772-1782.   http://circ.ahajournals.org/content/early/2016/03/18/CIRCULATIONAHA.115.016783.abstract
  7. Sapp JL, Wells GA, Parkash R, et al. Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs. New England Journal of Medicine. May 5, 2016 http://www.nejm.org/doi/full/10.1056/NEJMoa1513614
  8. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657-65. http://www.nejm.org/doi/full/10.1056/NEJMoa065457
  9. Kuck KH, Schaumann A, Eckardt L, et al. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart dis- ease (VTACH): a multicentre randomized controlled trial. Lancet 2010;375:31-40   http://www.sciencedirect.com/science/article/pii/S014067360961755
  10. Watz, Henrik et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. The Lancet Respiratory Medicine , 2016, 4:5 , 390 – 398 http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(16)00100-4/abstract
  11. Garcia-Ruiz JM, Fernandez-Jimenez R, Garcia-Alvarez A. Impact of the timing of metoprolol administration during STEMI on infarct size and ventricular function. JACC. 2016, 67:18. 2093-2104 http://content.onlinejacc.org/article.aspx?articleid=2512372#tab1
  12. Agnandji ST.,Huttner A, Zinser ME, et al. Phase 1 trials of rVSV Ebola vaccine in Africa and Europe. N Engl J Med 2016; 374:1647-1660 http://www.nejm.org/doi/full/10.1056/NEJMoa1502924
  13. Crump C, Sundquist J, Winkleby MA, et al. Physical Fitness Among Swedish Military Conscripts and Long-Term Risk for Type 2 Diabetes Mellitus: A Cohort Study. Ann Intern Med. 2016;164:577-584 http://annals.org/article.aspx?articleid=2499473

 

 

 

Primecuts – This Week In The Journals

May 2, 2016

Mars_HubbleBy Nydia Ekasumara, MD

Peer Reviewed

Fighting resumes in Syria as an air strike hit the Al Quds hospital in the divided city of Aleppo, killing 27 people including children and staff members. This is just one in a disconcerting chain of attacks by government forces against health services in Syria, as two hospitals in Maarat al-Noaman were hit earlier this year [1]. Meanwhile, in the United States, the Defense Department announced “administrative” punishment, but no criminal charges, for the 16 American military personnel involved in an attack against a Doctors Without Borders hospital in Kunduz, Afghanistan that resulted in 42 deaths. This ruling stems from the conclusion that the American military team responsible for carrying out the attack had no deliberate intent to strike a medical facility, and instead acted on incorrect intelligence. Human rights groups are unsatisfied with the ruling, classifying the attack as a war crime. [2] As war zones continue to jeopardize the lives of thousands on Earth, a collaborative effort of the private company SpaceX and NASA announced plans to investigate whether Mars could one day be inhabitable by humans using an un-manned scientific expedition by 2018 [3]. In similarly impressive medical news this week, new studies showed a benefit from using invasive interventions to control two common heart diseases, a new diagnostic tool was proposed to prognosticate ICU admission in patients presenting with community acquired pneumonia, and a potential new strategy to reduce post-operative acute kidney injury in patients admitted for coronary artery bypass grafting (CABG) was highlighted.

There were multiple studies published this week in interventional cardiology. The first article addresses the very common clinical problem of atrial fibrillation (AF). It is estimated that 42% patients with AF have concomitant heart failure (HF) [3]. When patients’ symptoms are not controlled by medical therapy alone, catheter ablation (CA) is a treatment option. The Ablation vs Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted ICD/CRTD (AATAC) multicenter randomized trial [4] looked at the effect of CA versus amiodarone in over 200 patients with persistent AF and HF (defined by New York Heart Association (NYHA) functional class II to III and reduced LVEF <40%). Patients with AF with reversible etiology or previous valvular or coronary heart disease requiring surgical intervention were excluded. At the end of 24 months, more patients in the CA group were free from AF (70% in the CA group versus 34% in the amiodarone group; P<0.001) and there was a significantly lower rate of both the composite outcome of AF and HF- related unplanned hospitalization and all-cause mortality, with a number needed to treat of 3.8 and 10 respectively. The CA group also showed a statistically significant improvement in LV ejection fraction (LVEF), functional status as measured by the 6 minute walk distance, and patient reported quality of life measured by the Minnesota Living With Heart Failure Questionnaire (MLHFQ) score. Taken altogether, CA appears to be superior to amiodarone in reducing the recurrence of AF among patients with HF. For patients with AF and HF who do not tolerate rate control drugs, CA is a good treatment option to maintain sinus rhythm.

The second study of emerging invasive techniques in cardiology evaluated the treatment of aortic stenosis with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement in intermediate risk patients. TAVR is a minimally invasive procedure that uses a catheter to insert a bioprosthetic aortic valve which is typically reserved for patients with aortic stenosis (AS) who are at high- risk for surgical complications. The Placement of Aortic Transcatheter Valves (PARTNER) 2 trial [10] compares TAVR with surgical aortic valve replacement among intermediate-risk patients. In this study, 2032 patients with severe AS were randomly assigned to TAVR or surgical repair. Among the cohort assigned to TAVR, some were assigned to transthoracic or transfemoral access. Both the TAVR and surgical groups saw a significant reduction in symptoms as measured by NYHA class and improvement of echocardiographic findings (increase of aortic valve area and LVEF, and decrease of aortic-valve gradients), without a significant difference in the incidence of disabling stroke or death at 2 years. Within the TAVR group, the transfemoral-access TAVR group had a lower death and stroke rate compared to surgery (hazard ratio 0.79; P=0.05). The TAVR group also had significantly shorter ICU and total length of stay compared to the surgery group (2 vs 4 days, P<0.001 and 6 vs 9 days P<0.001, respectively). A higher rate of major vascular complications (i.e. vascular dissection, vessel perforation, and access site hematoma) was seen in the TAVR group compared to the surgery group (7.9% vs 5%, P=0.008). The authors did not stratify whether transthoracic or transfemoral access causes more complications in patients undergoing TAVR. The surgical repair group suffered higher rates of life-threatening bleeding (10.4% vs 3.4%, P<0.001), AKI (1.3% vs 3.1%, P=0.006), and new onset AF (9.1% vs 25.4%, P<0.001) as compared to the TAVR group. Taken together, this study shows that among intermediate risk patients, TAVR is non-inferior to surgical aortic valve replacement in mortality and stroke outcomes. The benefit of TAVR includes shorter hospital and ICU stay, and lower risk of surgical complications. The findings of this study suggest that TAVR is a viable choice for intermediate-risk patients with severe AS, expanding the population of patients for whom TAVR may be considered in the future.

Patient selection and risk stratification is not only critical in studies of invasive interventions like the one above, but is also important of clinical triage in patients presenting to the hospital for care. This week in a study published in Chest, the paradigm for risk stratification in patients presenting with community acquired pneumonia was revisited. The Etiology of Pneumonia in the Community (EPIC) study [7] is a prospective cohort study that assessed whether procalcitonin (PCT) can be used as a biomarker in determining whether patients with community acquired pneumonia (CAP) will require invasive respiratory or vasopressor support (IRVS). Out of the 1770 adults with CAP, 115 (6.5%) subjects required IRVS within 72 hours. Initial serum PCT concentrations were higher in those who required IRVS compared to those who did not (median 1.43 ng/ml in the IRVS group vs 0.14 ng/ml in the usual care group; p<0.01). A logistic regression model showed a linear correlation between PCT level and IRVS risk between 0.05 ng/ml to 10 ng/ml. An undetectable PCT level (<0.05 ng/ml) corresponded to a 4.0% IRVS risk while a level of 10 ng/ml corresponded to a 22.4% risk. Adding PCT to existing pneumonia severity score (American Thoracic Society (ATS) Minor Criteria for severe CAP, Pneumonia Severity Index (PSI), and SMART-COP) [8,9,10] improves the discriminatory ability of the test to predict which patients may require a higher level of care. For example, adding PCT > 0.83 ng/ml to the high risk criteria reduces the number of misclassified patients (patients who are considered low risk from ATS criteria but ended up requiring IRVS) from 77 to 44 out of 1770 patients. The strong association between PCT concentration and the risk of IRVS augments existing pneumonia severity scoring systems and may aid in earlier identification of patients presenting with CAP who will require an ICU admission.

Finally, risk for post-operative acute kidney injury (AKI) was addressed in an article published in the New England Journal of Medicine. AKI is often seen after coronary artery bypass surgery (CABG) due to intraoperative hypoperfusion and the systemic inflammatory response. Albumin maintains oncotic pressure and intravascular volume. A low pre-operative serum albumin is associated with post-operative AKI in patients undergoing CABG. This study [11] looks at whether preoperative albumin repletion decreases the risk of developing AKI among patients undergoing CABG. In this study, 220 pre-CABG patients with serum albumin < 4.0 g/dl were randomly selected to receive albumin or normal saline (NaCl) prior to surgery. During the intra-operative period, there was higher urine output in the albumin group compared to the control group (P=0.006); however no significant difference in hemodynamics, vasopressor requirements, or additional volume of infusion (NaCl or albumin). There was a statistically significant reduction in the incidence of postoperative AKI in the albumin versus control group (13.7% in the albumin group vs 25.7% in the control group). There was no significant difference between the two groups in the incidence of severe AKI, need for renal replacement treatment (RRT), hospital or ICU stay, and in 30-day mortality. Based on the results of this study, preoperative albumin infusion appears to have some renal protective benefit without a significant change in mortality or hospitalization. This study corroborates previous literature that showed that the addition of albumin in patients with severe sepsis improves hemodynamics without conferring a survival benefit [12]. The mechanism behind this reno-protective effect remains unclear. Additional study is warranted prior to incorporating this intervention into standard clinical practice.

Mini cuts

A 24-year prospective cohort study of 189,158 female nurses (Nurses’ Health Studies) showed that longer duration of rotating night shift work is associated with a statistically significant increase in coronary artery disease (CAD) [13].

The VitamIN D treatIng patients with Chronic heArT failurE (VINDICATE) study [14] showed that high-dose vitamin D supplementation for 1 year is associated with significant improvement in LVEF and reversal of LV remodeling in patients with left ventricular systolic dysfunction (LVSD) on echocardiography. There was no significant effect on functional status as measured by the 6-minute walk test.

There is an association between lower lung function as measured by FVC with increased exposure to ambient pollution, as measured by proximity to major roadway, estimated exposure to particulate matter with diameter smaller than 2.5 μm (PM2.5), and black carbon exposure. This study again suggests pollution adversely affects children’s lung health [15].

Dr. Nydia Ekasumara, internal medicine resident,  NYU Langone Medical Center

Peer reviewed by Kerrilynn Carney, 3rd year internal medicine resident at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References 

1. http://www.nytimes.com/2016/04/29/world/middleeast/aleppo-syria-strikes.html?src=me

2. http://www.nytimes.com/2016/04/30/world/asia/afghanistan-doctors-without-borders-hospital-strike.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=first-column-region&region=top-news&WT.nav=top-news 

3. http://www.npr.org/sections/thetwo-way/2016/04/28/476015372/mars-by-2018-spacex-and-nasa-announce-a-new-space-project

4. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol. 2003;91():2D–8D. http://www.ajconline.org/article/S0002-9149(02)03373-8/fulltext 

5. Di Biase L, Mohanty P, Mohanty S, Santangeli P, et al. Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial. Circulation. 2016;133:1637-1644, published online before print March 30 2016, doi:10.1161/CIRCULATIONAHA.115.019406 http://circ.ahajournals.org/content/133/17/1637.full#cited-by  

6. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609-20. http://www.nejm.org/doi/full/10.1056/NEJMoa1514616?query=featured_home  

7. Self WH, Grijalva CG, Williams DJ, et al.Procalcitonin As An Early Marker Of The Need For Invasive Respiratory Or Vasopressor Support In Adults With Community-Acquired Pneumonia Chest. 2016. doi:10.1016/j.chest.2016.04.010 http://journal.publications.chestnet.org/article.aspx?articleid=2518224

8. Brown, SM, Jones BE, Jepson AR, et al. Validation of the Infectious Disease Society of America/American Thoracic Society 2007 guidelines for severe community-acquired pneumonia. Crit Care Med. 2009 Dec;37(12):3010-6. doi: 10.1097/CCM.0b013e3181b030d9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783880/

9. Flanders DW, Tucker G, Krishnadasan A, et al. Validation of the Pneumonia Severity Index. J Gen Intern Med. 1999 Jun; 14(6): 333–340. doi: 10.1046/j 1525-1497.1999.00351.x http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1496595/ 

10. Charles PG, Wolfe R, Whitby M, et al. SMART-COP: A Tool for Predicting the Need for Intensive Respiratory or Vasopressor Support in Community-Acquired Pneumonia. Clinical Infectious Diseases 2008; 47:375–84. DOI: 10.1086/589754 http://www.aamr.org.ar/secciones/infecciones_pulmonares/indicesmart_cop.pdf

11. Lee EH, Kim WJ, Kim JY, et al. Effect of Exogenous Albumin on the Incidence of Postoperative Acute Kidney Injury in Patients Undergoing Off-pump Coronary Artery Bypass Surgery with a Preoperative Albumin Level of Less Than 4.0 g/dl. Anesthesiology 5 2016, Vol.124, 1001-1011. doi:10.1097/ALN.0000000000001051 http://anesthesiology.pubs.asahq.org/Article.aspx?articleid=2498480  

12. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L; ALBIOS Study Investigators: Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014; 370:1412–21 http://www.nejm.org/doi/full/10.1056/NEJMoa1305727

13. Vetter C, Devore EE, Wegrzyn LR, et al. Association Between Rotating Night Shift Work and Risk of Coronary Heart Disease Among Women. JAMA. 2016;315(16):1726-1734. doi:10.1001/jama.2016.4454. http://jama.jamanetwork.com/article.aspx?articleid=2516715  

14. Witte KK, Byrom R, Gierula J, et al. Effects of Vitamin D on Cardiac Function in Patients With Chronic HF: The VINDICATE Study. J Am Coll Cardiol. 2016;():. doi:10.1016/j.jacc.2016.03.508. https://content.onlinejacc.org/article.aspx?articleid=2507290#tab1

15. Rice MB, Rifas-Shiman SL, Litonjua AA, et al. Lifetime Exposure to Ambient Pollution and Lung Function in Children, American Journal of Respiratory and Critical Care Medicine, Vol. 193, No. 8 (2016), pp. 881-888. doi: 10.1164/rccm.201506-1058OC http://www.atsjournals.org/doi/abs/10.1164/rccm.201506-1058OC#.VyENqRIrKt8

Primecuts – This Week In The Journals

April 25, 2016

tubman-20-us-money-billBy: Scott Statman, MD

 Peer Reviewed

The widely anticipated New York State presidential primaries were held this past Tuesday. In the Democratic contest Hilary Clinton won a 60% majority, solidifying her commanding lead over Bernie Sanders. On the Republican side Donald Trump also secured a decisive 60% majority. He maintains a significant lead over Ted Cruz, however significant doubt remains over Mr. Trump’s ability to secure enough delegates should he not win the 1,237 needed to avoid a contested convention in Cleveland this July [1].

In other news, the United States Treasury Department announced that Harriett Tubman will replace Andrew Jackson on the new $20 bill to be released in 2020 [2]. In response presidential candidate Donald Trump stated, “I think it’s pure political correctness…Andrew Jackson had a great history. I think it’s very rough when you take somebody off the bill [3].”

In medical news, the Centers for Disease Control (CDC) released a review acknowledging for the first time a causal relationship between Zika virus infection and birth defects such as microcephaly. This is intended to encourage increased focus on Zika virus prevention, diagnosis, and research [4].

Proton Pump Inhibitors Again Linked to Increased Risk of Chronic Kidney Disease

A large retrospective cohort study [5] used national Veteran’s Affairs databases to identify new users of proton-pump inhibitors (PPIs, n=173,321) and H2 blockers (H2Bs, n=20,270) with normal baseline estimated glomerular filtration rate (eGFR) and ≥ 1 additional measurement of renal function over a 5 year period after starting each medication. Results showed a statistically significant association between PPI use and risk of chronic kidney disease (CKD) compared to H2B use (36.8 vs 25.7/1000 person-years, HR 1.28, CI 1.23-1.34, attributable risk 1.11%, number needed to harm [NNTH] 90). Similarly, a significant association was found between PPI use and CKD progression, as evidenced by increased rates of eGFR decline >30% (61.7 vs 45.3 per 1000 person-years, HR 1.32, CI 1.28-1.37, attributable risk 1.63%, NNTH 61). PPIs also increased the risk progression to end-stage renal disease (4.13 vs 2.65 per 1000 person-years, HR 1.96, CI 1.21-3.18, attributable risk 0.01%, NNTH of 6780). Importantly, investigators found a graded association between duration of exposure and risk of renal outcomes. These results corroborate a recent cohort study [6] that showed an association between self-reported PPI use in 10,482 participants and risk of developing CKD. The pathophysiology behind these findings likely relates to the knowledge that PPIs increase the risk of acute intersitial nephritis (AIN), which is often subclinical, delaying diagnosis and allowing progression to chronic interstitial nephritis and CKD [7]. Despite the low incidence of outcomes reported in this study, it raises more concern over the frequent long-term use of PPIs, often without strong clinical indications.

Use of coronary CTA to guide management of angina due to suspected coronary artery disease

The 2015 SCOT-HEART Trial [8] showed that coronary computed tomography angiography (CCTA) is useful for clarifying the diagnosis of angina due to coronary artery disease (CAD) when added to the standard of care such as stress testing. In a follow up study [9] using the same data, investigators compared CCTA findings with those seen during invasive coronary angiography (ICA). The trial included 4,146 adult subjects referred to Scottish cardiology clinics with suspected angina due to CAD. They were randomized to receive either CCTA or standard care and followed for a median of 20 months. Between groups there was no difference in the number of ICA procedures however in the CCTA group results were less likely to show normal coronary arteries (20 vs 56, HR 0.39, p < 0.001) and more likely to show obstructive CAD (283 vs 230, HR 1.29, p=0.005). There was a non-significant trend towards more coronary revascularization procedures (233 vs 201, HR 1.20, p = 0.061). As a result of CCTA results, clinicians were more likely to discontinue (77 vs 8, OR 10.75, p < 0.001) or initiate (293 vs 84, OR 4.21, p < 0.001) preventative oral medications. Importantly, CCTA decreased rates of fatal and nonfatal myocardial infarction (26 vs 42, HR 0.62, p=0.053). This effect was more pronounced when only including events taking place ≥ 50 days after CCTA (17 vs 34, HR 0.50, p=0.020), coinciding with the timing of preventative therapy implementation. These results suggest that CCTA allows clinicians to more effectively select patients for ICA and choose more appropriate preventative medications. A major limitation of this study is the low event rate despite the large sample size, however the results suggest a potential future role for CCTA in the workup of suspected stable angina.

Controversial re-evaluation of the Minnesota Coronary Experiment suggests that decreasing dietary saturated fats may not lead to decreased mortality.

The diet-heart hypothesis suggests that replacing saturated fats with oils rich in linoleic acid (such as in corn, sunflower seeds, and soybeans) decreases mortality. Investigators called this into question with the recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE). This study [10], conducted from 1968-1973, included 9,570 adult subjects admitted to a nursing home and 6 state mental facilities in Minnesota. Subjects were randomized to receive either a control diet containing significant amounts of trans-fat or an experimental diet that used corn oil to decrease dietary saturated fat and increase linoleic acid. Investigators recovered serum cholesterol data from 2,355 of 2,403 participants enrolled in the study for ≥ 1 year. The experimental diet significantly lowered serum cholesterol (mean change -31.2 mg/dL or -13.8%, p < 0.001) compared to the control group (-5.0 mg/dL or -1.0%, p < 0.001). Surprisingly researchers found that a 30 mg/dL decrease in serum cholesterol was associated with increased risk of all-cause mortality in the experimental group (HR 1.22, CI 1.09-1.51), control group (HR 1.28, CI 1.09-1.51), and all groups combined (HR 1.22, CI 1.14-1.32). This appears to be driven by the subgroup age ≥ 65, in which for all groups combined the same decrease in cholesterol was associated with a 35% increased mortality (HR 1.35, CI 1.18-1.54). This may be explained by the fact that linoleic acid, an omega-6 fatty acid commonly found in processed foods, places great oxidative stress on the body. This post-hoc analysis of an incomplete data set has numerous limitations as pointed out by nutrition experts [11], however it highlights the need for further research into the diet-heart hypothesis.

Extended 10-year follow up of STICH trial shows that CABG is superior to medical therapy alone in ischemic cardiomyopathy  

In the 2011 Surgical Treatment for Ischemic Heart Failure (STICH) trial [12], investigators randomized 1,212 patients with an ejection fraction ≤ 35% and coronary artery disease (CAD) to receive either coronary artery bypass grafting (CABG) or medical therapy alone.  After a median of 4.7 years of follow up, results showed no significant difference between groups with respect to death from any cause. In the STICH-Extension Study (STICHES) [13] investigators followed the same subjects for a median of 9.4 years. Results showed that CABG significantly reduced the risk of death from any cause compared to medical therapy alone (58.9% vs 66.1%, HR 0.84, CI 0.73-0.97). The CABG group survived 1.44 years longer and the number needed to treat to prevent one death was 14. Similar results were found with respect to death from cardiovascular causes (40.5% vs 49.3%, HR 0.79, CI 0.66-0.93). It should be noted that 119 patients in the medical therapy group eventually underwent CABG, and 55 patients in the CABG group never underwent surgery. When analyzing the data as-treated (instead of intention-to-treat as above), results suggest that the crossovers led to an underestimation of the benefits of CABG. These results suggest that after accounting for the increased 30-day mortality following surgery (3.6% in this trial), CABG plus medical therapy provides significant benefit over medical therapy alone in patients with ischemic cardiomyopathy.

MINI-CUTS

An international committee of thyroid experts changed the nomenclature for the encapsulated follicular variant of papillary thyroid carcinoma to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). They hope to prevent the aggressive treatment of this common indolent tumor, which represents 10-20% of all thyroid cancers [14].

A group of NYU researchers including Dr. Martin Blaser discovered that helminth infection protects susceptible mice from developing inflammatory bowel disease (IBD) by promoting changes in gut flora. This is further evidence that alterations in the microbiome contribute to the rising incidence of IBD in developed nations. [15].

An analysis of data from 3,387 US hospitals found that following passage of the Affordable Care Act (ACA) in 2010, readmission rates decreased while observation unit stays increased. After finding no significant association between these changes, investigators concluded that hospitals’ responses to financial incentives, not increased use of observation units, account for decreased readmissions following passage of the ACA [16].

Dr. Scott Statman is a 1st year internal medicine resident at NYU Langone Medical Center

Peer reviewed by Anish B. Parikh, MD, Chief Resident, Department of Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

 

  1. http://www.nytimes.com/2016/04/20/us/politics/new-york-primary.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=span-ab-top-region&region=top-news&WT.nav=top-news
  2. http://www.nytimes.com/2016/04/21/us/women-currency-treasury-harriet-tubman.html
  3. http://nypost.com/2016/04/21/donald-trump-its-wrong-to-put-harriet-tubman-on-the-20-bill/
  4. Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika Virus and Birth Defects – Reviewing the Evidence for Causality. N Engl J Med. Published Online: April 13, 2016. doi: 10.1056/NEJMsr1604338. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMsr1604338?query=featured_zika
  5. Xie Y, Bowe B, Li T, Xian H, Balasubramanian S, Al-aly Z. Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD. J Am Soc Nephrol. Published Online: April 14, 2016. doi:10.1681/ASN.2015121377. http://jasn.asnjournals.org.ezproxy.med.nyu.edu/content/early/2016/04/13/ASN.2015121377
  6. Lazarus B, Chen Y, Wilson FP, Sang Y, Chang AR, Coresh J, Grams ME: Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med 2016; 176: 238–246. http://archinte.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2481157
  7. Moledina DG, Perazella MA. Proton Pump Inhibitors and CKD. J Am Soc Nephrol. Published Online: April 14, 2016. doi:10.1681/ASN.2016020192. http://jasn.asnjournals.org.ezproxy.med.nyu.edu/content/early/2016/04/13/ASN.2016020192
  8. The SCOT-HEART Investigators. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. Lancet 2015;385:2383–91. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0140673615602914
  9. Williams MC, Hunter A, Shah AS, Assi V, Lewis S, Smith J, Berry C, Boon NA, Clark E, Flather M, Forbes J, McLean S, Roditi G, van Beek EJ, Timmis AD, Newby DE, SCOT-HEART investigators. Use of Coronary Computed Tomographic Angiography to Guide Management of Patients With Coronary Disease. J Am Coll Cardiol. 2016;67(15):1759-68. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0735109716008196
  10. Ramsden CE, Zamora D, Majchrzak-Hong S, Faurot KR, Broste SK, Frantz RP, Davis JM, Ringel A, Suchindran CM, Hibbeln JR. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ. 2016;353:i1246. http://www.bmj.com/content/353/bmj.i1246.long
  11. http://11.http://well.blogs.nytimes.com/2016/04/13/a-decades-old-study-rediscovered-challenges-advice-on-saturated-fat/?smprod=nytcore-ipad&smid=nytcore-ipad-share
  12. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med. 2011;364:1607-1616. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1100356
  13. Velazquez EJ, Lee KL, Jones RH, et al. Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy. N Engl J Med. 2016;374(16):1511-1520. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1602001?query=featured_home
  14. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA Oncol. Published online April 14, 2016. doi:10.1001/jamaoncol.2016.0386. http://oncology.jamanetwork.com/article.aspx?articleid=2513250
  15. Ramanan D, Bowcutt R, Lee SC, et al. Helminth infection promotes colonization resistance via type 2 immunity. Science. Published Online: April 14, 2016. doi: 10.1126/science.aaf3229. http://science.sciencemag.org.ezproxy.med.nyu.edu/content/early/2016/04/13/science.aaf3229.full
  16. Zuckerman RB, Sheingold SH, Orav EJ, Ruhter J, Epstein AM. Readmissions, Observation, and the Hospital Readmissions Reduction Program. N Engl J Med. 2016;374(16):1543-1551. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMsa1513024#t=article

 

Primecuts – This Week In The Journals

April 19, 2016

curryBy B. Corbett Walsh, MD 

Peer Reviewed

As many of us reflect on the Democratic Presidential Debate held this past Thursday in our backyard in Brooklyn, we prepare for the New York Primary scheduled for this Tuesday, April 19th. Across the coast, the Golden State Warriors broke the Chicago Bulls 1995-96 NBA record by having the most wins in any regular season, finishing 73-9. On that same night, Kobe Bryant retired from the Los Angeles Lakers after an illustrious 20-year professional NBA career resulting in 5 Championship titles. As votes are decided, records broken, and legends retire, we turn now to key medical news in this week’s Primecuts.

Do we still need Chest X-Ray after an ultrasound guided right internal jugular central line? [1]

Placement of central venous lines is a common procedure performed on critically ill patients to administer lifesaving medications. It is standard practice to obtain a chest x-ray post-procedure to ensure appropriate placement and assess for complications. However, a new study published in Critical Care Medicine challenges the need for routine chest x-rays to confirm placement. The study authors retrospectively chart reviewed 1322 right IJ central lines that were placed under ultrasound guidance in emergency departments, ICUs, and general wards at an academic tertiary hospital system. Procedures were performed by resident physicians and attending physicians in various specialties including critical care medicine, emergency medicine, anesthesia, internal medicine, and general surgery. Residents and fellows performed the majority of lines (75%), while interns performed 12%. Chest radiographs were obtained post-procedure to assess for misplacement (defined as any catheter tip position that was not in the SVC to upper RA confluence) and the presence of pneumothorax. The overall rate of success of ultrasound-guided right internal jugular vein central venous line placement was 96.9%, with 79% accomplished during the first attempt. Complications were limited to only one pneumothorax (0.1% [95% CI, 0–0.4%]), and the rate of catheter misplacement requiring repositioning or replacement was 1.0% (95% CI, 0.6–1.7%). Multivariate regression analysis showed no correlation between high-risk patient characteristics and composite complication rate. The authors note that routine chest radiograph after this common procedure is an unnecessary use of resources (costing approximately $200[2-3]) and may delay resuscitation of critically ill patients.

FDA revises warnings regarding the use of metformin for type 2 diabetes in certain patients with reduced kidney function [4]

In 2012, 29.1 million Americans were diagnosed with diabetes, with approximately 1.4 million new diagnosed each year.[5] Metformin is typically the first pharmacologic agent used when behavior modification for type-two diabetes has failed. Indeed, approximately 14.4 million patients received a prescription for metformin in 2014.[6] The FDA, however, has restricted its use in patients with kidney disease as the medication is renally cleared and may increase the risk of lactic acidosis. As these concerns have not been evident in the medical literature, the FDA conducted a literature review and has now revised its recommendations as below.

  • Before starting a patient on metformin and at least annually thereafter, obtain the patient’s estimated glomerular filtration rate (eGFR). Patients with other risk factors for kidney disease, such as advanced age, should have their eGFRs checked more frequently.
  • Metformin is contraindicated in patients with an eGFR below 30 mL/minute/1.73 m2 and shouldn’t be initiated in eGFRs of 30–45 mL/minute/1.73 m2. For patients whose eGFR declines into the 30–45 mL range while on treatment, clinicians should assess risks and benefits before continuing.
  • Metformin should be stopped at or before an iodinated contrast imaging procedure in patients whose eGFR is 30–60 mL/minute/1.73 m2; in those with a history of liver disease, alcoholism, or heart failure; or in those who will be given intra-arterial iodinated contrast. [7-10]

This will likely shift the focus towards using a patient’s calculated GFR rather than their serum creatinine to decide on the safety of using metformin, potentially allowing more patients to use and benefit from the medication.

Is it Ethical to Withhold Prevention? [11]

In a Perspective piece featured in the most recent issue of the New England Journal of Medicine, Dr. Thomas Farley describes how the medical profession conceptualizes the provision of highly advanced, often costly, medical care, but refrains from providing public health measures even when they are effective and low in cost. The author proposes two commonly encountered cases; an elderly woman with metastatic lung cancer who could undergo radiation & chemotherapy that might extend her life for a few months at a cost of over $100,000, or a proposal to help smokers quit smoking (and thereby reduce the incidence of lung cancer). The first case places emphasis on the value of extending human life while the second on the cost of the intervention. Dr. Farley points out that both scenarios expose complicated issues of ethics, cost, and cost-effectiveness and highlight a troubling structural bias against prevention inherent in the medical industry. The author notes two contrasting themes driving medical care between the two cases. The first is the nature of the patient. The woman with lung cancer will receive treatment regardless of cost because she is a human being with a name and a face with whom we can empathize, and whose suffering from lack of treatment we can see tangibly. The public health campaign, in contrast, prevents suffering in people who are unnamed and unseen, and thus easier to ignore. The second point is the manner in which our society pays for medical care. The woman receives treatment because as a society, we reimburse hospitals and doctors for the costs of her care (with government funding of uncompensated care). In contrast, we finance most primary preventive services through budgets for public health agencies, which are subject to fixed annual appropriations and must compete with budgets for schools, police, and other public needs. Recognizing that our ethical frameworks for weighing costs in the two scenarios are inconsistent is an important step in addressing what Dr. Farley calls “a systematic bias against prevention”.

Is Thrombocytopenia an Early Prognostic Marker in Septic Shock? [12]

Earlier this year, the sepsis guidelines were updated to take into account the latest understanding of its fundamental pathophysiology, abandoning the old SIRS criteria in favor of the “sepsis related organ failure score” (SOFA). One element of the SOFA score is platelet count, which is based on the belief that thrombocytopenia is indicative of the severity of illness in the patient. [13] In the latest issue of Critical Care Medicine, Thiery-Antier et al. designed a prospective multicenter observational cohort study at academic hospitals to assess if early thrombocytopenia during septic shock was associated with an increased risk of death at day 28 and to evaluate the risk factors associated with low platelet count. Of the 1486 patients studied, simplified Acute Physiology Score II score of greater than or equal to 56, immunosuppression, age of more than 65 years, cirrhosis, bacteremia (p ≤ 0.001 for each), and urinary sepsis (p = 0.005) were globally associated with an increased risk of thrombocytopenia within the first 24 hours following the onset of septic shock. Additionally, a platelet count of less than or equal to 100,000/mm3 was independently associated with a significantly increased risk of death within the 28 days following the onset of septic shock. The risk of death increased with the severity of thrombocytopenia (hazard ratio, 1.65; 95% CI, 1.31–2.08 for a platelet count below 50,000/mm3 vs > 150,000/mm3; p < 0.0001). Therefore, measuring platelet count can serve as a simple way for physicians to determine a prognosis for patients or their families if they are admitted to an ICU with septic shock. Also in the news, Among patients with AF with a single additional stroke risk factor (CHA2DS2-VASc score = 1 in men, 2 in women), oral anticoagulation use was associated with an improved prognosis for stroke/systemic thromboembolism/death. [14] The U.S. Preventive Services Task Force updates its 2007 and 2009 recommendations regarding aspirin for primary prevention of cardiovascular disease and colorectal cancer in some high-risk adults in their 50s and 60s. Low-dose aspirin is now recommended for adults aged 50–59 who have at least a 10% risk for a cardiovascular event in the next decade, low bleeding risk, and a life expectancy of at least 10 years; patients must also be willing to take aspirin daily for at least 10 years (grade B recommendation). [15] The CDC announced the first male-to-male sexual transmission of the Zika Virus.[16] Previously there had been one prior case report of a sexual transmission via vaginal intercourse.

Dr. B. Corbett Walsh is a medical intern at NYU Langone Medical Center 

Peer reviewed by Amar Parikh, MD, 2nd year medicine resident at NYU Langone Medical Center  

Image courtesy of The Associated Press

References:

[1] Hourmozdi JJ1, Markin A, Johnson B, Fleming PR, Miller JB. Routine Chest Radiography Is Not Necessary After Ultrasound-Guided Right Internal Jugular Vein Catheterization. Crit Care Med. 2016

[2] Pikwer A, Bååth L, Perstoft I, et al: Routine chest x-ray is not required after a low-risk central venous cannulation. Acta Anaesthesiol Scand 2009; 53:1145–1152 8.

[3] Lessnau KD: Is chest radiography necessary after uncomplicated insertion of a triple-lumen catheter in the right internal jugular vein, using the anterior approach? Chest 2005; 127:220–223

[4] http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm

[5] http://www.diabetes.org/diabetes-basics/statistics/

[6] http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm

[7] Rachmani R, Slavachevski I, Levi Z, Zadok B, Kedar Y, Ravid M. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 2002;13:428.

[8] Kamber N, Davis WA, Bruce DG, Davis TM. Metformin and lactic acidosis in an Australian community setting: the Fremantle Diabetes Study. Med J Aust 2008;188:446-9.

[9] Roussel R1, Travert F, Pasquet B, Wilson PW, Smith SC Jr, Goto S, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 2010;170:1892-9.

[10] Ekström N, Schiöler L, Svensson AM, Eeg-Olofsson K, Miao Jonasson J, Zethelius B, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open 2012;2.pii:e001076

[11] Farley TA. When Is It Ethical to Withhold Prevention? N Engl J Med. 2016 Apr 7;374(14):1303-6. https://www.ncbi.nlm.nih.gov/pubmed/?term=Farley+TA.+When+Is+It+Ethical+to+Withhold+Prevention%3F+N+Engl+J+Med.+2016+Apr+7%3B374(14)%3A1303-6.

[12] Thiery-Antier N, Binquet C, Vinault S, Meziani F, Boisramé-Helms J, Quenot JP; EPIdemiology of Septic Shock Group. Is Thrombocytopenia an Early Prognostic Marker in Septic Shock? Crit Care Med. 2016 Apr;44(4):764-72.

[13] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D5, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10.

[14] Fauchier L, Lecoq C, Clementy N, Bernard A, Angoulvant D, Ivanes F, Babuty D, Lip GY.Oral Anticoagulation and the Risk of Stroke or Death in Patients With Atrial Fibrillation and One Additional Stroke Risk Factor: The Loire Valley Atrial Fibrillation Project. Chest. 2016 Apr;149(4):960-8.

[15] Bibbins-Domingo K; U.S. Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016 Apr 12.

[16] D. Trew Deckard, PA-C; Wendy M. Chung, MD; John T. Brooks, MD; Jessica C. Smith, MPH Senait Woldai, MPH; Morgan Hennessey, DVM; Natalie Kwit, DVM; Paul Mead, MD. Morbidity and Mortality Weekly Report (MMWR): Male-to-Male Sexual Transmission of Zika Virus. Weekly / April 15, 2016 / 65(14);372–374

Primecuts – This Week In The Journals

April 12, 2016

drugsBy Neha Jindal, MD

Peer Reviewed

Pharmaceutical companies made headlines last week when the $150 billion Pfizer-Allergan merger was called off shortly after the Obama administration issued new rules designed to crack down on corporate tax avoidance[1].  This comes on the heels of reports that major drug companies have set significantly higher prices on medications in the last five years.  According to a Reuters analysis, four of the top ten prescribed drugs in the United States had a price increase of over 100% since 2011.  AbbVie Inc. was at the top of the list raising the price of arthritis medication Humira by more than 126% for a typical monthly treatment to $3797.10 compared with $1676.98 in December 2010[2]. In more encouraging money news, $589 million of federal money left over from the successful fight against Ebola will now go to the growing threat of Zika virus[3].

In the face of soaring healthcare costs, the medical community continues to investigate new therapies and optimal use for existing treatments. This week’s primecuts highlights some of these studies.

PCSK9 Inhibitors effective in statin intolerant patients

In their recent study published in JAMA, Nissen et al. use a meticulous protocol to investigate the use of the PCSK9 inhibitor evolocumab among patients with statin intolerance associated with muscle-related adverse effects[4]. This two-staged randomized clinical trial enrolled 511 patients with a history of intolerance to 2 or more statins. Phase A randomized 491 patients to receive either 20mg atorvastatin daily or placebo for 10 weeks, followed by a 2 week washout, followed by a crossover to the alternate treatment for 10 weeks. In phase B, 218 patients who exhibited muscle-related adverse effects while taking atorvastatin but not while taking placebo, or who had experienced a 10-fold increase in creatine kinase level after statin administration were randomized to receive ezetimibe (n=73 patients) or evolocumab (n=145 patients) for 24 weeks. Coprimary endpoints were the mean percentage change in LDL-C level from baseline to the mean of weeks 22 and 24, and from baseline to week 24 levels. At 24 weeks, LDL-C levels were reduced by 16.7% (from 221.1mg/dL to 181.5mg/dL) with ezetimibe and by 52.8% (from 218.8mg/dL to 104.1 mg/dL) with evolocumab (P<.001). Both medications were generally well tolerated, muscle symptoms leading to discontinuation of medication occurred in 5 of 73 ezetimibe treated patients (6.8%) and 1 of 145 evolocumab treated patients (0.7%). This GAUSS-3 trial supports previous studies showing benefit of PCSK9 inhibitors in statin intolerant patients, however this study goes beyond existing literature by using a rigorous protocol to identify patients with true statin intolerance as opposed to relying on patient history alone[5][6] . 

Rectal indomethacin does not prevent post ERCP pancreatitis in Consecutive Patients 

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is the most prevalent cause of iatrogenic pancreatitis, often leading to hospital admission and considerable morbidity for patients[7].  Since 2003 there have been over six randomized, controlled trials showing that periprocedural NSAIDs reduce the risk of post-ERCP pancreatitis (PEP) by 50-60%[8][9][10][11][12].  A single institution randomized, controlled trial published in the current issue of Gastroenterology contests existing research, finding no evidence of indomethacin’s efficacy in preventing PEP [13]. In this study, 449 patients were randomized to 100mg indomethacin suppository or placebo, inserted after attempted cannulation of the major papilla during ERCP. The primary study outcome of PEP occurred in 16 of 223 (7.2%) patients in the treatment group compared to 11 of 226 (4.9%) patients in the placebo group (P=.33). There was no significant benefit in terms of relative risk reduction for indomethacin vs. placebo.  Secondary outcomes of pancreatitis severity, gastrointestinal bleeding, 30-day hospital readmission, and death were not significantly different.  This trial was stopped early by the Dartmouth Data and Safety Monitoring Committee for futility given no evidence of indomethacin’s efficacy. Limitations of this study include single center enrollment and low event numbers in each study arm.  It is important to note that most research to date shows benefit of rectal NSAIDs in patients at high risk for PEP such as those with history of PEP, difficult cannulation, or Sphincter of Oddi dysfunction.  Levenick et al. intentionally randomized all patients regardless of risk to include those with average risk for PEP as well.  This study delivers concrete evidence for providers to reconsider use of rectal indomethacin to prevent PEP, particularly in average risk patients.

Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

In the ELITE study, Hodis et al. test the hormone-timing hypothesis[14]. That is, cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation.  In this single center double blind randomized control trial, 643 women without cardiovascular disease were stratified to either early (<6 years since start) or late (>/= 10 years since start) menopause and were randomly assigned to receive either oral 17beta-estradiol (1mg per day, plus 45mg progesterone vaginal gel administered sequentially for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus) for a median of 5 years.  Women with diabetes, uncontrolled hypertension, history of venous thromboembolism, kidney disease, untreated thyroid or liver disease were amongst those excluded.  The primary outcome-rate of change in carotid-artery intima-media thickness (CIMT), differed between early and late postmenopause strata (p=.007 for the interaction). Among women in early menopause, women receiving estradiol (with or without progesterone) had slower mean CIMT increased (0.0078mm per year in the placebo vs. 0.0044mm per year in the estradiol group, P=.008). No significant difference was seen in the late menopause stratum (0.0088mm per year in placebo vs. 0.0100mm per year in estradiol, P=0.29). Secondary outcomes included assessment of coronary atherosclerosis by Cardiac CT. There was no significant difference in CT measurement of coronary atherosclerosis between the placebo and estradiol groups within either postmenopause stratum. Of note, these measurements were only performed in a subset of patients and no baseline measurements were available. No significant difference was found in the frequency of serious adverse events among all groups.

Despite favorable effect of early estrogen use found in the ELITE trial, CIMT remains a surrogate measure of coronary heart disease and this study was not designed or powered to assess coronary events. Clinically significant benefit of early estrogen therapy on the occurrence of myocardial infarction and stroke remains in question.

Bisphosphonates vs. Parathyroidectomy for reducing fracture risk in Primary Hyperparathyroidism

A retrospective cohort study from the Annals of Internal Medicine investigates the relationship of parathyroidectomy and bisphosphonates with skeletal outcomes in patients with biochemically confirmed primary hyperparathyroidism (PHPT)[15].  In 6272 PHPT patients from the Kaiser Permanente Southern California integrated health system followed for fracture, parathyroidectomy was associated with decreased absolute risk for hip fracture at 10 years (absolute risk 20.4 events per 1000 patient, absolute risk reduction -35.5 [95% CI -38.4 to -32.5]) whereas bisphosphonate therapy was associated with an increased risk (absolute risk 85.5 events per 1000 patients, absolute risk difference 29.7 [CI 27.3-31.9]) when compared to observation alone (absolute risk 55.9 events per 1000 patients). Similar trends were seen for any fracture type and when patients were stratified by satisfaction of 2002 consensus guideline criteria for parathyroid removal in PHPT.  Further analysis stratified patients by baseline bone mineral density status. Parathyroidectomy remained protective against all fractures in both osteopenic and osteoporotic patients, while patients in both groups on bisphosphonate therapy had higher rates of fractures when compared to observation alone.

It has been shown that most patients with PHPT managed in the community who meet guideline criteria for parathyroidectomy do not have surgery[16][17]. Although limited by retrospective design, this study brings to light a potential protective effect of parathyroidectomy against fractures in patients with PHPT, regardless of whether they meet guideline criteria for surgery. This study develops a need for prospective randomized trials to further investigate the protective benefit of parathyroidectomy in PHPT.

Also in the journals this week-

Data from the HOPE-3 trial shows statins significantly lower risk of cardiovascular events compared to placebo in an intermediate-risk population without cardiovascular disease[18].

Pioglitazone was associated with a lower risk of stroke or myocardial infarction among patients without diabetes but with insulin resistance and recent ischemic stroke or TIA[19].

Ramakers et al. investigate a growing problem of temporary hearing loss following loud music exposure. They find earplugs were effective in preventing recreational noise-induced hearing loss in their randomized controlled trial looking at 51 people attending an outdoor music festival in Amsterdam[20].

Dr. Neha Jindal is an instructor of medicine, NYU School of Medicine

Peer reviewed by Neil Shapiro, Editor-In-Chief, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References: 

[1] Thomas, K and Bray, C. Pfizer Faces Limited Options after Its Dead Deal with Allergen. The New York Times. Published April 6, 2016. http://www.nytimes.com/2016/04/07/business/dealbook/pfizer-allergan-merger.html  

[2] Humer, C. Exclusive: Makers took big price increased on widely used U.S. Drugs. Reuters. Published on April 5, 2016. http://www.nytimes.com/2016/04/07/business/dealbook/pfizer-allergan-merger.html.

[3] Taylor, A. White House: $589M to go to fight Zika virus. Associated Press. Published April 6, 2016. http://hosted.ap.org/dynamic/stories/U/US_WHITE_HOUSE_ZIKA?SITE=AP&SECTION=HOME&TEMPLATE=DEFAULT.

[4] Nissen  SE, Stroes  E, Dent-Acosta  RE,  et al.  Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. Published online April 3, 2016. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2511043.

[5] Stroes  E, Colquhoun  D, Sullivan  D,  et al; GAUSS-2 Investigators.  Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-2548.

[6] Moriarty  PM, Thompson  PD, Cannon  CP,  et al; ODYSSEY ALTERNATIVE Investigators.  Efficacy and safety of alirocumab vs. ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-769.

[7] Peery AF, Dellon ES, Lund J et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 2012; 143: 1179-1187.

[8] Elmunzer BJ, Scheiman HM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. New England Journal of Medicine 2012; 366:1414-1422.  http://www.nejm.org/doi/full/10.1056/NEJMoa1111103

[9] Soutoudehmanesh R, Khatibian M, Kolahdoozan S, et al. Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. American Journal of Gastroenterology 2007;102:978-983.

[10] Murray B, Carter R, Imrie C, et al. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography. Gastroenterology 2003; 124: 1786-1791.

[11] KoshbatenM, Khorram H, Madad L, et al. Role of diclofenac in reducing post-endoscopic retrograde cholangiopancreatography pancreatitis. Journal of Gastroenterology and Hepatology 2008; 23:11-16.

[12] OtsukaT, Kawazoe S, Nakashita S, et al. Low dose rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized controlled trial. Journal of Gastroenterology 2012; 47: 912-917.

[13] Levenick JM, Gordon SR, Fadden LL et al. Rectal indomethacin does not prevent post-ERCP pancreatitis in consecutive patients. Gastroenterology 2016; 150:911-917.

[14] Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221-1231 http://www.nejm.org/doi/full/10.1056/NEJMoa1505241

[15] Yeh MW, Zhou H, Adams AL, Ituarte PH, Li N, Liu IA, et al. The Relationship of Parathyroidectomy and Bisphosphonates with Fracture Risk in Primary Hyperparathyroidism: An Observational Study. Ann Intern Med. Epub ahead of print 5 April 2016. http://annals.org.ezproxy.med.nyu.edu/article.aspx?articleid=2511009.

[16] Wu B, Haigh PI, Hwang R, Ituarte PH, Liu IL, Hahn TJ, et al. Underutilization of parathyroidectomy in elderly patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2010; 95:4324-30.

[17] Yeh MW, Wiseman JE, Ituarte PH, Pasternak JD, Hwang RS, Wu B, et al. Surgery for primary hyperparathyroidism: are the consensus guidelines being followed? Ann Surg. 2012; 255:1179-83.

[18] Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. Published online April 2, 2016. http://www.nejm.org.ezproxy.med.nyu.edu/doi/10.1056/NEJMoa1600176

[19] Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-1331.

[20] Ramakers GJ, Kraaijenga VC, Cattani G et al. Effectiveness of Earplugs in Preventing Recreational Noise–Induced Hearing Loss: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. Published online April 07, 2016. http://archotol.jamanetwork.com/article.aspx?articleid=2507069&utm_source=BHClistID&utm_medium=BulletinHealthCare&utm_term=040816&utm_content=MorningRounds&utm_campaign=BHCMessageID

 

Primecuts – This Week In The Journals

April 5, 2016

yogaBy Ajay Prakash, MD

Peer Reviewed

Another week, and the Republican Primary continues to provide significant political intrigue. Donald Trump’s national [1] and primary [2] poll numbers collapse in the wake of a disastrous town hall performance [3], largely based on his continuing inability to define his stances on any major issue. The fight between Clinton and Sanders becomes more heated as both celebrities [4], and the candidates themselves [5] have strong words about their respective campaigns. And, in a turn of events which almost no one could have predicted, a massive leak of information, both about a global bribery scandal [6], and the tax havens of the rich and famous [7], remind us of the growing inequality which these campaigns are attempting to address. At least things stayed fairly sane in the scientific world. On to our Primecuts!

New insulin drugs safe for your heart (we think)

Much attention has been paid to the concern that several glucose lowering drugs may increase the risk of heart failure, with the large-scale SAVOR TIMI 53 trial specifically showing an increased rate of heart failure hospitalizations in patients taking saxagliptin [8, 9]. A new, multicenter observational study demonstrates that these concerns may be allayed for at least the GLP-1 analogues and the DPP-4 inhibitors (incretin-based antidiabetic medications) [10]. The study included a total cohort of about 1.5 million patients from Canada, the US, and the UK. It tracked their use of all non-insulin antidiabetic medications and created cohorts of patients who were either taking or not-taking an incretin-based medication. These patients were subsequently case-controlled based on their admission for heart failure based on ICD coding. Using this methodology, there was no apparent increase in hospitalizations for those in the incretin cohort from those in the non-incretin cohort (hazard ratio 0.82; 95% CI 0.67-1.00). Subgroup analysis of the DDP-4 and GLP-1 compounds also showed no difference in heart failure rates, with hazard ratios of 0.84 (95% CI 0.69-1.02) and 0.95 (95% CI 0.83-1.10), respectively. This was even true when those with a prior history of heart failure were analyzed as a sub-group, with the incretins demonstrating a hazard ratio of 0.86 (95% CI 0.62-1.19). Though these data are promising, there are several limitations. The primary among these is that a pre-disposition for heart failure among incretin medications may be matched by a similar increase in heart failure for patients on thiazolidinediones or sulfonylureas used in the control group, which the authors note. However, the fact that sulfonylureas or thiazolidinediones are regularly used as second line anti-diabetic medications makes this comparison clinical meaningful. Secondarily, relying entirely on ICD codes for diagnosis may limit the clinical applicability of these data as not all heart failure admissions are the same. Broader use of these medications over the coming decades will ultimately reveal their limitations and may highlight risks that have not been described yet.

Treating heart failure with preserved ejection fraction (HFpEF) with extra holes in your heart

HFpEF is difficult to treat primarily because the pathophysiology is so poorly understood. Several etiologies have been propose but one fundamental mechanism appears to be a rise in left atrial pressure (LAP) during exertion, which leads to  pulmonary congestion. Hasenfub and colleagues posited that an intracardiac shunt from the left to right atrium may be effective in reducing LAP and thus reducing the symptoms of HFpEF [11]. These clinicians enrolled 68 patients, in which 64 had successful shunts placed, and followed the course of their disease for 6 months. The authors measured response in terms of heart failure symptoms, like subjective exercise tolerance, along with signs such as measure exercise testing, and PCWP as a surrogate for LAP. The patients had a notable decrease in their heart failure symptomology over that time, with the average NYHA class improving from III to II (p < 0.0001). In addition, the patients’ average exercise time increased after 6 months from 7.3 to 8.2 minutes (p = 0.0275). This could be attributed to a decrease in LAP as exercise-related PCWP was shown to be statistically lower over this time period (32 vs 29 mmHg). The major limitations of this study are the sample size, lack of controls, and invasive intervention.  It is difficult to generalize from 64 patients all selected for a clinical trial to the broader population of HFpEF patients who differ in ethnicity and comorbidities from the trial subjects. A lack of a control arm means that it is difficult to determine whether the changes observed here are better, or equivalent to those seen by HFpEF under usual therapy. The assertion by the authors that there is no effective usual therapy serves to mitigate, but not eliminate, this limitation. Finally, though the authors report no device-related or procedural complications, even catheter based cardiac procedures carry risk. A larger RCT, as proposed by the authors in the discussion, would address many of these concerns and presents a fascinating path forward in HFpEF treatment.

Hope on the Yoga Mat for Low Back Pain

Low back pain is another condition with poorly understood pathophysiology which likely conflates a whole host of organic pathologies into a single syndrome. Since each sufferer of low back pain experiences it in a unique way, it has been difficult to recommend universally useful non-pharmocologic methodologies for treatment. A new RCT from Cherkin and colleagues [12] suggests that mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT) may be effective in treating this condition. This study included 342 low back pain patients between ages 20 and 70, randomly assigned to MBSR vs CBT vs usual care. The usual care group lumped all other pharmacologic and non-pharmocologic (i.e. exercise interventions) into one large group. They were also given $50 with which to pursue any additional treatments they wished. The MBSR program did not focus specifically on back pain, but included instruction in all mindfulness practices. The CBT included education on harmful thoughts or behaviors and instruction on how to go about changing those thoughts. The patients were then evaluated for relief of symptoms by the Pain Bothersomeness Rating, and maintenance/gain of function after 6 months by the Roland Disability Questionnaire. Those who underwent MBSR or CBT showed a significant increase in relief of symptoms by the PSR (43.6%/44.9% vs 26.6% for usual care), and functional status by the RDQ (60.5%/57.7% vs 44.1%). Notably, there was no difference between the MBSR and CBT groups in outcome. Thus, it would appear that MBSR or CBT offer significant improvement over the usual care of exercise and education currently being offered low back pain patients. The primary limitations of this study are considerations over the durability of these findings, and the ability to generalize these findings to all patients. First, given the chronic nature of back pain, it is unclear whether the improvement seen in the 6-month follow-up in this study would persist over the course of the next 6 months, or even several years. The study does not address whether these patients would need to be enrolled in these therapies for the rest of their lives, or if they may need a new course every few years to maintain the benefits. Second, the authors acknowledge that the study participants were well educated and all selected from a single site, making it unclear if poorly educated patients would see similar improvements. Finally, it would be of interest to further analyze these findings to sub-categorize low back pain and determine whether these interventions are of additional benefit within certain sub-categories. It is conceivable, for example, that MBSR is more helpful with paraspinal low back pain vs CBT, or that the opposite might be true in sciatic low back pain. Overall, we should continue to explore non-pharmacologic interventions like these as an important alternative to chronic medication use in low back pain.

Antibiotics and Childhood Obesity

It is well understood that antibiotic over-prescription presents an ongoing clinical challenge for physicians. This issue is particularly important in pediatrics where the patient’s inability to describe their own symptoms, and their perceived, vulnerable status, often leads to defensive prescription practices. Childhood obesity is also on the rise leading to the hypothesis that childhood alterations in the gut microbiome may contribute to childhood obesity [13]. Gerber and colleagues performed a retrospective, longitudinal study of over 200,000 children in an attempt to analyze this possible phenomenon [14]. They defined cases as exposure to antibiotics within the first 6 or 24 months of life.  They chose this time period because it best mimics the age in animal models when microbiome alteration leads to obesity. They included any antibiotic exposure (oral, intramuscular, or intravenous), except if oral antibiotics were given for less than 3 days. The authors defined outcome was measured weight in the first 8 years of life. While antibiotic exposure by 6 months showed no significant change in weight (0.7%, 95% CI 0.1-1.5%), exposure within the first 24 months showed a weight gain of 2.1% (95% CI 0.8-3.3%). This amounts to about 150g of excess weight gain or an average total weight gain of ~7.34kg vs 7.19kg over the period studied. While these data are statistically significant for the 24 month exposure group, the authors agree that it does not represent a clinically significant change, and is likely an artifact of the large study population and the high power of the analysis. Interestingly, the authors performed a subgroup analysis of 46 twin sets discordant on antibiotic exposure and found that neither exposure window resulted in weight gain. Antibiotic exposure at 6 months showed an average weight change of -0.09kg (95% CI -0.26-0.08kg), while exposure at 24 months showed an average weight change of -0.11kg (95% CI -0.28-0.05kg). This study appears to demonstrates that antibiotic exposure does not significantly change weight gain over the first 8 years of life. However, the study does not address specific changes to the microbiome, which may still be affected by antibiotic exposure, and may miss effects which arise at different age ranges (adolescence, puberty, adulthood). Given the wealth of publication on this issue, it is likely to be an active area of investigation for some time.

In Other Medical News

In a meta-analysis of symptomatic carotid artery stenosis in elderly patients (age > 70), carotid endarterectomy was shown to be clearly superior to carotid artery stenting. Specifically CAS is associated with a morbidity hazard ratio of 2.09 when compared with CEA (95% CI 1.32-3.32) [15]. This risk was shown to be entirely attributable to the increased rate of stroke and death when compared to CAS.

The management of chronic symptoms related to Lyme disease is a difficult clinical quandary. Unfortunately, a recent RCT provided no clarity, showing that longer antibiotic treatment provided no benefit as measured by an SF-36 physical-component summary score [16].

And finally, another case report adds to the volume of observational data suggesting a correlational link between Zika virus and fetal neuropathology [17]. Interestingly, no microcephaly or calcification was present in this case, with the abnormalities instead being heterogeneous intracranial anatomic abnormalities of the grey/white matter and ventricular spaces. The brain also showed high levels of Zika viral RNA and viral particles, further suggesting a causational link between the virus and teratogenicity.

Dr. Ajay Prakash is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Matthew Dallos, MD, Chief Resident, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

  1. Sarlin, B. Donald Trump’s Poll Numbers Collapse as General Election Looms. 2016 [cited 2016 3/31]; Available from: http://www.nbcnews.com/politics/2016-election/donald-trump-s-poll-numbers-collapse-general-election-looms-n548731?cid=par-time_20160331.
  2. Enten, H. Wisconsin Could Be Trouble For Trump. 2016 [cited 2016 3/31]; Available from: https://fivethirtyeight.com/features/wisconsin-could-be-trouble-for-trump/.
  3. Bradner, E. Takeaways from the GOP town hall. 2016 [cited 2016 3/31]; Available from: http://www.cnn.com/2016/03/30/politics/republican-town-hall-takeaways/.
  4. All In With Chris Hayes – Extended interview with Susan Sarandon. [cited 2016 3/31]; Available from: http://www.msnbc.com/all-in/watch/extended-interview-with-susan-sarandon-653901891895.
  5. Kreutz, L. Hillary Clinton Tells Greenpeace Activist She’s ‘Sick of the Sanders Campaign Lying About Me’. 2016 [cited 2016 3/31]; Available from: http://abcnews.go.com/Politics/hillary-clinton-tells-greenpeace-activist-shes-sick-sanders/story?id=38068903.
  6. Nick McKenzie, R.B., Michael Bachelard, Daniel Quinlan. Unaoil: The Company that Bribed the World. 2016 [cited 2016 3/31]; Available from: http://www.theage.com.au/interactive/2016/the-bribe-factory/.
  7. Frederik Obermaier, B.O., Vanessa Wormer, Wolfgang Jaschensky. About the Pnama Papers. 2016 [cited 2016 4/3]; Available from: http://panamapapers.sueddeutsche.de/articles/56febff0a1bb8d3c3495adf4/.
  8. Udell, J.A., et al., Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol, 2015. 3(5): p. 356-66.
  9. Scirica, B.M., et al., Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation, 2014. 130(18): p. 1579-88.
  10. Filion, K.B., et al., A Multicenter Observational Study of Incretin-based Drugs and Heart Failure. N Engl J Med, 2016. 374(12): p. 1145-54.
  11. Hasenfuss, G., et al., A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet, 2016. 387(10025): p. 1298-304.
  12. Cherkin, D.C., et al., Effect of Mindfulness-Based Stress Reduction vs Cognitive Behavioral Therapy or Usual Care on Back Pain and Functional Limitations in Adults With Chronic Low Back Pain: A Randomized Clinical Trial. JAMA, 2016. 315(12): p. 1240-9.
  13. Cox, L.M. and M.J. Blaser, Antibiotics in early life and obesity. Nat Rev Endocrinol, 2015. 11(3): p. 182-90.
  14. Gerber, J.S., et al., Antibiotic Exposure During the First 6 Months of Life and Weight Gain During Childhood. JAMA, 2016. 315(12): p. 1258-65.
  15. Howard, G., et al., Association between age and risk of stroke or death from carotid endarterectomy and carotid stenting: a meta-analysis of pooled patient data from four randomised trials. Lancet, 2016. 387(10025): p. 1305-11.
  16. Berende, A., et al., Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med, 2016. 374(13): p. 1209-20.
  17. Driggers, R.W., et al., Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities. N Engl J Med, 2016.

 

Primecuts – This Week In The Journals

March 22, 2016

trump-hillary-clinton-pic-666By Vaughan Tuohy, MD

Peer Reviewed

This week saw the beginning of March Madness [1] with major upsets by 15-seed Middle Tennessee over 2-seed (and perennial contender) Michigan State, Hawaii over California, Stephen F. Austin over West Virginia, Little Rock over Purdue, and Yale over Baylor. Although in the 30+ years of the NCAA tournament, a 16-seed has yet to defeat a 1-seed, popular statistics wizard Nate Silver determined that the Middle Tennessee victory was perhaps the third biggest tournament upset of all time.  He also surmised that the 2016 Michigan State Spartans were the best team to ever lose in the first round.  In other news, Donald Trump continued his seemingly unstoppable march to the G.O.P. nomination on Tuesday with wins in Florida, Illinois, and North Carolina.  Marco Rubio dropped out of the race and John Kasich stayed in, although his victory in his home state of Ohio is his only win to date.  Mainstream Republicans are now gathering behind closed doors to try and figure out what to do about their Donald problem, while Democrats watch Hillary Clinton methodically dismantle the Sanders “revolution.”

Apart from the madness in basketball and politics, it was a pretty interesting week in medicine.

Stents or surgery for average risk patients with asymptomatic, severe carotid artery stenosis? [2]

Published this week in the New England Journal of Medicine, the Asymptomatic Carotid Trial (ACT I), a randomized non-inferiority trial of stenting with embolic protection versus carotid endarterectomy for asymptomatic carotid stenosis. A previous trial, CREST, for which ten-year follow up data was also published in this week’s NEJM, found no difference between stenting and surgery on stroke or major cardiovascular outcomes in patients with or without symptoms. The current ACT I trial randomized patients under 80 years of age with severe carotid artery stenosis (defined as 70 to 99% by ultrasound or angiography) without prior symptoms (e.g. prior ipsilateral stroke or transient ischemic attack) at “standard” surgical risk to carotid artery stenting with embolic protection versus carotid endarterectomy.  Study participants were excluded if they were considered “high risk” for surgical complications.  All patients were prescribed Aspirin following intervention; Clopidogrel was administered only in the stenting group for 30 days after revascularization.  The study was sponsored by Abbott Vascular, the stent manufacturers.  On the primary endpoint of death, stroke, or myocardial infarction within 30 days or ipsilateral stroke within one year, stenting was noninferior to endarterectomy (event rate of 3.8% vs. 3.4% for stenting vs. surgery; p=0.01 for noninferiority based on a prespecified 3-percentage point noninferiority margin).  There was a trend towards more minor strokes within 30 days in the stenting group (2.4% vs. 1.1% in stenting vs. surgery, p=0.2), but no difference in major strokes. On secondary outcomes of five-year freedom from ipsilateral stroke and stroke-free survival, there was no significant difference between the two treatment arms (97.8% vs. 97.3% for stenting vs. surgery, p=0.51; 93.1% vs. 94.7% for stenting vs. surgery, p=0.44, respectively).  The authors acknowledged that the lack of a medical therapy arm in the trial was a weakness because improvements in medical therapy have led to increasingly lower rates of stroke in this population.  Overall, while this study suggests that stenting is probably non-inferior to carotid endarterectomy for severe asymptomatic carotid stenosis, it does not settle the question of which of the three options (stenting, surgery, or medical therapy) is best.  Therefore, decisions will likely remain individualized.

Comprehensive molecular testing for community-acquired pneumonia? [3]

Diagnostic methods identify a causative pathogen in only 30-40% of cases of community-acquired pneumonia (CAP), making empiric antimicrobial therapy the most widely applied treatment strategy. This week, a study published in Clinical Infectious Diseases compared comprehensive molecular testing (quantitative PCR testing capable of identifying a wide range of bacterial and viral antigens within 24 hours) to standard culture testing.  In this study, lower respiratory tract specimens were gathered from 323 adults with CAP admitted to two hospitals in Scotland.  Study participants were included if they were admitted with symptoms and radiographic findings consistent with pneumonia and could produce a sputum specimen.  Patients with underlying bronchiectasis, cystic fibrosis, or meeting criteria for healthcare-associated pneumonia were excluded.  Comprehensive molecular testing identified a pathogen in 87% of cases as compared to 39% of cases when only standard culture-based methods were used.  Not surprisingly, the most commonly identified pathogens were H. Influenza and S. Pneumoniae.  Viruses were identified in 30% of cases, most (82%) co-detected with another bacterial pathogen.  While these are encouraging results, it remains to be seen whether comprehensive molecular testing can be used to tailor antimicrobial therapy in practice.

Financial incentives for exercise in overweight and obese adults? [4]

You may not want to exercise, but what if money were on the line? A randomized trial published in Annals of Internal Medicine this week studied three different financial incentive strategies aimed at encouraging physical activity.  Included were 281 employees with BMI greater than 27 at the University of Pennsylvania.  All participants were given a goal of achieving 7,000 steps per day.  Step counts were tracked using a smart phone application.  To be tracked, participants simply had to install the application and carry their phone.  Participants were randomized to one of three intervention groups or a control group.  All four groups received daily feedback about their 7,000-step goal for 26 weeks. The three intervention groups received one of the following during the first 13 weeks: 1) $1.40 for each day the goal was met; 2) $1.40 framed as a loss (taken from a monthly stipend each day the goal was not met); 3) a daily lottery with up to a $50 payout with an expected value of $1.40. The control group received only the daily feedback with no financial incentive.  The mean proportion of participant-days achieving the goal was 0.30 (95% CI: 0.22-0.37) in the control group, 0.35 (CI: 0.28-0.42) in the gain-incentive group, 0.36 (CI: 0.29-0.43) in the lottery group, and 0.45 (CI, 0.38-0.52) in the loss-incentive group.  Only the loss-incentive group had a significantly greater proportion of participant-days achieving the goal than controls.  If only Mayor Bloomberg was still around…

Closer to an Ebola cure? [5]

Two articles were published in Science this week on Ebola virus neutralization using human antibodies. The first described the structural and molecular basis for Ebola virus neutralization, and the second described a specific monoclonal antibody effective against the Ebola virus.  In the second article, [6]monoclonal antibodies were obtained from a survivor of the 1995 Kikwit Ebola outbreak.  The monoclonal antibody (mAb114) neutralized recent and previous outbreak variants of Ebola virus by mediating antibody-dependent cell-mediated cytotoxicity in vitro.  When given to macaques, monotherapy with mAb114 was protective against a lethal inoculum of Ebola virus as late as five days after exposure.  All macaques given the monoclonal antibodies within five days survived (n=7) and were symptom-free, whereas control macaques that did not receive the monoclonal antibodies (n=2) died from Ebola infection.  Later administrations of neutralizing monoclonal antibody were not studied.  Indeed, this raises hope that a cure for Ebola may one day be discovered.

Alcohol and cardiovascular events: short-term risks, long-term benefits? [7]

A systematic review was published this week in Circulation on the immediate risks of alcohol consumption on cardiovascular events. The review included 23 studies.  In the meta-analysis, they found that moderate alcohol consumption was associated with an immediately higher cardiovascular risk that attenuated over 24 hours and was generally protective within one week.  In contrast, heavy alcohol consumption was associated with higher cardiovascular risk within 24 hours and remained elevated after one week.  Overall, the study suggests that alcohol has a time-dependent effect on cardiovascular health.

Risk of recurrent MI in medically managed ACS? [8]

An article published this week in the Journal of the American College of Cardiology analyzed data from the TRILOGY ACS trial to characterize the risk of recurrent myocardial infarction in those who have unstable angina or NSTEMI that is medical managed (i.e. do not undergo revascularization). 10.7% had a recurrent myocardial infarction within 30 months.  The strongest predictors of recurrent MI were older age, NSTEMI rather than unstable angina, diabetes, and higher serum creatinine.  This information could be used help further risk stratify patients presenting with NSTEMI or unstable angina.

Neurologic consequences of chronic hyponatremia? [9]

This week in the Journal of the American Society of Nephrology, a new study challenged the notion that chronic hyponatremia is an asymptomatic condition. Recent studies have linked chronic hyponatremia to attention deficits, gait disturbances, fall risk, and cognitive impairment, but it is unclear to what extent this may be due to the underlying causes of low serum sodium (e.g. cirrhosis, heart failure).  Using an SIADH rat model, this study found that a sustained reduction in serum sodium was associated with multiple neurologic deficits (using special rat tests of gait disturbance, cognitive impairment, etc.).  In vivo analysis showed elevated extracellular glutamate concentrations in the hippocampus and decreased glutamate uptake by astrocytes in the chronically hyponatremic rats, suggesting a mechanism for the neurologic effects.  Furthermore, when the serum sodium was corrected, the neurologic performance of the hyponatremic rats improved and was equivalent to controls.  If this data applies to humans, perhaps careful correction of serum sodium could improve neurologic function and quality of life in patients with chronic hyponatremia.

Sleep apnea and cardiovascular risk in the ESRD population? [10]

Finally, a shout out for my own article published last month in BMC Nephrology.   Sleep-disordered breathing (e.g. obstructive sleep apnea) is a known contributor to cardiovascular disease and is highly prevalent in patients with ESRD, as 30-80% have sleep-disordered breathing when a sleep study is performed.  We sought to elucidate the association between sleep-disordered breathing and cardiovascular outcomes in the ESRD population.  We used Medicare claims data to identify >180,000 patients with ESRD age 67 or older.  When controlling for BMI and demographic factors only, sleep-disordered breathing was associated with slightly higher risks of death and atrial fibrillation, while no significant association was found with myocardial infarction or ischemic stroke.  In a larger model including multiple demographic, comorbidity, and laboratory variables, we found that sleep-disordered breathing was actually associated with slightly lower risks of death, myocardial infarction, and ischemic stroke.  The major limitations of our study were the exclusion of younger patients and the use of Medicare diagnosis codes to identify patients with sleep-disordered breathing.  Overall, our study suggests against any clinically significant association between sleep-disordered breathing and cardiovascular outcomes in patients with ESRD.  In fact, the diagnosis of sleep-disordered breathing carried a mildly protective effect in some instances making it perhaps another risk factor with paradoxical associations in the ESRD population.

Dr. Vaughan Tuohy is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Anish B. Parikh, MD, Chief Resident, Medicine, NYU Langone Medical Center

Image courtesy of eonline.com

References

 

1. Silver N.  Michigan State and The Biggest NCAA Tournament Upsets Ever.  fivethirtyeight.com.  March 18, 2016.

2. Rosenfield K et al.  Randomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis.  N Engl J Med. 2016 Mar 17;374(11):1011-20.  http://www.nejm.org/doi/full/10.1056/NEJMoa1515706?query=featured_home

3. Gadsby N et al.  Comprehensive Molecular Testing for Respiratory Pathogens in Community-Acquired Pneumonia. Clin Infect Dis. (2016).  62 (7): 817-823. http://www.mdlinx.com/infectious-disease/medical-news-article/2016/02/04/pneumonia/6488295/?category=focus-on&page_id=1

4. Patel M et al. Framing Financial Incentives to Increase Physical Activity Among Overweight and Obese Adults: A Randomized, Controlled Trial. Ann Intern Med. 2016;164(6):385-394.

5. Miasi J et. Al. Structural and molecular basis for Ebola virus neutralization by protective human antibodies.  Science. 18 Mar 2016: Vol. 351, Issue 6279, pp. 1343-1346.  http://science.sciencemag.org/content/351/6279/1343

6. Davide C et. Al.  Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science. 18 Mar 2016: Vol. 351, Issue 6279, pp. 1339-1342.

7. Mostofsky E et al.  Alcohol and Immediate Risk of Cardiovascular Events: A Systematic Review and Dose-Response Meta-Analysis.  Circulation. Published online before print March 2, 2016.  http://www.ncbi.nlm.nih.gov/pubmed/26936862

8. Lopes R et al.  Spontaneous MI After Non–ST-Segment Elevation Acute Coronary Syndrome Managed Without Revascularization.  J Am Coll Cardiol. 2016;67(11):1289-1297  http://m.amedeo.com/26988949

9. Fujisawa H et al.  Chronic Hyponatremia Causes Neurologic and Psychologic Impairments. JASN March 2016 vol. 27 no. 3 766-780  http://jasn.asnjournals.org/content/early/2015/09/16/ASN.2014121196.abstract

10. Tuohy CV et al.  Sleep disordered breathing and cardiovascular risk in older patients initiating dialysis in the United States: a retrospective observational study using medicare data.  BMC Nephrol. 2016; 17: 16.

 

Primecuts – This Week In The Journals

March 9, 2016

479px-Pink_tulip_flowerBy: Alexandra Price, MD

Peer Reviewed

This past Super Tuesday made clear that Donald Trump and Hilary Clinton are dominating the race to the White House, with both candidates winning a total of 7 out of 11 states. Ted Cruz is trailing behind Trump as the 2nd place Republican nominee, with 3 campaign wins in Alaska, Oklahama, and his home state of Texas. Marco Rubio is in 3rd place with his win in Minnesota. Dr. Ben Carson dropped out of the race after his Super Tuesday losses.1 And now onto some more clinically relevant news in this week’s Primecuts…

The association between Zika virus and Guillain-Barré Syndrome

With Zika virus rapidly spreading across the Americas, we are just beginning to understand the signs and symptoms of the disease. Interestingly, a closer look at one of the largest Zika virus outbreaks in French Polynesia between 2013-2014 revealed a concomitant rise in the incidence of Guillain-Barré syndrome (GBS).2 A case control study delved into further into this observation and found an association. Serologic evidence suggests that Zika virus can lead to GBS. In the study, 98% of patients with GBS had anti-Zika IgM or IgG antibodies, compared to 36% in the control group (OR 59.7, p<0.001). Moreover 100% of patients with GBS had neutralizing antibodies against Zika virus, compared to 56% in the control group (OR 34.1, p<0.0001). Most patients with GBS had a recent history of a viral syndrome, manifested most commonly by rash, arthralgia, and fever, a median of 6 days before the onset of neurological symptoms. 38% of patients were admitted to ICUs and 29% required respiratory support, but the clinical outcome was generally favorable. All patients survived and 3 months after discharge, 57% were able to walk without assistance. With the rising incident of Zika virus infections in America, clinicians should be aware of this association when approaching patients with viral illness or neurologic symptoms.

Use of procalcitonin level guided duration of antibiotic therapy offers mortality benefit in critically ill patients 

Antibiotic treatment, while saving so many lives from bacterial infections, when prolonged, has the potential to lead to antimicrobial resistance and adverse outcomes. As of now, there are no specific markers to guide length of antibiotic therapy with most physicians relying on established guidelines or clinical gestalt. A groundbreaking multicenter, randomized, controlled trial showed the value of procalcitonin in guiding the duration of antibiotic therapy in critically ill patients.3 Patients were randomly assigned to receive antibiotic therapy by standard-of-care protocols versus a procalcitonin-guided protocol. In the procalcitonin-guided group, procalcitonin level was measured daily as close to study enrollement as possible. In this group it was advised to discontinue antibiotics if procalcitonin concentration had decreased by 80% or more of its peak value or to 0.5 μg/L or less. In the standard-of-care group, length of antibiotic therapy was determined by local antibiotic protocols. Patients in the procalcitonin-guided group had reduced duration of antibiotic therapy compared to the standard of care-group (p<0.0001). Importantly, this reduction in treatment duration in the procalcitonin-guided group was associated with a significant decrease in mortality, resulting in a 5% improvement in mortality at 28 days by intention-to-treat analysis. The mortality benefit at 28 days in the per-protocol analysis was even higher at 7%. The study also found a 7% decrease in mortality at 1 year in the procalcitonin-guided group. All of these results were statistically significant.

This study shows that procalcitonin can safely and effectively be used to guide antibiotic therapy in critically ill patients. The mortality difference seen with procalcitonin guidance may not be fully explained by antibiotic related adverse events. Instead, the mortality difference could also be from prompt recognition of other diagnosis afford by the use of procalcitonin levels.

Efficacy of Prevention Strategies for Contrast-Induced Nephropathy 

Iodine contrast has provided a major advancement in diagnostic imaging but comes at the risk of contrast-induced nephropathy (CIN). To date, several interventions have been postulated to reduce CIN with conflicting results. Finally, a systematic review and meta-analysis analyzed the relative effectiveness of various interventions.4 The study analyzed 54 randomized controlled trials (RCTs) on N-acetylcysteine, 19 RCTs on IV sodium bicarbonate, 7 RCTs on N-acetylcysteine vs sodium bicarbonate, 13 studies on statins, and 8 RCTs on ascorbic acid. The primary outcome was CIN, defined as an increase in serum creatinine levels of greater than 25% or 0.5 mg/dL within 3 days of receiving IV contrast. The greatest reduction in CIN was achieved with low-dose N-acetylcysteine in patients receiving low-osmolar contrast (RR, 0.69, CI 0.58 to 0.84) and with statins plus N-acetylcysteine (RR 0.52, CI, 0.29 to 0.93). While these findings were clinically important and statistically significant, the strength of evidence was low-to-moderate due to limitations in the quality of the studies and inconsistency in results. Other comparisons which were clinically important but not statistically significant included: sodium bicarbonate versus IV saline in patients receiving LOCM, statins plus IV saline versus IV saline, and ascorbic acid versus IV saline. Importantly, most studies involved patients receiving intra-arterial contrast, thereby making the results difficult to extrapolate to patients receiving intravenous contrast. 

Erythropoietin-Stimulating Agents Do Not Impact Health-Related Quality of Life 

Up until now it has been unclear whether providing erythropoietin-stimulating agents to patients with anemia of chronic kidney disease provides any benefit with regard to improving health-care related quality of life (HRQOL). A systematic review and meta-analysis tackled this question by analyzing data from 17 studies.5  In total, the studies involved 10,049 patients with chronic kidney disease (CKD). Twelve studies were in the nondialysis CKD population, 4 were in the dialysis population, and 1 was in a combined sample. The lower hemoglobin target ranged from 7.4 to 12 g/L, and the higher hemoglobin target ranged from 10.2 to 13.6 g/L. The primary measure was change in baseline and follow-up scores of HRQOL instruments, specifically the 36-item Short Form Health Survey (SF-26) and the Kidney Disease Questionnaire (KDQ). The patient follow up periods ranged from 8 weeks to 36 months. The systematic review found that randomization to a higher hemoglobin target resulted in no statistically or clinically significant differences in HRQOL. Current evidence suggests that treatment of anemia with erythropoietin-stimulating agents to higher hemoglobin targets leads to increased health care costs without improving quality of life and may even increase morbidity and mortality in patients with CKD.6,7

Other highlights from this week:

Computer-assisted stethoscopes that can both record and help to differentiate respiratory sounds (e.g. wheezes, crackles, rhonchi, rales) through data analysis algorithms are on the rise.8 Before we know it, these sounds will be uploaded and stored in patient charts on EMRs

A cohort study showed that women undergoing transcatheter aortic valve replacement had a lower mortality rate than men at 1 year, despite having more frequent postprocedural vascular and bleeding complications.9 Several plausible reasons were cited, including lower levels of cardiac fibrosis and more rapid LV remodeling in women.

A multicenter double-blind, randomized trial found oral prednisone and indomethacin had similar analgesic effectiveness among patients with acute gout, paving the way for oral corticosteroids to compete as a first-line treatment option.10

Dr. Alexandra Price is a medical intern at NYU Langone Medical Center

Peer reviewed by Ian Henderson, MD, 2nd year medicine resident at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References: 

  1. Ben Carson Suspends 2016 Campaign at CPAC. NBC News. March 4, 2016. http://www.nbcnews.com/politics/2016-election/ben-carson-suspends-2016-campaign-cpac-n532056
  2. Cao-Lormeau V-M, Blake A, Mons S, et al. Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. The Lancet.
  3. de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. The Lancet Infectious Diseases. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(16)00053-0/abstract
  4. Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann. Intern. Med. Feb 2 2016. http://annals.org/article.aspx?articleid=2484876
  5. Collister D, Komenda P, Hiebert B, et al. The Effect of Erythropoietin-Stimulating Agents on Health-Related Quality of Life in Anemia of Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann. Intern. Med. Feb 16 2016. http://annals.org/article.aspx?articleid=2491918
  6. Inrig JK, Barnhart HX, Reddan D, et al. Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. Am. J. Kidney Dis. Sep 2012;60(3):390-401.
  7. Lau JH, Gangji AS, Rabbat CG, Brimble KS. Impact of haemoglobin and erythropoietin dose changes on mortality: a secondary analysis of results from a randomized anaemia management trial. Nephrol. Dial. Transplant. Dec 2010;25(12):4002-4009.
  8. Ohshimo S, Sadamori T, Tanigawa K. Innovation in Analysis of Respiratory Sounds. Ann. Intern. Med. Feb 16 2016. http://annals.org/article.aspx?articleID=2491914
  9. Kodali S, Williams MR, Doshi D, et al. Sex-Specific Differences at Presentation and Outcomes Among Patients Undergoing Transcatheter Aortic Valve Replacement: A Cohort Study. Ann. Intern. Med. Feb 23 2016:377-384. http://annals.org/article.aspx?articleid=2494535
  10. Rainer TH, Cheng CH, Janssens HJ, et al. Oral Prednisolone in the Treatment of Acute Gout: A Pragmatic, Multicenter, Double-Blind, Randomized Trial. Ann. Intern. Med. Feb 23 2016.

 

 

Primecuts – This Week In The Journals

February 22, 2016

Antonin_Scalia_official_SCOTUS_portrait_cropBy Edson Carias, MD

Peer Reviewed

For politicos, the ongoing buzz for potential Supreme Court justice nominees following Justice Scalia’s sudden death last week keeps them in suspense [1].  For music lovers, the suspense was over after winners were announced at this year’s annual Grammy awards.  Lady Gaga paid tribute to David Bowie in grand style, while Kendrick Lamar gave a performance that many are still praising [2].  For movie buffs, awards season will continue with the 88th Annual Academy Awards next week.  Awards for important contributions also extend to medical literature, here at PrimeCuts.  This week, the PrimeCuts “nominees” are:

In patients with Diabetes Mellitus not complicated by renal disease, all anti-hypertensives are created equal

Conflicting guidelines regarding the choice of first line anti-hypertensive in diabetic patients have complicated management decisions. Based on historical data, certain guidelines recommend the use of renin angiotensin system (RAS) inhibitors, which include angiotensin converting-enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs), as first line agents [3]. However, the JNC8 and other European organizations recommend any class of antihypertensives in diabetic patients without renal disease [4,5].

A recently published meta-analysis may help in this decision-making [6].  A thorough database search of randomized controlled trials of RAS blocker effect on outcomes in diabetics yielded 19 randomized controlled trials (RCTs), enrolling 25,414 diabetics, with a follow-up totaling 95,910 patient years.  Most of these RCTs used an ACE-I over ARB and compared RAS inhibition against calcium channel blockers; the remainder compared outcomes against diuretics and β-blockers.  Only three trials enrolled patients with micro-albuminuria or proteinuria.  Outcomes included all-cause mortality, cardiovascular death, myocardial infarction (MI), angina, stroke, heart failure, and revascularization.  Using an intent-to-treat analysis, RAS inhibitors were associated with a similar risk in all outcomes when compared to other antihypertensives.  These findings held in subgroup analyses, with the exception of RAS inhibitors showing a significant reduction in the risk of heart failure compared to calcium channel blockers (0.70 [95% CI: 0.70-0.88]).  As the authors note, the jury is still out when it comes to the choice of first line agent in diabetic patients with renal impairment, as prior studies have defined “renal impairment” and controls differently.  All together, these findings lend credence to recent JNC 8 guidelines and support providers considering any antihypertensive agent as first line in diabetic patients, particularly those without renal impairment.

Targeted thermal vapor ablation for emphysema can improve lung function and quality of life

In patients with severe upper-lobe emphysema, lung volume reduction can result in improved lung function. Unfortunately, surgery carries a high morbidity which limits its widespread use.  Less invasive bronchoscopic interventions consisting of either coil or valve implantation are done at a lobar level and can result in superfluous reduction of less diseased lung in a heterogenous lobe.  Bronchoscopic vapor ablation, a therapy that uses heated water vapor to induce an inflammatory response leading to lung parenchyma scarring and lung volume reduction, is another area of research interest.  The authors of the STEP-UP trial have published 6 month follow up results in an effort to better evaluate selective, sequential vapor ablation as a treatment option.

In this multicenter, parallel-group, open-label, randomized controlled trial, 70 patients with a forced expiratory volume in 1 second (FEV1) between 20% and 45% of predicted were randomized in a 2:1 allocation to receive either two sub-lobar vapor ablation sessions or standard medical management [7]. Primary efficacy endpoints were change in FEV1 and scores on a COPD-specific version of the St. George’s Respiratory Questionnaire (SGRQ-C), a quality of life metric used in respiratory disease.  At 6 months, patients in the ablation group (n=41) showed a significant increase in FEV1 compared to those in the control group (n=23)(14.7% [95%CI: 7.8-21.5]; p<0.0001) as well as a reduction in SGRQ-C points (-9.7 [95%CI: -15.7 to -3.7]; p=0.0021). Overall complication rate from any serious respiratory adverse event was 36% in the treatment group, comprised mostly of Chronic Obstructive Pulmonary Disease (COPD) exacerbations or pneumonia.  As FEV1 can be severely reduced in patients with emphysema, these results show a marked benefit to vapor ablation.  Although several study exclusion criteria may limit the applicability of these results to a wider patient population, future research in segment-preserving vapor ablation therapy is promising.

Mailing nicotine patches improves tobacco cessation rates in adult smokers, even without behavioral support

Nicotine replacement therapy (NRT) is an effective aid in tobacco cessation. Interestingly, many studies evaluating NRT in smoking cessation have included some form of behavioral support [8].

A randomized clinical trial was designed to assess the efficacy of providing free NRT by mail without behavioral support [9].  Participants were recruited via a telephone survey which screened for adults who smoked 10 or more cigarettes per day and answered affirmatively to the question “If nicotine patches were offered for free, would you be interested in receiving them?”  A total of 1,000 participants were found to be eligible for the trial.  Of these, 500 were randomized to the experimental group which received a 5-week supply or NRT and 499 to the control group, which received only follow up, but no additional intervention.  Primary outcome was 30-day smoking cessation at 6 month follow up, evaluated by self-report and/or saliva sample.  Due to sample evaporation and incomplete sample return, only 50.9% of participants in both the treatment and control arm had usable saliva samples for biochemical verification of smoking cessation.  Participants in the treatment arm were more likely to have verified abstinence at 6 month follow up (2.8% vs 1.0%; odds ratio [OR], 2.85; 95% CI, 1.02-7.96; p=.046)..  Treatment group participants were also more likely to self-report abstinence at 6 months (7.6% vs. 3.0%; OR 2.65; 95% CI: 1.44-4.89; p=.002).  At 6 month follow up, the number needed to treat to achieve cessation was 56. Although the improvement in absolute numbers is small, the authors have shown a potentially cost-effective way to improve smoking cessation rates.

Caplacizumab, an anti-von Willenbrand factor immunoglobulin, reduces recovery time in acquired thrombotic thrombocytopenic purpura (TTP)

Acquired TTP occurs when auto-antibodies diminish ADAMTS13 activity, leading to uncleaved von Willebrand factor (vWF) multimers. These uncleaved multimers cause platelet aggregation and microvascular thrombosis, resulting in ischemia and end organ damage.  Although plasma exchange and immunosuppressive therapy improve outcomes, mortality rates remain as high as 10-20% [10]. The TITAN study introduces caplacizumab, an anti-vWF immunoglobulin which prevents platelet aggregation, as a future candidate for treatment of TTP [11].

In this single-blind, parallel-design, multicenter study, 36 patients with TTP were randomized to receive caplacizumab in addition to standard therapy (plasma exchange and immunosuppressants), while 39 patients were randomized to receive placebo (standard therapy). Six patients had undergone a plasma exchange session prior to enrollment. The primary endpoint was time to achieve a platelet count of 150,000 per mm3.  Secondary endpoints included exacerbations, relapse, and duration and volume of plasma exchange. For the 69 patients who had not undergone plasma exchange prior to enrollment, median time to achieving primary endpoint was decreased in the caplacizumab group compared to placebo (3.0 days [95% CI: 2.7-3.9] vs. 4.9 days [95% CI: 3.2-6.6]), representing a significantly reduced time to response (39% reduction; event rate ratio 2.20; 95% CI: 1.28-3.78; p=0.005). Results were similar for the six patients who underwent a plasma exchange session prior to enrollment (2.4 days [95% CI: 1.9-3.0] vs. 4.3 days [95% CI: 2.9-5.7]).  Analysis of secondary endpoints also showed mostly favorable results in the treatment group. Bleeding complications, mostly mild to moderate, were higher in the caplacizumab group, likely due to caplacizumab-induced inhibition of vWF (54% vs. 38%).  Future studies are necessary to evaluate caplacizumab’s effect on a larger patient population.  If reproducible, caplacizumab may change our approach to TTP treatment.

And in the supporting-role category, the nominees this week are:

The BEAT-HF randomized clinical trial questions the effectiveness of tele-monitoring in CHF patients after discharge in decreasing all-cause readmissions [12].

The tTrials showed a moderate benefit in sexual function and some benefit in mood with testosterone treatment in older men [13].

Results of the PUNCH CD Study show safety and durability of a microbiota suspension for the treatment of recurrent C. diff infections [14].

Dr.  Edson Carias, Internal Medicine, NYU Langone Medical Center

Peer reviewed by David Kudlowitz, MD, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons 

References:

  1. President Obama to “dig into” potential Supreme Court nominations this weekend. ABC News. Feb 19, 2016. http://abcnews.go.com/Politics/president-obama-dig-potential-scotus-nominations-weekend/story?id=37063998
  2. Kendrick Lamar sweeps rap field at Grammys; Taylor Swift wins best album. New York Times. Feb 15, 2016. http://www.nytimes.com/2016/02/16/arts/music/grammys.html?_r=0
  3. Weber MA, Schiffrin EL, White WB, Mann S, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J of Hypertension 2014; 32:1:3-15. http://journals.lww.com/jhypertension/Citation/2014/01000/Clinical_Practice_Guidelines_for_the_Management_of.2.aspx
  4. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-20. http://jama.jamanetwork.com/article.aspx?articleid=1791497
  5. Mancia G, Fagard R, Narkiewicz K, et al.  2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013;31:1281-357. http://journals.lww.com/jhypertension/Citation/2013/07000/2013_ESH_ESC_Guidelines_for_the_management_of.2.aspx
  6. Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ 2016;352:i438. http://www.bmj.com/content/352/bmj.i438
  7. Herth FJF, Valipour A, Shah PL, Eberhardt R, et al. Segmental volume reduction using thermal vapour ablation in patients with severe emphysema: 6-month results of the multicenter, parallel-group, open-label, randomized controlled STEP-UP trial. Lancet Respir Med. 2016 Feb [published online]. http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(16)00045-X/abstract
  8. Hughes JR, Shiffman S, Callas P, Zhang J. A meta-analysis of the efficacy of over-the-counter nicotine replacement. Tob Control 2003;12:1:21-27. http://Tobaccocontrol.bmj.com/content/12/1/2
  9. Cunningham JA, Kushnir V, Selby P, Tyndale RF, et al. Effect of mailing nicotine patches on tobacco cessation among adult smokers: a randomized clinical trial. JAMA Inter Med 2016;176:2:184-190. http://archinte.jamanetwork.com/article.aspx?articleid=2484297
  10. George JN. Corticosteroids and rituximab as adjunctive treatments for thrombotic thrombocytopenic purpura. Am J Hematol 2012;87:S88-91. http://onlinelibrary.wiley.com/doi/10.1002/ajh.23126/full
  11. Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016;374:511-522. http://www.nejm.org/doi/full/10.1056/NEJMoa1505533#t=article
  12. Ong MK, Romano PS, Edgington S, et al. Effectiveness of remote patient monitoring after discharge of hospitalized patients with heart failure: the better effectiveness after transition-heart failure (BEAT-HF) randomized clinical trial. JAMA Int Med. Published online Feb 08, 2016. http://archinte.jamanetwork.com/article.aspx?articleid=2488923
  13. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, et al. Effects of testosterone treatment in older men. N Eng J Med 2016;374:611-624. http://www.nejm.org/doi/full/10.1056/NEJMoa1506119
  14. Orenstein R, Dubberke E, Hardi R, Ray A, et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD study. Clin Infect Dis 2016;62:5:596-602. https://cid.oxfordjournals.org/content/62/5/596.full

 

Primecuts – This Week In The Journals

February 9, 2016

Rally_to_support_Planned_ParenthoodBy Nicole Van Groningen, MD

Peer Reviewed

Last week we watched Hillary Clinton become the democratic favorite in the Iowa caucus – only narrowly avoiding getting Bern’ed. On the GOP side, Rand Paul, Mike Huckabee and Rick Santorum pulled out of the Republican race and Donald Trump, who came in second to Ted Cruz, demanded a do-over [1]. The New England Journal of Medicine maintained political relevance this week with its release of a study examining the impact of Texas’ ban on Planned Parenthood services. Also in the journals this week, we learned about the surprising benefits of waiving certain resident duty-hours restrictions, the role of azithromycin in treating (some) people with chronic cough, and the lesser-known benefits of angiotensin receptor blockers.

The impact of Texas’ ban on planned parenthood 

Legislation aimed at excluding Planned Parenthood affiliated providers from participating in state-administered, federally funded family-planning programs is now in various stages of development in 17 states [2]. In 2013, Texas became the first state to enforce such a law. A study published this week examined claims data for all participants in the state-funded Texas Women’s Health Program to ascertain whether the exclusion of Planned Parenthood affiliates had an impact on the provision of contraception and rates of childbirth [3].

In the three months after the Planned Parenthood exclusion, there was a sharp decrease in claims for both long-acting reversible contraceptives (LARC), from 1042 to 672, and injectable contraceptives, from 6832 to 4708, corresponding with relative reductions of 35.5% and 31.1%, respectively. Counties that didn’t have Planned Parenthood services to begin with – serving as a “control” group in the study – showed no change in the provision of either of these contraceptive methods. The difference in the differences was statistically significant (p < 0.001), suggesting a drop in utilization of contraception related to the Planned Parenthood withdrawal. The study’s most stark finding, however, was that 18 months after the withdrawal of Planned Parenthood in counties where Planned Parenthood previously operated, the percentage of women on injectable contraception who underwent childbirth covered by Medicaid increased from 7% to 8.4%, a relative increase of 27.1%. Again, this difference, when compared to that of counties who did not previously offer Planned Parenthood services, was statistically significant.

The observational study is limited by its inability to show causality, lack of adjustment for other county-level changes, and absent data on women who paid out-of-pocket for contraception or used private insurance for childbirth. Still, its findings raise concern that Texas’ divorce from Planned Parenthood may have hurt low-income Texan women by decreasing access to contraception.

Duty hour restrictions make no difference in well-being of America surgical residents

Another NEJM article published this week argues against the benefit of ACGME duty hour restrictions imposed between 2003 and 2011. Although prior studies among surgical residents have failed to show a difference in patient post-operative outcomes in the post-duty hour restriction era, promoters of the hour restrictions maintain that resident well-being and fatigue are bolstered under the regulations [4]. The Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) trial challenged this idea [5]. Investigators randomly assigned 118 ACGME-accredited general surgery residency programs to a flexible-policy (intervention) group, in which no restrictions on shift lengths were imposed, or a standard-policy (control) group, which followed all current ACGME duty hour regulations.

The study’s primary patient-centered outcome, the rate of death or serious complications, didn’t differ between the groups (9.1% in flexible-policy group versus 9.0% in the standard-policy group, p = 0.92), confirming previous reports. However, the study’s surprising finding was that among the 4330 residents surveyed, there was no significant difference between the flexible-policy residents and the standard-policy residents in terms of the resident-centered primary outcomes, which included dissatisfaction with educational quality (11.0% versus 10.7% respectively, p=0.86) and overall well-being (14.9% and 12.0%, p=0.10). Fexible-policy residents were more satisfied with continuity of care and quality of hand-offs, were significantly less likely to leave during an operation, miss an operation, or hand off an active patient care issue. The study highlights residents’ dissatisfaction in transitions of care in standard duty-hours programs, and makes the novel point that residents without shift-length regulations do not experience decreased well-being or educational satisfaction. Still, the study’s lack of generalizability to other specialties limits any potential impact on duty-hour restrictions anytime soon.

Azithromycin Investigated in the Treatment-resistant cough  

Last week, Clinical Correlations reported on strategies to decrease antibiotic use in upper respiratory infections. Now, a study published in Chest questions the role of azithromycin in treating a common non-infectious respiratory condition, the treatment-resistant cough [6]. The study enrolled 54 patients with treatment-resistant cough, a condition occurring in patients with structurally normal lungs after common causes of chronic cough (asthma, GERD, and rhinitis) have been ruled out. Participants were randomly assigned to receive azithromycin (500mg for 3 days, followed by 250mg three times weekly for 8 weeks) or placebo.   The supposed benefit of the macrolide was its anti-neutrophil and anti-inflammatory effects, previously shown to be independent of its antimicrobial effect.[7]

After 4 weeks, the treatment group experienced a clinically and statistically significant improvement in symptoms as measured by the LCQ score, a self-reported quality of life measure in chronic cough (mean change 2.4 vs. 0.7, p=0.01). Among treatment-group patients there was a nearly 20% decrease in exhaled nitric oxide, indicating decreased airway inflammation (p = 0.01). But before prescribing azithromycin to all-comers with chronic cough, consider this: azithromycin’s therapeutic effect was driven almost entirely by the sub-group of patients with asthma. Of the 7 asthmatics included in the study, all had a response to azithromycin, with strikingly high improvements in LCS scores (mean improvement of 6.19, p = 0.01). Given that these patients had failed to improve with usual asthma care, the study invites further investigation of azithromycin’s role in the management of treatment-resistant cough in asthma.

ACE Inhibitors and Angiotensin Receptor Blockers provide similar benefit, in contrast to previous thought 

The benefit of a renin-angiotensin-aldosterone system blockade in improving outcomes in patients with CVD or multiple other cardiovascular risk factors has long been established. But the relative advantages of ACEIs and ARBs have been debated, with ACEIs historically winning out as first-line therapy.

A recent meta-analysis published in the Mayo Clinic Proceedings argues differently [8]. The study identified 106 randomized trials including a total of 254,301 patients without heart failure that compared either ACEIs or ARBs to placebo, ACEI or ARB to active controls, or head-to-head comparisons of ACEIs to ARBs. Compared to placebo, ACEIs conferred a significant reduction in all-cause mortality (RR 0.91; 95% CI 0.86-0.96), cardiovascular death (RR 0.85; 95% CI 0.79-0.92), and MI (RR 0.83; 95% CI 0.78-0.90) whereas ARBs did not. Still, the authors questioned whether ACEIs were truly superior. In a meta-regression analysis, they showed that the placebo event rate had a significant effect on the apparent efficacy of ACEIs and ARBs. The ARB trials, which were conducted around 10 years after the majority of ACEI trials, in an era where cardiovascular risk profiles were better optimized by other factors, had significantly lower placebo event rates, around 5%, compared to 10.5% for most ACEI trials. The authors therefore argue that the lower placebo event rate in the ARB trials is responsible for the apparent lack of efficacy in reducing all-cause and cardiovascular mortality. The authors further support this claim by a meta-analysis of head-to-head comparison trials between ACEIs and ARBs, which showed similar risk for all outcomes, including all-cause mortality and cardiovascular death, between ACEIs and ARBs. Importantly, these trials also found that ARBs were associated with a 28% lower rate of adverse events, such as hyperkalemia, (RR, 0.72, CI, 0.65-0.81) when compared to ACEIs. Great news for drug companies who manufacture ARBs.

Skimmed off the top of other journals: 

Fruits and vegetables may have an impact on body weight independent of their calorie content, according to a recent observational study of participants in the Nurse’s Health Study and the Health Professionals Follow-Up Study. Participants who consumed high levels flavonoids, found in blueberries, citrus fruits, green tea, and various other types of produce, self-reported significantly lower levels of weight gain over 4-year intervals than those who filled their plates with meat and potatoes [9].

The BMJ reported that a vaccine for the Zika virus could be in production by the end of 2016, marketed by Invovio Pharmaceuticals. Public health officials, however, doubt this bold prediction, and insist that the focus must remain on battling mosquitos. The Unites States and Brazil are reportedly “examining approaches that involve the release of genetically modified male mosquitos to interrupt reproduction [10].”

Proenkephalin (proENK) is a novel biomarker that may become beneficial in estimating prognosis in patients with heart failure. A 4-year single center prospective cohort study of 200 participants with heart failure found that those with higher proENK levels at the beginning of the study had a significantly increased rate of cardiovascular-related hospital admission or death at follow up (HR 3, 95% CI, 1.4-6.7) [11].

The CDC recommended that all sexually active women not on contraceptives abstain from alcohol in order to prevent fetal alcohol syndrome. Literal buzzkill [12].

 

Dr. Nicole Van Groningen is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Matthew Dallos, MD, chief resident, internal medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

  1. Donald Trump accuses Ted Cruz of Fraud in Iowa, calls for new election. CBS News. February 3, 2016. http://www.cbsnews.com/news/donald-trump-accuses-ted-cruz-of-fraud-in-iowa-calls-for-new-election/
  2. Medicaid family planning eligibility expansions. New York: Guttmacher Institute. January 2016. http://www.guttmacher.org/statecenter/spibs/spib_SMFPE.pdf
  3. Stevenson AJ, Flores-Vazquez IM, Allgeyer RL, Schenkkan PJD, Potter JE. Effect of Removal of Planned Parenthood from the Texas Women’s Health Program. N Engl J Med. 2016 Feb 2 [Epub ahead of print]. http://www.nejm.org/doi/full/10.1056/NEJMsa1511902#t=article
  4. Effects of resident duty hour reform on surgical and procedural patient safety indicators among hospitalized Veterans Health Administration and Medicare patients. Med Care. 2009; 47: 723-731.
  5. Billmoria KY, Chung JW, Hedges LV et al. National cluster-randomized trial of duty-hour flexibility in surgical training. N Engl J Med. 2016 Feb 2 [Epub ahead of print]. http://www.nejm.org/doi/full/10.1056/NEJMoa1515724#t=article
  6. Hodgson D, Anderson J, Reynolds C, et al. The Effects of Azithromycin In Treatment Resistant Cough: A Randomised, Double Blind, Placebo Controlled Trial. Chest. 2016 January [published online]. http://journal.publications.chestnet.org/article.aspx?articleid=2484869
  7. Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther. 2000 Jan; 292(1): 156-63. http://jpet.aspetjournals.org/content/292/1/156.long
  8. Bangalore S, Fakheri R, Toklu B, Ogedegbe G, Weintraub H, Messerli FH. Angiotensin-Converting Enzym Inhibiros or Angiotensin Receptor Blockers in Patients Without Heart Failure? Insights From 254,301 Patients From Randomized Trials. Mayo Clinic Proceedings. 2016; 91(1): 51-60. http://www.mayoclinicproceedings.org/article/S0025-6196(15)00856-3/fulltext
  9. Bertoia ML, Rimm EB, Mukamal KJ, et al. Dietary flavonoid intake and weight maintenance: three prospective cohorts of 124 086 US men and women followed for up to 24 years. BMJ. 2016; 352: i17. http://www.bmj.com/content/352/bmj.i17
  10. Dyer O. Zika vaccine could be in production by year’s end, says maker. BMJ. 2016; 352 :i630. http://www.bmj.com/content/352/bmj.i630
  11. Arbit B, Marston N, Shah K, et al. Prognostic Usefulness of Proenkephalin in Stable Ambulatory Patients with Heart Failure. American Journal of Cardiology. [Article in Press]. http://www.ajconline.org/article/S0002-9149(16)30164-3/abstract

12. Vital Signs: Alcohol and Pregnancy. The Centers for Disease Control and Prevention. February 2, 2016. http://www.cdc.gov/vitalsigns/fasd/