PrimeCuts

Primecuts – This Week In The Journals

December 8, 2016

Tobacco-free_zoneBy Robert Freilich, MD

Peer Reviewed

Levels of smoking have dropped to record lows in the United states. Per a NY Times article1, the CDC reports that smoking levels are down in Americans from 21% in 2005 to 15% in 2015. This represents a reduction of almost 9 million Americans who are smoking. Encouragingly, smoking declined the greatest among the youngest age groups. Fifteen percent is the lowest level since the US began recording levels of smoking 50 years ago. Moving from population changes leading to better health outcomes to medical research into future health improving interventions, here are this week’s Prime Cuts:

Patient Outcomes in Patients Receiving Palliative Care

Palliative care, a scary and difficult to understand consultation for patients, is defined as patient and family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering2. This past week in JAMA, Kavalieratos, et al. attempt to estimate the association of palliative care with patient Quality of Life (QoL), symptom burden and survival3. The authors performed systematic review of 23 palliative care randomized-controlled trials from 2008 to present and included 12,731 patients a meta-analysis. Each trial underwent an independent review by at least 2 investigators and assessed a risk of bias (high, low, or unclear) as part of the data stratification process.  Due to the variety of instruments used to evaluate QoL and symptom burden, pooled effects were summarized as Standard mean differences (SMDs).  The study was separated into 1-3 month follow-up and more longer term look at 4-6 month follow-up.  After adjusting for risk of bias, this study demonstrated that Palliative care was associated with improved patient QoL (SMD 0.20; 95% CI, 0.06 to 0.34), but not symptoms burden or survival (SMD −0.21; 95% CI, −0.42 to 0.00; HR 0.90; 95% CI, 0.69 to 1.17). This study suggests that palliative care services are only partially achieving their defined outcomes, specifically not providing adequate symptom relief. Given the significant variation in study designs, the associations found is this study are weak. Overall, the study shows that current palliative care services improve QoL all patients with severe or life-threatening illness, and can for some patients help address symptom burden and possibly extend survival.

Goals of Care Discussion in Advanced Dementia

Discussions of code status, health care proxy, and desired interventions, frequently called Goals of Care(GOC), are increasingly important in an aging American population. Despite this many patients do not have such conversations. In a JAMA Internal Medical article, Hanson, et al. performed a single-blind cluster randomized clinical4 trial focused at patients with advanced dementia and their family/caregivers with an intervention associated with Goals of Care (GOC).   Hanson et el. point out that from the CASCADE study only 38% of decision makers ever recalled any discussion about Goals of care.  This study compares a GOC intervention, comprising of a video discussion aid describing common GOC elements (end of life care, dementia information, treatment options… ect.) and a structured care plan meeting for family decision to and attention control.   Outcomes were measured at 3, 6, 9 months or death, which looked at quality of communication, concordance of GOCs with caregivers, and an Advanced Care Planning problem score.  In the study, 22 nursing homes participated and 302 Dyads (patient and family/caregivers) were enrolled in both arms of the study.  However, only 128 in the intervention group and 127 in the control group completed 9 month follow up with a total of 60 deaths combined groups completed the study. The study found that the intervention group had Family decision makers reported better quality of communications and better end-of-life communications.  Goal concordance at three months did not differ but after 9 months was better than control.  Ultimately, this study demonstrated that this brief GOC intervention improved end-of-life communications for nursing home residents with dementia and their family/caregivers.

Comparison of The Efficacy and Safety of a Novel P2Y12 Inhibitor with Current Therapy

P2Y12 inhibitors, a class of anti-platelet agents, play a major role in the management of atherothrombotic disease and have reduced the mortality of several forms of cardiovascular disease. Since there initial use numerous new, more potent P2Y12 inhibitors have been developed. Vaduganathan, et al. compare the ischemic and bleeding risks between a newer more potent P2Y12 inhibitor, Cangrelor, and Glycoprotien IIb/IIIa inhibitors (GPIs) plus Clopidogrel5. The author’s pool results from three previous phase III trials from “The Cangrelor vs. Standard Therapy to Achieve optimal Management of Platelet Inhibition program” the CHAMPION trials. Study subjects were >18 YO requiring PCI for Stable angina, non-ST elevation acute coronary syndrome (ACS).  Patients who had received either other P2Y12 inhibitor or abciximab within 5-7 days, or eptifibatide, tirofiban or fibrinolytic therapy within 12 hours were excluded.   A key aspect of this studies design was noting that the original CHAMPION trial had an imbalance between the two groups. For example, the Clopidogrel-GPI group was slightly younger and carried a lower comorbid disease (diabetes, PAD, or Heart failure) burden when compared with the Cangrelor group. To account for difference in baseline risk profile imbalances and other confounders, a propensity score (PS)-matched analysis was performed that found 1021 unique matched pairs to compare.  Overall, when using the PS-Matched analysis the study found  .  This contradicts previous results that showed there was higher risk of bleeding which the authors adjusted to remove any discrepancies in patient profiles.

PCSK9 Inhibitors for CVD Risk Reduction: A Genetic Approach

In NEJM this past week6, Ference, et al. demonstrates that inhibition of Proprotein convertase subtilisin–kexin type 9 (PCSK9), known to already lower LDL levels by ~50-60%, also reduces the risk of cardiovascular events or diabetes similar to Statins.  More importantly the authors sought to determine causality by performing a “Medelian randomization” approach at both the PCSK9 and 3-hydroxy-3-methyl-glutaryl–coenzyme A reductase (HMCR) genes. In short, Ference et al. constructed genetic scoring based which gene allele(s) were associated with lower LDL cholesterol levels, thus mimicking chemical inhibition of either the PCSK9 or HMGCR genes.  Primary cardiovascular outcomes were defined as the initial myocardial infarct (MI), death from coronary heart disease, stroke, and other vascular events.  Diabetes was determined by A1C levels and was defined as a primary safety outcome.  The study was performed on 62,240 case patients and 127,299 controls without such disease. Ference, et al demonstrated that the groups with either higher PCSK9 or HMGCR genetic scores had an 8.4% or 6.6 % respectively of lower risk of MI or death from coronary heart disease (OR, 0.92; 95% confidence interval [CI], 0.88 to 0.95/ OR 0.93; 95% CI, 0.90 to 0.97 respectively). Further, Ference, et al also demonstrate a dose–response analyses with either increasing PCSK9 or HMGCR scores were associated with a stepwise decrease in LDL cholesterol levels and a corresponding stepwise decrease in the risk of MI or death from coronary heart disease. Interestingly, increasing PCSK9 or HMGCR scores were associated with a 6.1% higher risk for diabetes, which the authors noted as appearing to be confined to persons with impaired fasting glucose. Overall, this study takes large steps at establishing causality between variations in either PCSK9 or HMGCR gene and LDL levels and cardiovascular events.

Mini Cuts

In a meta-analysis published in JAMA Internal Medicine7, the authors found existing interventions to reduce burnout in physicians were only associated with small benefits. The strongest evidence was found for organization-direction interventions.

This observational cohort study8 of more than 21,000 US adults aged 65 or older demonstrated a 2.8% reduction in the prevalence of Dementia from 2000 to 2012.

A study in JAMA Oncology9 showed a 33% increase in incidence in cancer when compared to 2005 levels. These estimates were made by applying the Global Burden of Disease methodology.

Dr. Robert Freilich is a 2nd year internal medicine resident at NYU Langone Medical Center

Peer reviewed by Ian Henderson, internal medicine resident, NYU Langone Medical Center and contributing editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

  1. Bakalar, Nicholas. (2016, December 5). A New Low for Cigarette Smoking. New York Times. http://www.nytimes.com/2016/12/05/health/cigarette-smoking-united-states.html?rref=collection%2Fsectioncollection%2Fhealth&action=click&contentCollection=health®ion=stream&module=stream_unit&version=latest&contentPlacement=1&pgtype=sectionfront

 

  1. Definition of Palliative Care. Center for Medicare and Medicaid Services. Federal Register 2008 – 73 FR 32204, June 5, 2008.

 

  1. Kavalieratos, D. PhD; et al. Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis. JAMA. 2016;316(20):2104-2114 http://jamanetwork.com/journals/jama/fullarticle/2585979
  2. Hanson LC, Zimmerman S, Song M, Lin F, Rosemond C, Carey TS, Mitchell SL. Effect of the Goals of Care Intervention for Advanced DementiaA Randomized Clinical Trial. JAMA Intern Med.Published online November 28, 2016. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2587643
  3. Vaduganathan M, Harrington RA, Stone GW, Deliargyris EN, Steg PG, Gibson CM, Hamm CW, Price MJ, Menozzi A, Prats J, Elkin S, Mahaffey KW, White HD, Bhatt DL. Evaluation of Ischemic and Bleeding Risks Associated With 2 Parenteral Antiplatelet Strategies Comparing Cangrelor With Glycoprotein IIb/IIIa InhibitorsAn Exploratory Analysis From the CHAMPION Trials. JAMA Cardiol.Published online November 30, 2016. http://jamanetwork.com/journals/jamacardiology/fullarticle/2589156
  4. Brian Ference, MD; et al. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med 2016; 375:2144-2153. http://www.nejm.org/doi/full/10.1056/NEJMoa1604304
  5. Panagioti M, Panagopoulou E, Bower P, Lewith G, Kontopantelis E, Chew-Graham C, Dawson S, van Marwijk H, Geraghty K, Esmail A. Controlled Interventions to Reduce Burnout in PhysiciansA Systematic Review and Meta-analysis. JAMA Intern Med.Published online December 05, 2016. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2588814

 

  1. Langa KM, Larson EB, Crimmins EM, Faul JD, Levine DA, Kabeto MU, Weir DR. A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012. JAMA Intern Med.Published online November 21, 2016. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2587084  
  2. Global Burden of Disease Cancer Collaboration. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol.Published online December 03, 2016. http://jamanetwork.com/journals/jamaoncology/fullarticle/2588797

 

Primecuts – This Week In The Journals

November 21, 2016

Hamilton_StarBy Maria Sunseri, MD

Peer Reviewed

This week we saw America’s favorite musical deliver an unscripted yet heartfelt message at the end of the performance to audience member Vice President-Elect Mike Pence. And while President-Elect Donald Trump rushed to Twitter to reprimand the Hamilton cast’s message as harassment, the Indiana governor and inadvertent Planned Parenthood donor (albeit in name only) had only good things to say about the hit Broadway show. And while Americans and the medical world continue to navigate the post-election fallout, the USPSTF released new recommendations on the use of statins for primary prevention, expanding upon the 2013 ACC/AHA guidelines in potentially surprising ways.

USPSTF Recommendation Statement – Use of Statins for Primary Prevention of Adult Cardiovascular Disease

Cardiovascular disease (CVD), including coronary artery disease and cerebrovascular disease, remains the leading cause of morbidity and mortality in the United States, potentially leading to one in three deaths in adults.1 HMG-CoA reductase inhibitors, the popular lipid-lowering drug class known as statins, have been shown to both reduce levels of total cholesterol and LDL-C while having additional benefits through anti-inflammatory effects and plaque stabilization. The current model of risk estimation for CVD and potential statin benefit is based in the Pooled Cohort Equations from the 2013 ACC/AHA guidelines, but some feel that this model may overestimate actual risk in validation cohorts. For this reason, the USPSTF guidelines seek to offer expanded recommendations based on lipid screening for adults aged 40 and older without history of clinical CVD.

Summary of recommendations for patients without history of CVD:

  1. For adults aged 40-75 with >/= 1 CVD risk factor and a calculated 10-year CVD event risk of >/= 10%, initiate low-to-moderate intensity statin (Grade B)
  2. For adults aged 40-75 with >/=1 CVD risk factor and calculated 10-year event risk of 7.5-10%, discuss with patient and selectively offer low-to-moderate dose statin (Grade C)
  3. For adults aged 76 and older with no history of CVD, there is insufficient evidence to recommend statin initiation for primary prevention.

For these purposes, risk factors for CVD include dyslipidemia (LDL-C >130mg/dL or HDL-C <40mg/dL), diabetes, hypertension, and smoking. The 10-year risk is calculated using the ACC/AHA Pooled Cohort Equations. Of note, the USPSTF statement points out that the 10-year risk assessment is heavily weighted by age, and so many adults aged 65-75 may meet the recommended treatment threshold without additional risk factors of dyslipidemia, hypertension, diabetes, or smoking. As no trial has evaluated statin benefit in this age group for patients without CVD risk factors, the USPSTF recommends using shared decision making to discuss the risks and benefits of initiating a statin inthis population. The task force also reported insufficient evidence to justify screening for dyslipidemia in adults below age 40. The statement also comments on use of high-dose statins for primary prevention, stating that the choice of intensity should be left to shared decision-making, given the limited data comparing benefit to harm when high-intensity statins are used in primary prevention populations.

Finally, many have questioned the utility of evaluating CVD risk factors in addition to using a risk calculator, and some have questioned why the USPSTF utilizes a different cutoff for treatment than the prior ACC/AHA guidelines. Until further research compares the two strategies, it will be left to individual providers and their patients to determine the best tool for starting statin therapy in primary prevention populations.

Comparing Risk of Hyperkalemia from Sacubitril/Valsartan Versus Enalapril

There have been numerous studies suggesting that mineralocorticoid receptor antagonists (MRAs) can reduce the risk of death or hospitalization for patients with symptomatic heart failure and reduced ejection fraction (HFrEF). Current guidelines therefore recommend adding an MRA for patients who remain symptomatic despite treatment with beta-blockers and inhibitors of the renin-angiotensin-aldosterone system (RAAS). Despite this, providers are often limited by the heightened risk of hyperkalemia when an MRA is combined with a RAAS inhibitor.

In this week’s JAMA, Desai et al revisit the PARADIGM-HF trial, in which treatment with the novel angiotensin receptor/neprolysin inhibitor (ARNI) sacubitril/valsartan was associated with reduced rates of death and hospitalization for heart failure patients when compared to enalapril. For this secondary analysis, Desai and colleagues specifically examined the risk of hyperkalemia among PARADIGM-HF patients treated with an MRA.2 The PARADIGM-HF trial was a randomized, double blind, prospective comparison of sacubitril/valsartan and enalapril among patients with NYHA class II-IV heart failure and a left ventricular ejection fraction of 40% or less. The addition of MRAs was left to the discretion of the investigators, but was encouraged if tolerated. In both groups, more patients were on an MRA at baseline when enrolled in the trial (2400 of 4212 patients assigned to enalapril (57%); 2271 of 4187 patients assigned to sacubitril/valsartan (54.2%)). Overall, the incidence of hyperkalemia (K > 5.5 mEq/L) and severe hyperkalemia (K > 6.0 mEq/L) were significantly higher among patients treated with an MRA (incidence of hyperkalemia: 10 vs 7.3 per 100 patient-years, HR 1.33; severe hyperkalemia: 2.7 vs 2.0 per 100 patient-years, HR 1.35). When compared between groups, rates of hyperkalemia were similar between patients assigned to sacubitril/valsartan and those assigned to enalapril. Severe hyperkalemia, however, was significantly more common in patients assigned to enalapril (3.1 vs 2.2 per 100 patient-years, HR 1.37). This increased risk of severe hyperkalemia remained significant when patients who initiated MRA therapy during the trial were included in the comparison. The authors suggest that based on these data, more patients could benefit by substituting sacubitril/valsartan for an ACE inhibitor or ARB. Limitations of this study include that randomization in PARADIGM-HF was not stratified by baseline MRA use, opening the door for potential confounding from baseline risk for hyperkalemia. Further, patients with chronic kidney disease were excluded, and rates of hyperkalemia in this study may underestimate those seen in clinical practice given the association between CKD and heart failure. That said, this new data about hyperkalemia is an important consideration for further research given the building evidence in support of novel therapy with ARNIs for patients with heart failure.

Reducing Albuminuria in Diabetic Nephropathy with Phosphodiesterase Inhibitors

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the Western world, and it affects one-third of all diabetic patients. Progression from nephropathy to ESRD is highest in patients with macroalbuminuria, and while therapy with ACE inhibitors or ARBs has been shown to reduce albuminuria and slow progression of renal disease, the residual degree of albuminuria still correlates with risk of progression to ESRD. Attempts have been made to mitigate this risk by combining ACE inhibitors or ARBs with a direct renin inhibitor (aliskiren in the ALTITUDE trial) or by combining treatment with both an ACE inhibitor and an ARB (NEPHRON-D trial). However, these trials were associated with worse patient outcomes, including hyperkalemia, strokes, and acute worsening of renal function.3

Scheele and colleagues studied the addition of phosphodiesterase inhibition in this week’s Journal of the American Society of Nephrology. Utilizing preclinical data that phosphodiesterase type 5 (PDE5) inhibition is renoprotective, the investigators conducted a multinational, multicenter, randomized, double-blind placebo-controlled trial to test the effects of a selective long-acting PDE5 inhibitor in subjects with type-2 diabetes and overt nephropathy already on ACE inhibitor or ARB therapy. The drug, known as PF-00489791, was found to significantly reduce albuminuria, with a 15.4% reduction from baseline in urinary albumin to creatinine ratio (UACR) at 12 weeks. This was compared to the placebo group who instead had a 0.4% increase in UACR over the same period. The trial had a major limitation in that sodium intake and excretion were not monitored during the trial. Further studies are required that include strict sodium monitoring, given the data that sodium intake reduction has meaningful impact on reducing albuminuria, and could act as a significant confounding factor if not controlled. That said, the significant improvement in albuminuria and minimal side-effect profile from long-acting PDE5 inhibitors offers a promising addition to the current standard of care in slowing progression to ESRD in diabetic nephropathy.

Evaluating Ustekinumab in Patients with Crohn’s Disease 

Crohn’s disease, a chronic inflammatory bowel disease, is commonly treated with glucocorticoids, immunosuppressants, tumor necrosis factor (TNF) antagonists, or integrin inhibitors. These medications have serious side effects including increased risk of infection and cancer. Ustekinumab, a monoclonal antibody to interleukin-12 and interleukin-23, has been used in treatment of psoriasis and psoriatic arthritis without increased risk of adverse events.4 In this week’s NEJM, Feagan et al presented a phase 3 trial investigating induction and maintenance therapy in patients with Crohn’s disease.

This trial consisted of two eight-week induction trials (UNITI-1 and UNITI-2) as well as one 44-week maintenance trial (IM-UNITI). These multicenter, multinational trials were double-blind and placebo-controlled. Patients in the induction trials were randomly assigned to placebo or ustekinumab; those who responded to the experimental drug were able to enroll in the maintenance trial, and were again randomized to placebo or ustekinumab therapy. In both UNITI-1 and UNITI-2, patients had significant improvement in symptoms at six weeks when treated with ustekinumab at either 130mg or 6mg per kilogram when compared to placebo (UNITI-1: 34.3%/33.7% vs 21.5% placebo; UNITI-2: 51.7%/55.5% vs 28.7% placebo). In each induction trial, both doses of ustekinumab were associated with greater reductions in C-reactive protein and fecal calprotectin than placebo. In IM-UNITI, there were significantly more patients in remission at week 44 receiving ustekinumab than placebo, regardless of drug dosing schedule (treatment every 8 weeks: 53.1% remission; treatment every 12 weeks: 48.8% remission; placebo: 35.9% remission). Rates of adverse events were similar between treatment and placebo groups. While this trial is limited by the subjective nature of the primary outcomes, the objective decrease in CRP and fecal calprotectin offer promise of reducing inflammation in patients with Crohn’s disease. More long-term data is needed to compare ustekinumab to the current standard of care, but this drug may be a promising alternative to those who cannot tolerate conventional therapy due to adverse drug effects.

Mini Cuts

A randomized, multicenter, double-blind, noninferiority trial (the PRECISION trial) investigated patients taking daily NSAIDs for arthritis pain in order to determine relative safety of the selective COX-2 inhibitor celecoxib. Investigators found that cardiovascular risk associated with celecoxib is not greater than that from the nonselective NSAIDs ibuprofen and naproxen. In fact, celecoxib was associated with fewer cardiovascular events than its nonselective counterparts.5

A single-center retrospective case-control study in Chest examined consecutive patients with nonventilated hospital-acquired pneumonia (NVHAP) and to investigate for causative pathogens. While the majority of cases were pathogen-negative (56.3%), respiratory viruses were identified in 24.1% of affected patients, as compared to gram-negative and gram-positive bacteria being identified in 14.4% and 11.5%, respectively.6

Investigators working with the National Drug Abuse Treatment Clinical Trials Network developed a new screening tool for commonly used substances that could easily fit into the primary care workflow. This tool, known as the Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) tool, was tested in a multisite study of five adult primary care clinics. The TAPS tool identified problematic tobacco use with a 93% sensitivity and 87% specificity, and problematic alcohol use with 74% sensitivity and 79% specificity.  For illicit and prescription drugs, sensitivity ranged from 82% for marijuana to 63% for seditives.7

Dr. Maria Sunseri is a resident at NYU Langone Medical Center

Peer reviewed by Dana Zalkin, 2nd year resident internal medicine at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

  1. US Preventive Services Task Force. Statin Use for the Primary Prevention of Cardiovascular Disease in AdultsUS Preventive Services Task Force Recommendation Statement. JAMA.2016;316(19):1997-2007. doi:10.1001/jama.2016.15450 http://jamanetwork.com/journals/jama/fullarticle/2584058
  2. Desai AS, Vardeny O, Claggett B, McMurray JJV, Packer M, Swedberg K, Rouleau JL, Zile MR, Lefkowitz M, Shi V, Solomon SD. Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With EnalaprilA Secondary Analysis of the PARADIGM-HF Trial. JAMA Cardiol.Published online November 14, 2016. doi:10.1001/jamacardio.2016.4733 http://jasn.asnjournals.org/content/27/11/3459.abstract
  3. Scheele W, Diamond S, Gale J, et al. Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy. J Am Soc Nephrol.2016;27(11):3459-3468. http://jasn.asnjournals.org/content/27/11/3459.abstract
  4. Feagan BG, Sandborn WJ, Gasnick C, et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med 2016; 375:1946-1960. November 17, 2016. DOI: 10.1056/NEJMoa1602773 http://www.nejm.org/doi/full/10.1056/NEJMoa1602773
  5. Nissen SE, Yeomans ND, Soloman DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for arthritis. N Engl J Med 2016 accessed November 13, 2016. DOI: 10.1056/NEJMoa1611593 http://www.nejm.org/doi/full/10.1056/NEJMoa1611593%20-%20t=article
  6. Micek ST, Chew B, Hampton N, Kollef MH. A Case-Control Study Assessing The Impact Of Nonventilated Hospital-Acquired Pneumonia On Patient Outcomes. Chest. 2016;150(5):1008-1014. doi:10.1016/j.chest.2016.04.009. http://journal.publications.chestnet.org/article.aspx?articleID=2518223
  7. McNeely J, Wu L, Subramaniam G, Sharma G, Cathers LA, Svikis D, et al. Performance of the Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS) Tool for Substance Use Screening in Primary Care Patients. Ann Intern Med. 2016;165:690-699. doi: 10.7326/M16-0317 http://annals.org/aim/article/2546703/performance-tobacco-alcohol-prescription-medication-other-substance-use-taps-tool

Primecuts – This Week In The Journals

November 15, 2016

hill trumpsBy Andrew ElDabh, MD

Peer Reviewed

This week finally concluded one of the more bizarre election seasons in American political history, as business magnate Donald Trump defeated heavy favorite Hillary Clinton in the 45th presidential election. The merging of reality television and the most powerful position in the

world wasn’t the only big news, as medical journals also had a “huge, tremendous” week that may have received a little less attention.

While many of us were awake and closely following the election coverage, some patients were intubated under deep sedation and will awaken to some surprising news. This brings us to the first article in this week’s Primecuts, which will discuss whether we should share the news of a Trump presidency to those folks at night or in the morning. 

Overnight Extubation and Outcomes in the ICU 

Because of the morbidity associated with mechanical ventilation, specifically pneumonia, weakness, and delirium, extubating ICU patients as soon as tolerated is beneficial. Usually this is done during the day when there is more staff and support present. In this week’s JAMA Internal Medicine, Gershengorn et al published a retrospective, cohort study that examined the relationship between overnight extubation and clinical outcomes.1

The study included adults (>18 years old) undergoing mechanical ventilation and were admitted to the ICU, but excluded patients with tracheostomies, had DNR orders, or died while intubated. The cohort consisted of 97,844 patients in 165 ICUs, 20.1% of whom underwent overnight extubation (defined as occurring between 7PM and 6:59 AM). They further divided the cohorts into 4518 matched pairs with mechanical ventilation duration of less than 12 hours and 5761 pairs with more than 12 hours. For the group that was ventilated for less than 12 hours, reintubation rates were similar for both day and nighttime extubations (5.6% vs 5.9%); however, mortality was higher in patients that underwent overnight extubation, both in the ICU (5.6% vs 4.6%, p=0.03) and in the hospital (8.3% vs 7.0%, p=0.01). A more dramatic difference was observed in the group that had more than 12 hours of mechanical ventilation. Reintubation was higher in the overnight extubation group (14.6% vs 12.4%, p <0.001), as was mortality in the ICU (11.2% vs 6.1%, p <0.001), and in the hospital (16.0% vs 11.1%, p <0.001).

This study was limited both by its retrospective design, which showed correlation but not causation, and also its lack of data on why the patient was extubated and why the time of extubation was chosen. While this makes it more difficult to risk stratify a specific patient, the results of the study should still be taken into consideration by clinicians when deciding whether to extubate an ICU patient during the day or at night.

Cranberry Capsules on Bacteriuria and Pyruia in Older Women 

Older women living in nursing homes frequently are affected by urinary tract infections. Because of a variety of risk factors such as incontinence and altered mentation, there has been consideration to treat bacteriuria in this population. Cranberry products are often thought to be a potential method for UTI prevention because of the active ingredient proanthocyanidin, which can inhibit the adherence of E. coli to uroepithelial cells. However, the data on this topic is far from conclusive.

In this week’s edition of JAMA, Juthani-Mehta et al continued to add to the research on cranberry prodcuts and urinary tract infections. They published a randomized, double-blind, placebo controlled efficacy trial to test the effect of oral cranberry capsules (total 72mg proanthocyanidins) on the presence of of bacteriuria and pyuria in 185 women over 65 in nursing homes.2 They excluded women who were not expected to be in the nursing home for at least one month and those that were on chronic antibiotics, undergoing dialysis, on warfarin, or had an indwelling catheter. For one year, each participant gave a clean catch urine sample looking for presence of bacteriuria and pyuria, which counted as a positive primary outcome. They found that there was no significant difference in bacteriuria and pyuria in the group that took the cranberry capsules versus the placebo group (29.1% vs 29.0%, OR 1.01, 95% CI 0.61-1.66).

They also looked at several secondary outcomes: symptomatic UTIs, hospitalizations, antibiotic administration for suspected UTI, and presence of multidrug resistant organisms. However, for each of these outcomes, there was no statistically significant difference between the two groups of the study.

The authors of this study concluded that cranberry capsules in this population are not effective in reducing the rates of bacteriuria and pyuria. The literature that has been published on the topic has been inconsistent. Therefore, it is difficult to say with any confidence that cranberry juice or capsules can significantly help older women who are especially susceptible to UTIs.

Azithromycin for Acute Asthma Exacerbations

When a patient presents with an acute asthma exacerbation, current recommendations are against giving antibiotics to treat them. However, there is often thought given to doing so, as asthmatics are more susceptible to bacterial infections. Johnston et al published a double-blind, placebo controlled clinical trial in this week’s JAMA Internal Medicine to determine whether the use of azithromycin (500 mg daily for three days), in addition to the standard of care, had any clinical benefit in adults with acute asthma exacerbations.3

The study included adult patients with a smoking history and documented history of asthma who presented with an acute asthma exacerbation requiring steroids. They excluded patients who received antibiotics within a month of enrollment, required ICU-level care, or had other substantial lung disease or decompensated CHF. The primary outcome measured was a symptom questionnaire, which assessed symptoms of wheezing, shortness of breath, and coughing, given at treatment initiation and 10 days later. These cards had scores from 0 (no symptoms) to 6 (severe symptoms). At presentation, the treatment group had a score of 4.14, and the placebo group had a score of 4.18. At the conclusion of treatment, patients in the treatment group reported a score of 2.09 and the placebo group a score of 2.2. This difference was found to not be statistically significant (difference of -0.166, 95% CI -0.670 to 0.337). When examining secondary outcomes, such as pulmonary function tests, they also found that there was no significant difference between the two treatment groups.

The authors noted that they had a large number of patients that were excluded from the study because they had already received antibiotics, despite current recommendations against it. This study reinforced this idea. In an age where antibiotic resistance continues to increase, it is prudent for clinicians to be discerning when making the decision to give antibiotics for asthma exacerbations unless there is convincing reason why a patient might benefit from them (such as patients who present with fever or productive sputum).

Semaglutide and Cardiovascular Outcomes in Type 2 Diabetes 

Semaglutide is a new GLP-1 analogue for the treatment of Type 2 Diabetes. It is administered subcutaneously once per week. As with any DM2 therapy, the goal is to reduce the risk of cardiovascular disease, which is the leading cause of morbidity and mortality in diabetics. In this weeks’s edition of the New England Journal of Medicine, Marso et al. published a randomized, double-blind, placebo-controlled clinical trial that assessed the noninferiority of semaglutide in terms of cardiovascular safety in type 2 diabetics.4

The trial included patients over age 50 with HgbA1c >7%, established cardiovascular disease, chronic heart failure, or chronic kidney disease stage 3 or higher. They also included patients over age 60 with at least one cardiovascular risk factor. Patients were excluded if they had been treated with a DDP-4 inhibitor within 30 days, a GLP-1 agonist or insulin other than basal or premixed within 90 days, had an acute coronary or cerebrovascular event within 90 days, or were on dialysis. 3297 patients were randomized to receive semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary outcome examined was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The composite hazard ratio of these three outcomes was 0.74 (95%CI 0.58-0.95, p<0.001). More specifically, the rate of nonfatal MI was lower in the semaglutide group (HR 0.74, 95% CI 0.51-1.08, p=0.12), as was the rate of nonfatal stroke (HR 0.61, 95% CI 0.38-0.99, p=0.04).

This study was a noninferiority study for preapproval by the FDA, so it was limited in its purpose and scope. However, this study is a step in the positive direction for a novel antihyperglycemic drug to come to market, and is something that should be on the radar of clinicians going forward.

MINI-CUTS:

Clostridium difficile infection is a significant cause of in-hospital morbidity, and one promising therapy is fecal microbiota transplantation (FMT).  This week in the Annals of Internal Medicine, Kelly et al published a randomized, controlled, double-blind trial that studied whether FMT with donor stool or the patient’s own stool was more efficacious in resolving the patient’s diarrhea. A higher proportion of patients who received donor stool had resolution of their diarrhea than in the group who received autologous transplant.5

Video laryngoscopes (VL) have a camera at the distal end of the blade to improve visualization during intubation; however, because of conflicting data and the need to train with multiple intubation devices, VL is not used frequently. Janez et al published a trial in this week’s Critical Care Medicine that showed that in ICU patients, there was no significant difference in intubation on first attempt, time to intubation, and in-hospital mortality when VL was used compared to direct laryngoscopy.6

Because of growing antibiotic resistance, the first-line therapy for treatment of H. pylori was re-evaluated by Liou et al in this week’s Lancet.7 Patients who tested positive for H. pylori were randomized to either receive concomitant therapy for 10 days, bismuth quadruple therapy for 10 days, or triple therapy for 14 days to determine which was most efficacious in the elimination of H. pylori. They found that bismuth quadruple therapy was preferable as the first-line treatment, as it had led to a statistically significant increase in eradication.

Dr. Andrew ElDabh is a 1st year resident at NYU Langone Medical Center. 

Peer reviewed by Dr. Amar Parikh, Contributing Editor, Clinical Correlations and 3rd-year resident at NYU Langone Medical Center. 

Image courtesy of cnn.com

References:

  1. Gershengorn HB et al. Association Between Overnight Extubation and Outcomes in the Intensive Care Unit. JAMA Intern Med 2016;178(11):1651-1660. http://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2547203
  2. Juthani-Mehta M et al. Effect of Cranberry Capsules on Bacteriuria Plus Pyuria Among Older Women in Nursing Homes: A Rrandomized Clinical Trial. JAMA 2016;316(18):1879-1887. http://jamanetwork.com/journals/jama/article-abstract/2576822
  3. Johnston SL et al. Azithromycin for Acute Exacerbations of Asthma: The AZALEA Randomized Clinical Trial. JAMA Intern Med 2016;176(11): 1630-1637. http://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2553295
  4. Marso SP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;37(19):1834-44. http://www.nejm.org/doi/full/10.1056/NEJMoa1607141
  5. Kelly CR et al. Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med. 2016;165(9):609-616. http://annals.org/aim/article/2545886/effect-fecal-microbiota-transplantation-recurrence-multiply-recurrent-clostridium-difficile-infection
  6. Janz DR, et al. Randomized Trial of Video Laryngoscopy for Endotracheal Intubation of Critically Ill Adults. Crit Care Med 2016; 44:1980-1987. http://journals.lww.com/ccmjournal/Abstract/2016/11000/Randomized_Trial_of_Video_Laryngoscopy_for.4.aspx
  7. Liou J1 et al. Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicenter, open-label, randomized trial. Lancet 2016;388:2355-65. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31409-X/fulltext

Primecuts – This Week In The Journals

November 7, 2016

Cubs_World_Series_Victory_Parade_(30146832074)By Nishan Bingham, MD

Peer Reviewed

This week, Ken Burns announced that he will have to remake his documentary series, Baseball, after the Chicago Cubs won the World Series for the first time in 108 years. While Wrigleyville reveled, health officials urged the remainder of Americans to avoid media through the final days of the presidential election in order to prevent unintentional Xanax overdoses. But to start off Primecuts, we revisit two familiar IM topics: PE and Syncope, after a new study showed the two may be more closely linked than previously thought… Enjoy!

Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope

Every year, thousands of patients are admitted to hospitals after experiencing a brief loss of consciousness due to cerebral hypoperfusion known as syncope. Determining the etiology of syncope relies heavily on patient history—were there prodromal symptoms, was the event associated with a change in position, etc. Similarly, pulmonary embolism (P.E.), remains a diagnostic challenge, with risk stratification tools marred by subjective components. However, although PE is a known cause of syncope, this life-threatening condition is not always considered high in the differential. A new cross-sectional study in the New England Journal of Medicine evaluated the prevalence of P.E. in patients admitted for syncope.

Out of nearly 2,400 patients at 11 different hospitals who presented with a first episode of syncope, 560 were deemed to warrant hospitalization, were not on anticoagulation, and agreed to participate in the study. A rule-out of P.E. was performed using both the modified Wells Criteria (score < 4 indicating low pre-test probability) and a D-dimer assay, followed by either computed tomography or ventilation-perfusion lung scanning for any patients with a high pre-test probability or positive D-dimer.

P.E. was diagnosed in 97 of the 560 patients hospitalized for syncope for a total prevalence of 17.3%. When the cause of syncope was unknown, the prevalence of P.E. was 25.4%; but when an alternative explanation was present, the prevalence was 12.7%. Interestingly, 24% of patients presenting with syncope found to have P.E. had no other signs or symptoms of PE(hypoxemia, tachypnea, tachycardia, unilateral edema, etc.) The authors note that P.E. likely causes syncope through abrupt obstruction of cardiac output; however, emboli may also induce arrhythmias as they pass through the heart en route to the pulmonary circulation, which can cause syncope. These results will hopefully encourage providers to consider P.E. in patients with syncope and prevent future missed diagnoses.

JAMA Clinical Guidelines Synopsis: Transfusion of Red Blood Cells

Millions of units of packed red blood cells are transfused annually (13 million in the U.S. alone in 2013). However, definitive guidelines regarding transfusion thresholds remain somewhat obscure. This may be attributable to relative risk/benefit differences among varying patient populations, in addition to the general scarcity and high cost of blood products. A new guideline developed by the UK National Clinical Guideline Centre and published in JAMA made recommendations based on meta-analysis of 34 randomized controlled transfusion trials involving 17,533 patients.

A multi-disciplinary guideline development group of healthcare workers, researchers, and lay persons was formed and vetted for conflicts of interest. The group analyzed the relative risks and benefits of a liberal transfusion strategy (defined as 8-10 g/dL) versus a conservative transfusion strategy (7-9 g/dL) in terms of 30-day mortality, new cardiac events, new infection, and hospital length of stay.

The group found no significant difference in terms of 30 day mortality, new cardiac events, new infection or length of stay between the two strategies. Unsurprisingly, the conservative transfusion strategy resulted in fewer units being transfused. The group’s recommendations echoed those of the American Association of Blood Banks, namely a conservative threshold of 7 g/dL for all patients without major hemorrhage or acute coronary syndrome. For the latter, they recommended a threshold of 8 g/dL. Setting individual thresholds for patients with transfusion-dependent chronic anemia was suggested. The authors hope to eliminate transfusions that provide no benefit to patients

Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass Grafting 

The first CABG was performed in 1960 in the Bronx. This surgery, which reduces mortality in patients with severe coronary disease, is traditionally performed with the use of a cardiopulmonary bypass circuit. However a growing number of surgeons are becoming proficient at CABG on beating hearts, or “off-pump CABG,” which eliminates the need to cross-clamp the aorta and may help conserve costs. A new study examined 5 year outcomes comparing on and off-pump CABG.

Data was collected from 4,752 patients in 19 countries who were randomized to either on-pump or off-pump CABG. The main outcome, analyzed previously at the 1 year mark, was a composite of death, myocardial infarction, new dialysis requirement, or repeat coronary revascularization. At one year, there was no significant difference in death, stroke, or myocardial infarction between the two groups. However there was a mild increase in repeat vascularization (PCI or CABG) in the off-pump group (hazard ratio 1.66; CI 0.95 to 2.89; p = 0.07).

The 5 year data showed no significant difference in death, stroke, MI, dialysis, or revascularization rates. A mild decrease in the 5 year incidence of diabetes was observed in the off-pump group (22.7% vs 26.1%; P=0.06). Neurocognitive outcome investigation was limited and requires further study. There was no significant difference in the financial cost of on-pump vs off-pump CABG; however, the authors note that hospitals keep the costs of CABG supplies confidential, limiting analysis. Reusable off-pump retractors could significantly boost savings compared to disposable bypass circuits and the need for a perfusionist. These results reflect a global trend toward less-invasive techniques, improved outcomes and contained costs that could allow millions of patients greater access to some of the most complicated treatments in the history of medicine.

Effect of Conscious Sedation vs General Anesthesia on Early Neurological Improvement Among Patients with Ischemic Stroke Undergoing Endovascular Thrombectomy

Thrombectomy for acute stroke can be performed under either conscious sedation or general anesthesia. Some studies have shown that general anesthesia may worsen neurological improvement, possibly due to treatment delay, ventilator complications, or hemodynamic instability. A randomized trial from Germany compared neurological improvement at 24 hours for patients with anterior strokes.

Patients at Heidelberg University Hospital presenting with occlusion of the internal carotid or MCA, and who had NIH Stroke Scale scores >10 and GCS scores > 8, were randomized to receive intubation with general anesthesia or conscious sedation. Primary outcome was NIH Stroke Score at 24 hours after endarterectomy. Long term independence (by modified Rankin Score) was a secondary outcome.

The mean difference in NIH Stroke Score at 24 hours after endarterectomy for the two groups was not significant; both groups showing similar degrees of improvement. The general anesthesia group had greater functional independence at 90 days (37% vs 18.2%; p=0.01); but these results were not consistent when Rankin score categories were adjusted. This study may assuage concerns over utilizing general anesthesia in anterior stroke patients.

Minicuts 

Thousands who ran in the NYC marathon on Sunday may be wondering about the amount of cardiovascular stress to which they are electively subjecting themselves. A new study in the Journal of Science and Medicine in Sport indicates that a run / walk strategy does not decrease cardiac stress in non-elite runners. However, runners that used a run / walk strategy finished with comparable times as those who ran the entire marathon and reported less muscle pain and fatigue.

A new injectable form of male birth control appears to be effective and reversible, according to a multicenter study published in the Journal of Clinical Endocrinology and Metabolism. The combination of long-acting progesterone and androgen, Norethisterone Enanthate (NET-EN) and Testosterone Undecanthoate (TU), given intramuscularly every eight weeks, had similar efficacy to female contraceptive methods by reversibly inhibiting spermatogenesis. Adverse events included increased mood swings, depression, and increased libido.

Although anesthetic agents have been in use since 1846, our understanding of their mechanisms remains vague at best. A new review article in Anesthesia & Analgesia provides an update on what functional MRI, multi-channel EEG, magnetoencephalography have been able to tell us about consciousness (or the lack thereof). The reviewers suggest that disruptions in connectivity networks of the lateral frontoparietal cortices, (areas of the brain which engage in “recurrent processing” to integrate information), result in a state of unresponsiveness. Notably, various agents may affect these networks through widely varying mechanisms.

Dantrolene is used to treat rare but life-threatening toxidromes such as neuroleptic malignant syndrome, malignant hyperthermia, and in some cases, refractory status epilepticus. Limited data exist on this drug’s safety profile, however a recent report from Clinical Psychopharmacology and Neuroscience indicates it may cause venous thromboembolism, when delivered intravenously. Ryanodine receptor blockade decreases intracellular calcium and reverses muscular rigidity, which could favor thrombogenesis.

Dr. Nishan Bingham is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Benjamin Milgrom, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

Prandoni P, Anthonie W.A., et al. Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope. N Engl J Med. 2016; 375:1524-1531 October 20, 2016. DOI: 10.1056/NEJMoa1602172  http://www.nejm.org/doi/full/10.1056/NEJMoa1602172

Lamy A, Devereaux P.J., et al. Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass Grafting. N Engl J Med 2016; October 23, 2016. DOI: 10.1056/NEJMoa1601564 http://www.nejm.org/doi/full/10.1056/NEJMoa1601564#t=article

Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994; 344:563-570  https://www.ncbi.nlm.nih.gov/pubmed/7914958

Alexandar J, Cifu A. Transfusion of Red Blood Cells. JAMA Oct. Published online October 12, 2016. DOI: 10.1001/jama.2016.12870. http://jamanetwork.com/journals/jama/fullarticle/2569054

Schonenberger S, et al. Effect of Conscious Sedation vs General Anesthesia on Early Neurological Improvement Among Patients with Ischemic Stroke Undergoing Endovascular ThrombectomyAMA. doi:10.1001/jama.2016.16623

Hottenrott K, Ludyga S, et al. Does a run/walk strategy decrease cardiac stress during a marathon in non-elite runners? Science and Medicine in Sport. 2016 Jan. 19 (1): 64-68.DOI: http://dx.doi.org/10.1016/j.jsams.2014.11.010. http://www.jsams.org/article/S1440-2440(14)00218-7/fulltext

Behre H, Zitzmann M, et al. Efficacy and Safety of an Injectable e Combination Hormonal Contraceptive for Men. J Clin Endocrinol Metab. 2016 Nov; 101: 2016-2141. doi: 10.1210/jc.2016-2141. http://press.endocrine.org/doi/pdf/10.1210/jc.2016-2141

Hudetz AG, Mashour GA. Disconnecting Consciousness: Is There a Common Anesthetic End Point? Anesth Analg. 2016 Nov; 123 (5): 1228-1240. PMID: 27331780

Chen PH, Lane HY, et al. Venous Thromboembolism Following Dantrolene Treatment for Neuroleptic Malignant Syndrome. Clin Psychopharmacol Neurosci. 2016 Nov 30;14(4):399-401. doi: 10.9758/cpn.2016.14.4.399.  https://www.ncbi.nlm.nih.gov/pubmed/27776396

Primecuts-This Week in the Journals

November 1, 2016

640px-Candy_Corn_AcresBy:  Aditya Sreenivasan, MD

For the Halloween edition of Primecuts, we resisted the temptation to follow the standard media trend and go exclusively with “spooky” or alarming articles. Though the subject of the dreaded Zika virus does come up below, we thought we’d start with some good news regarding improving outcomes for out-of-hospital arrest.

Increasing Access to AEDs and Improved Outcome for Out-of-Hospital Arrest 

The bad news is that survival rates for out of hospital arrest remain low – approximately 10% in industrialized countries. The good news is that studies show that with the increasing frequency of bystander CPR, the rate has increased over the last several years. But what about the contribution from publically available automated external defibrillators (AEDs)? The New England Journal attempted to answer this question with a study looking at survival rates for out of hospital arrest as the prevalence of AEDs increased in Japan.

Over the 9 years of the study (ending 2013), the number of AEDs publically available in Japan was estimated to have increased almost 40-fold (based on AED sales). Out of over 1 million out-of-hospital cardiac arrests, almost 200,000 were witnessed by bystanders. Because AEDs will only shock ventricular fibrillation, only the 43,000 events during which ventricular fibrillation was the initial recorded rhythm were included in the analysis. Interestingly, only 10% of these actually received defibrillation at all.

The primary outcome of favorable neurological outcome at 1 month was significantly increased in those who received defibrillation compared to the control group (adjusted odds-ratio 2.03). This result by itself is unsurprising, but it is encouraging that the rate of defibrillation for patients in v-fib arrest increased more than 16-fold over the course of the study. It appears that as we continue to promote CPR training and bystander use of AEDs, outcomes for out of hospital arrest will improve.

An Association Between Guillain-Barré Syndrome and Zika Virus

Zika virus has entered a rare pantheon of pop-culture viruses and has taken its place alongside “swine flu” and Ebola. These infections are household names, but still widely misunderstood by the general public. But while the flu has been around for literal centuries and Ebola for 40 years, we are still discovering new things about Zika virus all the time.

On October 20th, the New England Journal published an article describing a strong association between the Zika Virus and Guillain-Barré Syndrome in Colombia. Two prior studies in 2013 and 2014 described an outbreak of GBS that was temporally and spatially correlated to a Zika virus outbreak in French Polynesia. This NEJM study aimed to confirm this association by clinical and virologic data.

68 sequential cases of patients who met Brighton Criteria for GBS were included in the study. 66 of 68 had symptoms consistent with Zika virus infection 3-10 days before their diagnosis of GBS, and the remaining two were residents of a region with a known Zika virus outbreak. 40% of patients who were tested serologically had evidence of Zika virus infection in either their CSF, serum, or (most commonly) urine. As Zika spreads northward, this study is a reminder for U.S. physicians to remain aware of new literature on Zika and its related diseases, as we may have to incorporate it into our practice sooner than we hope.

A Brief Intervention for Obesity in the Primary Care Setting

The CDC reports that 30% of US adults are obese, based on data from 2014. It causes or is associated with many of the most common non-communicable diseases. This study, published last week in The Lancet, attempts to investigate an office-based intervention for physicians to encourage weight loss in their patients, similar to what already exists for smoking and alcohol consumption.

This randomized controlled trial looked at the effectiveness of two brief physician interventions and their effect on patient weight. Almost 8,500 adult patients were screened, and almost 3,000 met criteria for inclusion in the study (BMI > 30 kg/m2 and increased body fat percentage). 1882 of these patients were enrolled in the study and randomized to one of two 30-second interventions with their primary care physician. They were either referred to a weight management group (consisting of 12 1-hour sessions over 12 weeks) or briefly advised by their physician to lose weight.

The endpoint was weight loss after 12 months. Both groups lost weight: 2.43 kg in the weight management group and 1.04 kg in the advice group, but there was no statistical significance in the amount of weight loss between the two interventions. There was no difference in the way patients perceived the interventions either, with 81% saying their intervention was both appropriate and helpful. We can conclude that a brief intervention in obese patients encouraging weight loss is effective, it just probably does not matter exactly how it is done.

Reasonable Calcium Intake Does Not Increase Risk for Cardiovascular Disease

The role of calcium as an essential nutrient for bone health, vascular modulation, cell to cell signaling, and muscle contraction is well known. But calcium supplementation is poorly understood. Many studies, including meta-analyses on the study and subject level, have shown that calcium is linked to increased risk of cardiovascular disease. The Annals of Internal Medicine published a large meta-analysis looking at 4 randomized-controlled-trials and 27 observational studies to answer the question: does increase calcium intake increase the risk for cardiovascular disease?

The short answer is no. None of the RTCs that were investigated found any statistically significant difference in cardiovascular disease outcomes between calcium and placebo groups. It is important to note that two of the trials included vitamin D supplementation in their study, while the others did not. Perhaps more significant is the fact that cardiovascular disease events and mortality were a secondary outcome in all of these studies. These studies did not account for dietary intake of calcium either further decreasing our ability to make strong conclusions from this data.

Analysis of the observational studies showed similar results. There was no consistent dose-response curve shown between calcium intake and either cardiovascular mortality, stroke mortality, or stroke risk. None of the studies analyzed looked at calcium intake above 2-2.5 g/day (2 to 2.5 x times the daily value recommended by the NIH). For now it appears we can safely recommend calcium supplementation up to 2 g/day for patients who need it for bone health without worrying about causing cardiovascular disease.

Mini-Cuts:

JACC published a study this week investigating the safety and efficacy of endovascular repair of AAA dissections. The study followed 15 such repairs for a median of 6 years, noting 8 complications (ranging from atrophic kidney to temporary pericardial effusion), and requiring 4 re-interventions (from open surgery to PCI for cardiac ischemia). The study concludes that so far, endovascular intervention appears to be an acceptable alternative for those ineligible for direct surgical repair.

Is colonoscopy the best way to screen for colorectal cancer? Annals of Internal Medicine published a consensus statement promoting fecal immunochemical testing (FIT) as an equal, if not preferred method, for CRC screening. They cite the lack of controlled studies that show that colonoscopy reduces incidence or mortality from CRC, as well as the higher cost, rate of complication, and patient adherence compared to FIT as reasons for physicians to promote it as enthusiastically as screening colonoscopy.

We are taught in medical school that “every patient with PSC has IBD” but the frequency of the reverse association is not as well known. A study in Gastroenterology screened 322 IBD patients with magnetic resonance cholangiography and found that the incidence of PSC was three-times higher than the rate diagnosed by symptoms alone (7.5% compared to 2.2%). The importance of sub-clinical PSC is still unclear, but further research into this area may significantly impact the standard of care for IBD patients.

The BMJ published a meta-analysis investigating the relationship between fructose intake and gout. The only two studies that met their criteria were quite large, but they only looked at white health professionals and did not analyze the relationship between fructose and hyperuricemia. The investigators concluded there is a significant relationship between fructose intake and gout in this population, but the mechanisms are far from well understood.

Adity Sreenivasan  is a 1st year internal medicine resident at NYU Langone Medical Center

Peer reviewed by Kevin Hauck, MD, Associate Editor, Clinical Correlations

Picture of Candy Corn Acres at Disney’s California Adventure courtesy of Anna Fox/Wikimedia Commons

References

  1. Malta Hansen C, Kragholm K, Pearson DA, et al. Association of Bystander and First-Responder Intervention With Survival After Out-of-Hospital Cardiac Arrest in North Carolina, 2010-2013. JAMA. 2015 Jul 21;314(3):255-64. doi: 10.1001/jama.2015.7938. http://jamanetwork.com/journals/jama/fullarticle/2397833
  2. Wissenberg M, Lippert FK, Folke F, et al. Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest. JAMA. 2013 Oct 2;310(13):1377-84. doi: 10.1001/jama.2013.278483. http://jamanetwork.com/journals/jama/fullarticle/1745678
  3. Kitamura T, Kiyohara K, Sakai T, et al. Public-Access Defibrillation and Out-of-Hospital Cardiac Arrest in Japan. N Engl J Med. 2016 Oct 27;375(17):1649-1659. http://www.nejm.org/doi/full/10.1056/NEJMsa1600011#t=article
  4. Parra B, Lizarazo J, Jiménez-Arango JA, et al. Guillain–Barré Syndrome Associated with Zika Virus Infection in Colombia. N Engl J Med. 2016 Oct 20;375(16):1513-1523. Epub 2016 Oct 5. http://www.nejm.org/doi/full/10.1056/NEJMoa1605564#t=article
  5. Oehler E, Watrin L, Larre P, et al. Zika virus infection complicated by Guillain-Barre syndrome–case report, French Polynesia, December 2013. Euro Surveill. 2014 Mar 6;19(9). pii: 20720. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20720
  6. Cao-Lormeau VM, Blake A, Mons S et al. Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016 Apr 9;387(10027):1531-9. doi: 10.1016/S0140-6736(16)00562-6. Epub 2016 Mar 2. http://www.sciencedirect.com/science/article/pii/S0140673616005626
  7. Vriesendorp, FJ. Clinical features and diagnosis of Guillain-Barré syndrome in adults. Sep 2016. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-guillain-barre-syndrome-in-adults
  8. Nutrition, Physical Activity and Obesity Data, Trends and Maps web site. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (CDC), National Center for Chronic Disease Prevention and Health Promotion, Division of Nutrition, Physical Activity and Obesity, Atlanta, GA, 2015. http://www.cdc.gov/nccdphp/DNPAO/index.html.
  9. Aveyard P, Lewis A, Tearne S et al. Screening and brief intervention for obesity in primary care: a parallel, two-arm, randomised trial. Lancet. 2016 Oct 21. pii: S0140-6736(16)31893-1. doi: 10.1016/S0140-6736(16)31893-1. http://thelancet.com/journals/lancet/article/PIIS0140-6736(16)31893-1/fulltext
  10. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010 Jul 29;341:c3691. doi: 10.1136/bmj.c3691. http://www.bmj.com/content/341/bmj.c3691.long
  11. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011 Apr 19;342:d2040. doi: 10.1136/bmj.d2040. http://www.bmj.com/content/342/bmj.d2040.long
  12. Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium Intake and Cardiovascular Disease Risk: An Updated Systematic Review and Meta-analysis. Ann Intern Med. 2016 Oct 25. doi: 10.7326/M16-1165. http://annals.org/aim/article/2571713/calcium-intake-cardiovascular-disease-risk-updated-systematic-review-meta-analysis
  13. Calcium: Dietary Supplement Fact Sheet. NIH Office of Dietary Supplements. June 1, 2016. https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/#h2
  14. Li Z, Lu Q, Feng R, et al. Outcomes of Endovascular Repair of Ascending Aortic Dissection in Patients Unsuitable for Direct Surgical Repair. J Am Coll Cardiol. 2016 Nov 1;68(18):1944-1954. doi: 10.1016/j.jacc.2016.08.031. http://content.onlinejacc.org/article.aspx?articleID=2572321
  15. Weinberg Md DS, Barkun A, Turner BJ. Colorectal Cancer Screening in the United States: What Is the Best FIT? Ann Intern Med. 2016 Oct 25. doi: 10.7326/M16-2341. http://annals.org/aim/article/2571716/colorectal-cancer-screening-united-states-what-best-fit
  16. Lunder AK, Hov JR, Borthne A, et al. Prevalence of Sclerosing Cholangitis Detected by Magnetic Resonance Cholangiography in Patients With Long-term Inflammatory Bowel Disease. Gastroenterology. 2016 Oct;151(4):660-669.e4. doi: 10.1053/j.gastro.2016.06.021. Epub 2016 Jun 21. http://www.gastrojournal.org/article/S0016-5085(16)34678-9/fulltext
  17. Jamnik J, Rehman S, Blanco Mejia S, et al. Fructose intake and risk of gout and hyperuricemia: a systematic review and meta-analysis of prospective cohort studies. BMJ Open. 2016 Oct 3;6(10):e013191. doi: 10.1136/bmjopen-2016-013191. http://bmjopen.bmj.com/content/6/10/e013191.abstract

Primecuts – This Week In The Journals

October 25, 2016

depressionBy Danielle Brewington MD, MS

Peer Reviewed 

As October draws to a close, the presidential debates have wrapped up and most people are bracing until the end of the political season. Many of the revelations in politics this week have left the entire nation depressed, so first up for discussion this week is an article about how to predict if anti-depressants will work in patients presenting with MDD.

fMRI and History Predict Anti-Depressant Effectiveness1

Researchers have shown that the amygdala plays an important role in depression in animal and human models. There is also evidence that early life stress (ELS) can predict who is likely to develop depressive symptoms. ELS is also known to have an impact on the amygdala. While the reciprocal relationship between ELS and amygdala abnormalities and the role it plays in developing depression has been investigated, these factors have never been used to predict clinical outcomes in response to anti-depressant therapy. This week in Proceedings of the National Academy of Sciences, researchers evaluated the combined predictive capability of ELS and fMRI.

Neuro-imaging and ELS history was gathered on 70 patients who presented with Major Depressive Disorder. The patients were evaluated based on previous amygdala studies that focused on enhancement on fMRI to happy or fearful images. ELS history was used to categorize the patients into low, moderate, or high stress groups. The patients and their medication was followed until they achieved remission or the end of the study was reached.

The results demonstrated that combining fMRI data from happy and fearful responses along with ELS data was highly predictive of which patients would experience MDD remission on anti-depressant therapy with 89% sensitivity and 88% specificity. History gathering and fMRI are tools that are available to physicians and could be utilized by psychiatrists as well as those considering a referral to psychiatrists, since many primary care physicians are often first line responders for initial presentations of MDD.

Platelet transfusions in GI Bleeders on Dual Anti-platelet Therapy2

Anti-platelet therapy has had a tremendous impact on cardiac events in patient with heart disease. Gastrointestinal bleed (GIB) is a known potentially fatal side effect of mono and dual antiplatelet therapy. Since platelets are permanently inactivated by aspirin and clopidogrel, an option to combat this risk in a bleeding patient is platelet transfusion. While this is a good idea in theory, the outcomes of platelet infusions in this population have not previously been studied.

A new retrospective case-control study, in Clinical Gastroenterology and Hepatology, examined 204 patients admitted for GI bleed while on single or dual anti-platelet therapy. The intent of the study was to determine if platelets contributed the theoretical benefit in preventing rebleeds behind the American Society for Gastrointestinal Endoscopy recommendation. Importantly, the researchers also investigated obvious potential sequelae in this population including myocardial infarction (MI), mortality, length of stay, and major adverse cardiovascular events (MACE). Cases and controls were matched based on sex, age, and G.I. bleed location. Of note, all patients had to have a platelet count greater than 100,000 to rule out platelet infusion indicated for thrombocytopenia.

Their results showed that patients who received platelet transfusions had increased rebleeding rather than decreased, 14% in cases compared to 8% in controls. Predictably, thrombotic outcomes (MACE, MI) were increased after receiving platelets. Secondary to these issues, mortality and length of stay were also increased. The researchers unexpectedly found that deaths were more likely due to GIB rather than cardiac events, contrary to previously published data. While the researchers attempted to control for confounders, there is one important consideration. It appears that platelets were given to patients who presented with more severe initial GI bleeds, which may have put them at higher risk from the outset. Due to a lack of evidence of any benefit from platelet transfusions, the authors recommend a more conservative approach to patient presenting with GIB on anti-platelet therapy that includes early endoscopy with source control and PPIs as needed.

Clinical Importance of Short Episodes of Afib and Atach 3

Patients with implanted cardiac devices (ICDs or pacemakers) trigger their devices, causing them at a minimum to document electrical activity and at most deliver electricity to normalize the rhythm. Due to the high volume of data generated by these devices, researchers have previously boot-strapped the results by arbitrarily setting time limits to identify true arrhythmias (usually >5 min was deemed likely to be true arrhythmia). The issue with this method is the high-false positive rate in addition to lack of evaluation of clinical importance of events lasting less than the arbitrary minimum. A new study published in Circulation investigates this previously ignored set of events to determine their clinical importance.

The RATE researchers collected all device data for over 5000 patients in a prospective study over 2 years. Extensive demographic data and prospective clinical events were collected for all patients. All device ECG recordings were evaluated by physicians for a subset of patients including a 600 patient random sample in addition to selected “case-patients” (556 patients total who experienced symptomatic atrial arrhythmias, heart failure, stroke or TIA, syncope, and death.) and their matched controls (1112 total). Interestingly the researchers were not concerned with timing of captured atrial fibrillation or atrial tachycardia (AF/AT), but instead by the length of diagnosed arrhythmia on the device recording. As such, “short AF/AT” was on average 10-12 seconds and terminated within the recording strip, and “long AF/AT” had no time limit but was defined as unremitting past the end of the recording.

The end result was a comparison of groups with recorded AF/AT that was much shorter than previously studied groups. Interestingly the data showed that short AF/AT had no significant impact on adverse events, hospitalization for AF or heart failure, stroke, and all-cause mortality. Long AF/AT was associated with hospitalization for AF (OR 2.78, P=.032 in pacemaker group; OR 6.57, p=.0001 in ICD group), all adverse events (OR 1.65, p=.005 in pacemaker group), and all-cause mortality (OR 1.86, p=.009) but not with stroke or hospitalization for heart failure. Of note, 50% of patients in the random sample experienced at least one episode of AF/AT during the follow-up period, which was twice the rate that was expected based on Framingham study data. These results are especially useful to physicians practicing in hospitals that may be evaluating patients on telemetry for the first time. This study provides evidence that patients with short episodes of AF/AT are not a cause for concern. Furthermore, there is a lack of evidence that long AF/AT was associated with stroke in this population. This data calls into question the practice of placing all patients with AF/AT on anticoagulation. The greatest limitation of this study is the incomplete picture provided about the long AF/AT group. While it is clear that their episodes did not self-terminate within a single device recording, it is impossible to know the average length of their episodes and whether they cross the previously studied 5 minute threshold that has been shown to be associated with elevated risk. The most important conclusions from this study are about the short AF/AT group which are not at elevated risk for clinical events nor do they have an elevated risk of progressing to long AF/AT.

Neurostimulation for Central Sleep Apnea 4

Central sleep apnea, similar to obstructive sleep apnea, is associated with adverse cardiac outcomes, such as ischemia and arrythmias. There is little data for using continuous positive pressure therapy in central sleep apnea, which is most often associated with heart failure. Central sleep apnea is an independent condition that affects quality of life measures, but hasn’t been considered as a separate condition to treat. The researchers in a new Lancet article set out to evaluate an alternative therapy to reduce apneic episodes due to central sleep apnea in a randomized trial. 

In total, 151 patients were randomized to either a control or device group. All patients completed a sleep study and were required to have 20 apneic events per hour and less than 20% obstructive apneic index to participate. Neurostimulators were implanted in the device group and turned on after one month. The devices were designed to cause gradual diaphragm contraction, simulating normal breathing rather than hiccup-style gasps. The stimulators were automatically activated at a scheduled time each night when the patient was sleeping and in a reclined positioned, which was determined by sensors in the device.

The goal of the study was to evaluate the effectiveness of the device in achieving a 50% or greater reduction in apnea-hypopnic index (episodes per hour) at 6 months compared to initial polysomnography. In the device group, 51% of patients achieved a 50% or greater reduction in API compared to 11% in the control group. Patients also experienced significantly improved rates of oxygen desaturation, REM sleep, and daytime sleepiness. There was a 97% success rate of device placement on the first attempt with 91% experiencing no serious adverse events after 12 months. Since the device is implanted this therapy may be an option for central sleep apnea that is limited by adherence and discomfort.

Mini-cuts:

An egg a day may actually keep stroke away.5An analysis of studies between 1982 and 2014 of over 500,000 people showed eggs, commonly thought to be an unhealthy source of cholesterol, actually reduce stroke risk by 12% and have no impact on coronary heart disease. Congruently, recent guidelines have dropped recommendations to avoid dietary cholesterol and instead now focus on dietary fat.

If you’ve added a fitness tracker to your health regimen, the data says it probably isn’t helping.6

A 2 year randomized study of 470 young adults showed that a diet and exercise program plus electronic fitness trackers resulted in less weight loss than the diet and exercise program alone.

Thinking of extubating that PACU patient overnight, new data says it’s better to wait.7A study of over 97,000 intubated adults across 165 ICUs demonstrated that overnight extubations are associated with increased mortality and reintubation. Overnight extubation was more likely to be tried in patients admitted from the operating room or PACU.

Culture negative sepsis is on the rise and that’s bad news for patients.8 The rate of culture negative severe sepsis increased 28% (43.5% up from 33.9%) from 2000-2010. This diagnosis is an independent predictor of death with a 75% excess risk of death compared to culture positive severe sepsis.

Dr. Danielle Brewington is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Neha Jindal, internal medicine resident, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References 

  1. Goldstein-Piekarski AN, Korgaonkar MS, Green E, et al. Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants. Proceedings of the National Academy of Sciences. October 2016:201606671. doi:10.1073/pnas.1606671113.  http://www.pnas.org/content/113/42/11955
  2. Zakko L, Rustagi T, Douglas M, Laine L. No Benefit From Platelet Transfusion for Gastrointestinal Bleeding in Patients Taking Antiplatelet Agents. Clinical Gastroenterology and Hepatology. July 2016. doi:10.1016/j.cgh.2016.07.017.  http://www.sciencedirect.com/science/article/pii/S1542356516304384
  3. Swiryn S, Orlov MV, Benditt DG, et al. Clinical Implications of Brief Device-Detected Atrial Tachyarrhythmias in a Cardiac Rhythm Management Device Population: Results from the Registry of Atrial Tachycardia and Atrial Fibrillation Episodes. Circulation. 2016;134(16):1130-1140. doi:10.1161/CIRCULATIONAHA.115.020252.http://circ.ahajournals.org/content/134/16/1130
  4. Costanzo MR, Ponikowski P, Javaheri S, et al. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet. 2016;388(10048):974-982. doi:10.1016/S0140-6736(16)30961-8.  http://www.sciencedirect.com/science/article/pii/S0140673616309618
  5. Alexander DD, Miller PE, Vargas AJ. Meta-analysis of Egg Consumption and Risk of Coronary Heart Disease and Stroke. Journal of the …. 2016:1-13. doi:10.1080/07315724.2016.1152928. http://www.tandfonline.com/doi/abs/10.1080/07315724.2016.1152928
  6. Jakicic JM, Davis KK, Rogers RJ, et al. Effect of Wearable Technology Combined With a Lifestyle Intervention on Long-term Weight Loss. JAMA. 2016;316(11):1161. doi:10.1001/jama.2016.12858.  http://jamanetwork.com/journals/jama/fullarticle/2553448
  7. Gershengorn HB, Scales DC, Kramer A, Wunsch H. Association Between Overnight Extubations and Outcomes in the Intensive Care Unit. JAMA Internal Medicine. September 2016. doi:10.1001/jamainternmed.2016.5258. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2547203
  8. Gupta S, Sakhuja A, Kumar G, McGrath E, Nanchal RS, Kashani KB. Culture Negative Severe Sepsis – Nationwide Trends and Outcomes. Chest. September 2016. doi:10.1016/j.chest.2016.08.1460. http://www.sciencedirect.com/science/article/pii/S0012369216589569

 

 

Primecuts – This Week In The Journals

October 17, 2016

Bob_Dylan_June_23_1978By Jenna Conway, MD

Peer Reviewed 

With less than a month to Election Day, we learned this week what Donald Trump deems appropriate “locker room talk” about women, while several women came forward to accuse him of inappropriately touching them. Hillary Clinton continues to deal with email leaks, including thousands published on WikiLeaks that were hacked from her campaign manager’s inbox. Other notable events range from the death of the King of Thailand to Bob Dylan becoming the first songwriter to ever win the Nobel Prize in Literature.

This was also an important week in the journals with studies looking at quality of life after prostate cancer treatment, breast cancer overdiagnosis, supplement use among Americans, and post-stroke infection, among others. 

How do the different treatment options for prostate cancer affect function and quality of life?

Prostate cancer is the third most common type of cancer (after breast and lung) with approximately 1 in 7 men diagnosed with prostate cancer during their lifetime.1 Although prostate cancer is the second leading cause of death (after lung) in American men, the majority of men diagnosed with prostate cancer do not actually die from the disease, but rather with the disease.1 When considering treatment options, clinicians must account for the potential mortality from prostate cancer, the effectiveness of the treatment option in reducing mortality, and also the treatment’s impact on quality of life.

As covered previously in Primecuts on 9/19/2016, a New England Journal of Medicine (NEJM) study by Hamdy et al2 looked at 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. Although they found reduced disease progression and metastases for surgery and radiotherapy vs. monitoring, there was no significant difference in 10-year mortality among the three options.

Building on this study, another NEJM study by Donovan et al3 looked at patient-reported function and quality of life after treatment. Patients diagnosed with localized prostate cancer completed questionnaires before diagnosis, 6-12 months after randomization, and then annually that assessed function (urinary, bowel, and sexual) and effects on quality of life. Surgery had the greatest negative effect on urinary and sexual function at all time points (P<0.001), while radiotherapy had worse scores for bowel function at 6 months and more bloody stools from 2 years onward (P<0.001). Effects on quality of life mirrored the patient-reported changes in function.

These two NEJM studies reinforce the need to discuss with patients how the different treatment options for prostate cancer not only impact disease progression and mortality, but also function and quality of life. This data enables clinicians to speak more cogently with patients about the impact of the different treatment options. 

Does mammography screening result in overdiagnosis of breast cancer?

From prostate cancer we now transition to breast cancer screening. Breast cancer is the most common type of cancer and the leading cause of cancer-related deaths in women.1 As in prostate cancer, breast cancer screening can lead to overdiagnosis (i.e., cancer detected on screening that would not cause symptoms or lead to increased mortality). In turn, overdiagnosis can lead to invasive tests and unnecessary treatment, each with their own risks and long-term effects.

A NEJM by Welch et al4 looked at the effects of screening mammography on breast cancer diagnosis. While tumor size is now not as important as a tumor’s biological characteristics in breast cancer prognostics, screening mammography is based on tumor size rather than functional gene expression. Given that screening mammography detects small tumors before they are large enough to cause symptoms, the authors argue that effective screening should lead to greater detection of small tumors with less large tumors detected over time. Population-based data from the Surveillance, Epidemiology, and End Results (SEER) program (1975-2012) was used to calculate tumor-size distribution and size-specific incidence of breast cancer followed by a calculation of the size-specific cancer case fatality rate for the period before widespread screening (1975-1979) and a more recent period (2000-2002). The study found that screening mammography has allowed for greater detection of small tumors (from 36% to 68%) and less large tumors have been detected (from 64% to 32%). However, based on the authors assumptions and calculations of the amount of small tumors that would be expected to become large, it was shown that women were more likely to have breast cancer that was overdiagnosed than to have earlier detection of a small tumor destined to become large. As previously suggested,5,6 the authors also found that the reduction in breast cancer mortality from large tumors after initiation of screening mammography appears to be primarily from improved treatment rather than screening.

While the authors discuss the limitations of the study including their assumptions about underlying disease burden that cannot be verified, it does add to the existing literature6,7 that points towards a real problem of overdiagnosis of breast cancer secondary to mammography screening.

How many Americans use supplements?

Dietary supplements comprise various products ranging from vitamins, minerals, and botanicals to probiotics, protein powders, and fish oils.8 Numerous studies over the past two decades have failed to show a health benefit in association with supplements, some even demonstrating adverse effects. Thus it is clinically important to understand how many of our patients continue to use supplements.9

In a study published in JAMA this week, Kantor et al10 analyzed data from the National Health and Nutrition Examination Survey, a cross-sectional survey on 37,958 noninstitutionalized civilians living in the United States, in seven 2-year cycles (1999-2000 through 2011-2012). Overall supplement usage remained unchanged during the study period, with 52% reporting use in both the first and last cycle (difference 0.0%; 95% confidence interval [CI] −3.6% to 3.6%).

The proportion of respondents reporting use of four or more supplement products also did not change significantly, with 8.7% of respondents in 1999-2000 and 9.9% in 2011-2012 (difference 1.1%; 95% CI −0.8% to 3.0%). Use of multivitamins/multiminerals, defined as products containing at least 10 vitamins/minerals, fell from 37% to 31% (difference −5.7%; 95% CI −8.6% to −2.7%). A decrease was also found in the use of some individual vitamins and minerals, specifically vitamin C, vitamin E, and selenium; however, vitamin D supplementation increased from 5.1% to 19% (difference 14%; 95% CI 12% to 17%). Non-vitamin non-mineral supplements usage increased over the course of the study, with omega-3 fatty acid supplementation (primarily fish oil) rising almost sevenfold from 1.9% during 1999-2000 to 13% during 2011-2012 (difference 11%; 95% CI 9.4% to 13%). Various socio-demographic variables were associated with supplement use, including increased age, female sex, non-Hispanic white adults, and education level.

The study demonstrates that more than half of American adults continue to use nutritional supplements and their use remained stable between 1999-2012, while multivitamin use decreased slightly during the same period. Usage by our patients persists despite the evidence in randomized clinical trials that supplements and multivitamins provide no clear health benefit and that they may even result in adverse effects. This study serves as a good reminder to ensure that we are asking our patients about vitamin and supplement usage and counseling them appropriately.

Is post-stroke infection caused by translocation of gut bacteria?

Stroke is a leading cause of morbidity and mortality and the major cause of death after stroke is infection, most commonly bacterial pneumonia. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, Stanley et al in a Nature Medicine study11 found that the majority of the microorganisms detected in the patients who developed post-stroke infections comprised normal gut flora. Specifically, they found that in post-stroke patients with positive cultures (blood, urine, or sputum), more than 70% contained normal gut flora (Enterococcus spp., Escherichia coli and Morganella morganii). Using post-stroke mice, the authors demonstrated that post-stroke infection originated within the host endogenously rather than acquired from the environment exogenously and that the small intestine was the source of the bacteria forming the microbial community in the lungs of post-stroke mice. Finally, the authors also showed that stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. 

In conclusion, the authors demonstrate that stroke induces the activation of the sympathetic nervous system and triggers a series of events that increase gut permeability and impair host antibacterial and intestinal barriers to promote the translocation and dissemination of normal gut flora. Given current therapies do not address bacterial infection as a key modifiable issue in patients who have had a stroke, the identification of this novel mechanism for post-stroke infection may foster development of targeted therapies for stroke patients.

Mini-Cuts

A study published in the Lancet by Aldridge et al12 found that migrants to the UK from countries at high risk of tuberculosis (TB) and who were pre-screened for TB pose a negligible risk of transmission, despite being at increased risk of developing TB themselves. This increased risk of developing TB could potentially be prevented through treatment of those identified by the pre-entry screening program as having latent infection, which would continue the downward trend of TB incidence in the UK.

A systemic review and meta-analysis in the Annals of Internal Medicine by Bloomfield et al13 found that a Mediterranean diet with unrestricted fat intake may reduce incidence of cardiovascular events, breast cancer, and type 2 diabetes, however, it does not affect all-cause mortality relative to other diets.

Clostridium difficile (C difficile) infection is the number one cause of hospital-related diarrhea and a study in JAMA Internal Medicine by Freedberg et al14 showed that C difficile infection was increased in patients whose prior hospital bed occupants were treated with antibiotics, suggesting that antibiotics can directly affect risk for C difficile infection in patients who were not themselves treated with antibiotics.

Dr. Jenna Conway is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1 American Cancer Society: Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer Society (2016). http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/index

2 Hamdy, Freddie C., et al. “10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer.” New England Journal of Medicine (2016). http://www.nejm.org/doi/full/10.1056/NEJMoa1606220

3 Donovan, Jenny L., et al. “Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer.” New England Journal of Medicine (2016). http://www.nejm.org/doi/full/10.1056/NEJMoa1606221

4 Welch, H. G., et al. “Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness.” New England Journal of Medicine 375.15 (2016): 1438-47. Print. https://www.ncbi.nlm.nih.gov/labs/articles/27732805/

5 Kalager, Mette, et al. “Effect of screening mammography on breast-cancer mortality in Norway.” New England Journal of Medicine 363.13 (2010): 1203-1210.  http://www.nejm.org/doi/full/10.1056/NEJMoa1000727

6 Miller, Anthony B., et al. “Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial.” BMJ (2014): g366.

7 Bleyer, Archie, and H. Gilbert Welch. “Effect of three decades of screening mammography on breast-cancer incidence.” New England Journal of Medicine 367.21 (2012): 1998-2005. http://www.nejm.org/doi/full/10.1056/NEJMoa1206809

8 US Food and Drug Administration. “Dietary supplement health and education act of 1994.” December 1 (1995). https://ods.od.nih.gov/About/dshea_wording.aspx

9 Cohen, P. A. “The Supplement Paradox: Negligible Benefits, Robust Consumption.” Jama 316.14 (2016): 1453-54. Print.

10 Kantor, E. D., et al. “Trends in Dietary Supplement Use among Us Adults from 1999-2012.” Jama 316.14 (2016): 1464-74. Print. http://jamanetwork.com/journals/jama/fullarticle/2565748

11 Stanley, Dragana, et al. “Translocation and dissemination of commensal bacteria in post-stroke infection.” Nature Medicine (2016).

12 Aldridge, Robert W, et al. “Tuberculosis in migrants moving from high-incidence to low-incidence countries: a population-based cohort study of 519 955 migrants screened before entry to England, Wales, and Northern Ireland.” The Lancet (2016).

13 Bloomfield, Hanna E., et al. “Effects on Health Outcomes of a Mediterranean Diet With No Restriction on Fat Intake.” Annals of Internal Medicine 165.7 (2016): 491-500.  http://annals.org/article.aspx?articleid=2534409

14 Freedberg, D. E., et al. “Receipt of Antibiotics in Hospitalized Patients and Risk for Clostridium Difficile Infection in Subsequent Patients Who Occupy the Same Bed.” JAMA Intern Med (2016). Print.

Primecuts – This Week In The Journals

October 10, 2016

Pumpkin_Spice_Latte_SignBy Samir Bhalla, MD

Peer Reviewed

October is upon us, which typically is notable for cooler weather, pumpkin spice lattes and playoff baseball. The focus this year, however, is the upcoming presidential election. Last week, Governor Mike Pence and Senator Tim Kaine faced off in the Vice Presidential debate at Longwood University in Virginia. Kaine was on the offensive, frequently bringing up many of the highly contested ideals and proposals of Donald Trump, while Pence did his best to refute these points. Many polls including that from CNN1 and the Washington Post reported Pence winning this round of debating, giving the republican party rejuvenation. This past week has also been notable for many interesting articles in the journals.

Therapeutic Hypothermia for In-Hospital Cardiac Arrest

Targeted temperature management(TTM) or hypothermia(TH) protocol was initially studied in out-of-hospital cardiac arrest patients due to ventricular fibrillation, and was shown to improve post-arrest neurological outcomes. The benefit of TH or TTM in PEA/asystole arrests or in-hospital cardiac arrest is not as well studies. However, the 2010 ACLS guidelines recommend therapeutic hypothermia for all adult post-cardiac arrest patients.

This week in JAMA, Chan et al2 published the results of a retrospective cohort study comparing outcomes between patients with in-hospital cardiac arrest who received hypothermia therapy versus those who did not. Over 26,000 patients were eligible for the study, however, 1524 patients who received hypothermia treatment were matched to 3714 patients who did not. Interestingly, the patients who received hypothermia protocol were more likely to have acute myocardial infarction and ventricular fibrillation as etiologies of their arrest and were less likely to have signs of additional end-organ damage (shock, respiratory failure, renal insufficiency, acute CVA, etc.) compared to patients who were not cooled. 27.4% of patients that were cooled survived to discharge compared to 29.2% of patients who were not cooled. When stratified, there was a statistically significant decreased survival in patients with non-shockable rhythms who were cooled compared to those who were not (ARR -3.2%; [95%, CI -6.2% to -0.3%]). There was a non-significant difference in survival between the groups for shockable rhythms. The incidence of death within the first 24hours following arrest was lower in the cooled group (29.1 vs 45.0%, P<.001). Neurological status was assessed using the cerebral performance category scoring system (1 equaling little residual neurological deficits and 5 equaling brain death). Patients who did not receive therapeutic hypothermia were more likely to have a cerebral performance category score of 1 or 2 (indicating persistent function for ADLs or better) compared to patients that received TH.

The results of this retrospective study suggest that therapeutic hypothermia may have adverse effects on survival and neurological outcome following in-hospital cardiac arrests due to both shockable and non-shockable rhythms. Given the relative widespread use of hypothermia post-cardiac arrest, further randomized prospective clinical trials are warranted to further investigate the risk/benefit of hypothermia following in-hospital cardiac arrest.

Zika Virus and Guillen-Barre Syndrome

Zika virus was originally described in 1952 in Uganda, however this mosquito transmitted virus has dominated news headlines over the past two years as outbreaks have developed in South and Central Americas, and in the Caribbean. Most infected patients are asymptomatic and those with symptoms generally experience mild flu-like symptoms. However, the concern with Zika stems from its complications, namely its association with birth defects and Guillen-Barre Syndrome(GBS). Previously a quiescent disease, French Polynesia experienced the first reported outbreak of Zika Virus in 2013. Shortly thereafter, there was an increase in the number of cases of GBS reported in French Polynesia suggesting a link. As outbreaks have arisen in the western hemisphere, there have similarly been reports of increased cases of GBS.

This week, NEJM published an observational study investigating the association between Zika and GBS in Colombia3. 68 patients presenting to hospitals in Zika endemic regions of Colombia with clinical symptoms consistent with GBS based on the Brighton criteria were studied. Of these patients, 66 (97%) had symptoms consistent with recent acute Zika virus infection (fever, rash, headches, myalgias, arthralgias, conjunctivitis) in the preceding 4 weeks. 42 of the patients had testing for Zika virus infection via PCR and anti-flavirvirus immunoglobulins of blood, CSF and urine. Of these 42, 17 (40%) met criteria for definitive diagnosis Zika virus infection with positive PCR analysis for the virus. 32 of the 42 patients tested has positive IgG or IgM CSF or serum serologies suggesting exposure to the Zika virus. It is important to note that these patients also demonstrated negative Dengue virus serologies. This study provides virologic and serologic support for the association between Zika virus infection and GBS.

Can Aspirin help prevent ARDS?

ARDS is a clinical syndrome characterized by diffuse lung injury and acute hypoxic respiratory failure. The pathogenesis of ARDS is postulated to relate to an inflammatory surge that results in damage to the junction between alveoli and pulmonary capillaries resulting in pulmonary infiltration, ventilation/perfusion mismatch, and profound hypoxemia. More recently, there has been research looking into the role of platelet activation in promoting endothelial injury through production of leukotrienes, thromboxane and prostaglandins. Thus platelets have been a recent focus in the treatment of ARDS and sepsis. Small observational studies have suggested a possible benefit to antiplatelet therapy such as aspirin in ARDS. To this end, Kor et al4. published the results of a randomized double blind placebo controlled clinical trial in JAMA this week investigating the benefit of aspirin in prevention of ARDS.

The study utilized the Lung Injury Prediction Score5(LIPS) which in previous studies has been shown to reliably predict patients at high risk for developing ARDS. The LIPS incorporates hypoxia, tachypnea, and predisposing factors such as sepsis, shock, aspiration, trauma, toxic inhalations and drowning. 400 patients admitted with LIPS score >4 were randomized to receive aspirin (325mg loading dose followed by 81mg daily) or placebo.

10.3% of patients in the aspirin group developed ARDS while 8.7% of patients in the placebo group, a non-significant difference (OR 1.24, [92.6% CI, 0.67-2.31], P=.53). Additionally, there were no significant differences in death within 28 days, death by 1 year, rates of mechanical ventilation, ventilator free days or hospital length. Patients receiving aspirin had a higher incidence of bleeding events (5.6%) compared to placebo group (2.6%) but this difference was also not statistically significant. Thus, the findings of this study suggest that aspirin does not reduce the risk of development of ARDS in high risk patients.

The Health Effects of Electronic Cigarettes

The extensive adverse effects of cigarette smoking and increasing bans on the public cigarette use have led to the rising popularity of electronic cigarettes in recent years. Many current users of E-cigarettes are former non-smokers and young adults under the age of 18. E-cigarettes allow for inhalation of nicotine that is aerosolized by electrical heating of a solvent. This allows for nicotine inhalation like smoking a cigarette but without the additional toxic components found in traditional cigarettes. The increasing popularity and use of E-cigarettes has led to questions about their safety and side effects. This week, Dinakar and O’Connor published a review article6 in NEJM investigating the health effects of E-cigarettes.

Mass spectroscopy has shown that solvents and aerosols, like those in E-cigarettes, contain many toxic components. Diactyl and acetyl propionyl are two components found in flavored E-cigarettes that have been associated with respiratory disease. Many in vitro assays have shown cytotoxic effects when cells are exposed to extracts of e-cigarette solvent or aerosol. In vivo studies in mice have shown E-cigarette exposure increases oxidative stress, cytokine levels, and pulmonary inflammation. However, two studies showed that when compared to tobacco smoke, E-cigarette extracts have less cytotoxic effects.

With regards to E-cigarettes impact on health at a macro-level, there are several considerations. First are the effects relating directly to the e-cigarette device itself.  This week in NEJM, Brownson et al7. published a report of 15 patients who sustained burn and blast injuries from the E-cigarette directly. Second is the effect of nicotine directly on the human body. While highly addictive and associated with tachycardia and hypertension, no studies have documented long term adverse health effects of nicotine outside of the prenatal period. Prenatal maternal nicotine use is associated with cognitive and behavioral deficits in the child. Therefore nicotine use via any route is not recommended for pregnant women.

Thus, the authors conclude that it is difficult to generate a safety profile for E-cigarettes given the wide variety in formulations and limited current research. There is data to suggest that E-cigarettes are likely safer than conventional cigarettes, but they are still more harmful than no cigarette use. As such the authors suggest regulations to make E-cigarettes unavailable to children and initiatives to discourage use in non-smokers. The authors call for more research into the efficacy of E-cigarettes for smoking cessation before their use can be recommended.

MINI-CUTS:

Hospitals are routinely evaluated on the rates of mortality and complications post myocardial infarction. This week in NEJM, Bucholz et al., evaluated the results of the converse relationship8. Patients who were admitted with myocardial infarction to highly performing hospital centers had an increased 30 day and long term survival compared to patients admitted to low performing hospitals.

Physical therapy and patient mobilization in the ICU setting is often limited by mechanical ventilation and patient attachment to monitors and drips. This week in Science Direct9, Schaller et al. demonstrated the results of a multi-disciplinary goal oriented focus on patient mobilization with strict oversight in the surgical intensive care unit. The intervention led to increased patient mobility, decreased ICU length of stay and increased functional independence at discharge.

Presidential election on your mind? This week NEJM published10,11 a series of articles discussing democratic and republican views on health care reform, and how the presidential election may impact our health care structure.

Dr. Samir Bhalla 3rd year Internal Medicine Resident at NYU Langone Medical Center

Peer reviewed by Ian Henderson, MD, contributing editor, Clinical Correlations, 3rd year Internal Medicine Resident, NYU Langone Medical Center

Image courtesy of Wikimedia Commons 

Resources:

  1. 1. Agiesta, Jennifer. “Pence edges Kaine in VP debate instant poll.” CNN.com. CNN 5 October 2016. http://www.cnn.com/2016/10/05/politics/mike-pence-tim-kaine-vp-debate-poll/index.html
  2. Chan PS, Berg RA, Tang Y, Curtis LH, Spertus JA, for the American Heart Association’s Get With the Guidelines–Resuscitation Investigators. Association Between Therapeutic Hypothermia and Survival After In-Hospital Cardiac Arrest.JAMA.2016;316(13):1375-1382. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2565288
  3. Parra B, Lizarazo J, et al. Gullain-Barre Syndrome Associated with Zika Virus Infection in Colombia. N Engl J Med 2016. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1605564#t=article
  4. Kor DJ, Carter RE, Park PK, et al. Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial.JAMA.2016;315(22):2406-2414.  http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2522739
  5. Zachary M. Bauman, Marika Y. Gassner, Megan A. Coughlin, Meredith Mahan, and Jill Watras, “Lung Injury Prediction Score Is Useful in Predicting Acute Respiratory Distress Syndrome and Mortality in Surgical Critical Care Patients.”Critical Care Research and Practice. 2015. https://www.hindawi.com/journals/ccrp/2015/157408/
  6. Dinaker C, O’Connor GT. The Health Effects of Electronic Cigarettes. N Engl J Med 2016;372: 1372-1381. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMra1502466
  7. Brownson EG, Thompson CM, et al. Explosion Injuries from E-Cigarettes. N Engl J Med 2016; 375:1400-1402. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMc1608478?query=featured_home
  8. Bucholz, et al. Life Expectancy after Myocardial Infarction, According to Hospital Performance. N Engl J Med 2016; 375:1332-1342 http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1513223?query=featured_home
  9. Schaller, et al. Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial The Lancet, Volume 388, Issue 10052, 1–7 October 2016, Pages 1377–1388. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S0140673616316373
  10. Oberlander, Jonathan. From Obamacare to Hillarycare — Democrats’ Health Care Reform Agenda. N Engl J Med 2016; 375:1309-1311 http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMp1610712?query=featured_home
  11. Wilensky, Gail R.What Would a Republican Win Mean for Health Policy? N Engl J Med 2016; 375:1312-1313 http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMp1610716?query=featured_home 

 

Primecuts – This Week In The Journals

October 4, 2016

EhealthTree-2By Ian Henderson, MD

Peer Reviewed

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

The effect testosterone replacement therapy on the risk of venous thromboembolism

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

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

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

Primary prevention ICD implantation for non-ischemic cardiomyopathy

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

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

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

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

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

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

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

Short versus Long antibiotic course for treatment of CAP

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

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

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

Mini Cuts:

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

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

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

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

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

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

Image courtesy of Wikimedia Commons

References:

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

Primecuts – This Week In The Journals

September 26, 2016

Oh_these_Autumn_days___By Chio Yokose, M.D.

Peer Reviewed

This week, Keith L. Scott was shot to death by police in Charlotte, North Carolina while his wife recorded the scene. The footage was broadcast widely and re-ignited the intense discussion about race relations and law enforcement in America. While the police allege that he had a weapon and posed an imminent threat, his family members report that he was holding a book, not a gun, as he prepared to pick up a child from school. Along with many other details of the case, whether Mr. Scott possessed or brandished a weapon at officers remains unclear. Protests erupted in Charlotte, resulting in one fatality and injuries to protestors and law enforcement officers alike.

In medical-related news this week…

Effect of Wearable Technology Combined with a Lifestyle Intervention on Long-term Weight Loss: the IDEA Randomized Clinical Trial 

The obesity epidemic continues to pose a significant public health threat in the United States. This week in JAMA, the IDEA (Innovative Approaches to Diet, Exercise, and Activity) randomized clinical trial reports the effect of a technology-enhanced weight loss intervention over 24 months of follow-up [1].

The study enrolled 471 adult participants age 18-35 with BMI between 25-40 and randomized patients to a technology enhanced or a standardized behavioral intervention targeting weight loss. The study participants were predominantly female (71.1%) and white (77.2%). All participants received a standard behavioral weight loss intervention for 6 months. After 6 months, those in the standard intervention group initiated self-monitoring of diet and exercise while those in the enhanced intervention group were provided wearable technology to monitor physical activity and diet. The primary outcome was weight change at 24 months.

Interestingly, the standard intervention group achieved a 2.4 kilogram higher estimated mean weight loss at 24 months than those in the enhanced intervention group (95% CI 1.0-3.7, p=0.002) despite similar improvements in body composition, fitness, physical activity, and diet. While this study was unable to demonstrate a clear role of wearable technology for the initiation and maintenance of weight loss, the standardized behavioral intervention used in this program resulted in substantially more weight loss than previous reports and warrants further investigation.

Primary Care Screening and Treatment for Latent Tuberculosis Infection in Adults 

The US Preventive Services Task Force updated its 1996 recommendations regarding targeted screening and treatment of latent tuberculosis infection (LTBI) in the primary care setting. They issued a grade B recommendation in support of LTBI screening in populations at increased risk. A review of the available evidence used to inform the USPSTF in issuing this recommendation was published in JAMA [2].

The search included MEDLINE, Cochrane Library, and trial registries through August 2015 to yield English-language studies of LTBI screening, LTBI treatment with recommended pharmacotherapy, or accuracy of the tuberulin skin test (TST) or interferon-gamma release assays (IGRAs). 72 such studies were included in the review. The investigators identified no studies that evaluated benefits and harms of screening compared with no screening. The pooled estimates for sensitivity of the TST at both 5-mm and 10-mm induration thresholds were 0.79 (5-mm 95% CI 0.69-0.89, 10-mm 95% CI 0.71-0.87). The sensitivity of IGRAS ranged from 0.77-0.90. A randomized clinical trial of 24 weeks of isoniazid in more than 20,000 individuals without pulmonary fibrotic lesions and LTBI found a reduction in absolute risk of active TB at 5 years from 1.4% to 0.5% (RR 0.35, 95% CI 2.03-10.39) for 24 weeks of daily isoniazid compared to placebo. This translates to a number needed to treat of roughly 111. In comparison, the number needed to harm in regards to hepatotoxicity while on isoniazid is roughly 250. While this data may not persuade clinicians to screen all-comers in a primary care setting, it does support screening and treatment in those who have risk factors for LTBI.

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea 

Given the previously reported association between obstructive sleep apnea and cardiovascular events, particularly cerebrovascular events, CPAP has received attention as an additional therapeutic modality for secondary prevention of such events. The results of the SAVE (Sleep Apnea Cardiovascular Endpoints), designed to address this question, was recently reported in the New England Journal of Medicine [3].

In this randomized clinical trial, 2,717 eligible adults between 45-75 years of age with moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease were randomized to receive CPAP plus usual care or usual care alone. The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.

The study found that therapy with CPAP plus usual care did not prevent cardiovascular events in these patients after 3.7 years compared to usual care alone (17% in the CPAP group vs. 15.4% in the usual care group; hazard ratio with CPAP 1.10 (95% CI 0.91 to 1.32, p=0.34). Importantly, participants in the CPAP treatment group were adherent to an average of 3.3 hours on the CPAP machine at night, which is far fewer than what is generally considered to be adequate adherence to CPAP, therefore, it is unclear at this time if CPAP with optimal adherence has the potential to prevent cardiovascular events.

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors 

While factor Xa inhibitors have significantly simplified the lives of those that need long-term anticoagulation, one major drawback has been their lack of a clinically available reversal agent. Andexanet alfa is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy individuals. This week in the New England Journal of Medicine a multicenter, prospective, open-label, single-group study of the utility of andexanet in the setting of acute major bleeding [4] is reported.

This study included 67 patients with potentially life-threatening bleeds who had taken a dose of factor Xa inhibitor within 18 hours of presentation and who were not scheduled for emergent surgery within 12 hours of presentation. Participants were given a bolus of andexanet followed by a 2-hour infusion of the drug. As not all participants had baseline anti-Xa levels measured, the 47 patients who had had baseline anti-factor Xa activity levels of at least 75ng/mL were included in the efficacy analysis. 

After the bolus administration, median anti-factor Xa activity decreased by 89% (95% CI 58-94) in patients receiving rivaroxaban and by 93% (95% CI 87-94%) among patients receiving apixaban. 12 hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis based on predetermined criteria based on location of bleed (e.g. serial MRI in case of intracranial hemorrhage) (79%, 95% CI 64-89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up period, including 10 deaths (15%). This descriptive analysis demonstrated that an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors. Given the single-group nature of this study, additional randomized studies are needed to weigh the relative risk of thrombotic events after administration before it can be adopted for routine clinical use. 

Mini-Cuts: 

A troubling report of spreading antibiotic resistance in India was reported in Clinical Infectious Disease [5]. They found unexpectedly high rates of resistance to ceftazidime-avibactam in carbapenem-resistant Enterobacteriaceae bloodstream isolates in one institution in New Delhi.

As the Affordable Care Act has expanded insurance coverage to millions, secondary barriers to care, such as access to transportation, are gaining increasing attention. This JAMA article reflects on the role that companies such as Uber and Lyft, which have transformed personal transportation, may play in the changing landscape of medical transportation as well [6].

In patients with rheumatoid arthritis whose symptoms are inadequately controlled on a TNF inhibitor, switching to a non-TNF biologic may achieve better disease activity response than the trial of a second, different TNF inhibitor [7].

Dr. Chio Yokose is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Kerrilynn Carney, MD, NYU Internal Medicine Residency Program

at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References 

  1. Jakicic, J.M., et al., Effect of Wearable Technology Combined With a Lifestyle Intervention on Long-term Weight Loss: The IDEA Randomized Clinical Trial. JAMA, 2016. 316(11): p. 1161-1171. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2553448
  2. Kahwati, L.C., et al., Primary Care Screening and Treatment for Latent Tuberculosis Infection in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA, 2016. 316(9): p. 970-83. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2547761
  3. McEvoy, R.D., et al., CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med, 2016. 375(10): p. 919-31. http://www.nejm.org.ezproxy.med.nyu.edu/doi/10.1056/NEJMoa1606599
  4. Connolly, S.J., et al., Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med, 2016. 375(12): p. 1131-41. http://www.nejm.org.ezproxy.med.nyu.edu/doi/10.1056/NEJMoa1607887
  5. Aitken, S.L., et al., High Rates of Nonsusceptibility to Ceftazidime-avibactam and Identification of New Delhi Metallo-beta-lactamase Production in Enterobacteriaceae Bloodstream Infections at a Major Cancer Center. Clin Infect Dis, 2016. 63(7): p. 954-8. http://cid.oxfordjournals.org.ezproxy.med.nyu.edu/content/63/7/954
  6. Powers, B.W., S. Rinefort, and S.H. Jain, Nonemergency Medical Transportation: Delivering Care in the Era of Lyft and Uber. JAMA, 2016. 316(9): p. 921-2. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2547765
  7. Gottenberg, J.E., et al., Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial. JAMA, 2016. 316(11): p. 1172-1180. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2553449

 

 

Primecuts – This Week In The Journals

September 19, 2016

Police_after_2016_Manhattan_explosionBy Sara Stream, MD

Peer Reviewed 

A powerful explosion occurred in Chelsea on Saturday night, injuring at least 29 people, including one with a serious puncture wound. Authorities believe that a homemade bomb caused the explosion, referred to as “an intentional act” in a news briefing by Mayor Bill De Blasio. A second explosive device was later found several blocks away, which was removed by the Police Department bomb squad. Investigations are currently ongoing as New York City remains on high alert. [1-2]

In national news, as the presidential election nears, the health of the candidates has been a recent topic of discussion following Hillary Clinton’s near-collapse at the September 11 memorial last week. Hillary Clinton and Donald Trump released detailed health records from their personal physicians revealing their medical history, laboratory results, medications and health maintenance screening. [3,4]

10-Year Outcomes after Monitoring, Surgery or Radiotherapy for Localized Prostate Cancer 

The utility of prostate-specific antigen (PSA) testing remains controversial, as the increased use of PSA testing has resulted in increased rates of diagnosis and treatment of prostate cancer. However, it is unclear whether these treatment interventions, which often have significant side effects, are more effective than watchful waiting.

A recent study published in the New England Journal of Medicine [5] included 2664 men who were diagnosed with localized prostate cancer based on a positive PSA result. Of those, 1643 were randomized to active monitoring, radical prostatectomy, or radiotherapy groups at the time of diagnosis. Serum PSA levels were monitored for all participants, and those with concern for progression of disease were referred for further testing and treatment as necessary regardless of randomization group. At the end of the 10-year period, 85% of those in the radiotherapy or surgery group received a radical intervention, while 53% in the active monitoring group received a radical intervention.

The primary treatment outcome was prostate-cancer-specific mortality at 10 years, along with secondary outcomes of all-cause-mortality, rates of metastases, clinical progression, primary treatment failure and treatment complications. At 10 years follow-up, there was no statistically significant difference among prostate-cancer-specific deaths across groups, with prostate-cancer-specific survival of at least 98.8% in all groups. In contrast, the incidence of disease progression was higher in the active monitoring group compared to the surgery and radiotherapy groups (112 compared to 46 and 46, respectively: p<0.001). It was found that a total of 9 men would need either prostatectomy or radiotherapy to prevent 1 patient from having progression of disease.

This study suggests that early radiation therapy and prostatectomy are more effective at preventing progression of prostate cancer compared to active monitoring. However, it also shows that death due to prostate cancer at 10 years is very low regardless of treatment group, though longer follow-up may necessary to identify further differences among groups. In addition, the results of the study may be skewed towards survival, as study participants were generally healthy individuals who were diagnosed based on screening PSA level.

Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage 

For patients with acute cerebral hemorrhage, the current recommendation is to maintain a systolic blood pressure (SBP) of less than 180 mmHg to prevent hematoma expansion and to minimize associated morbidity and mortality. A recent randomized, multi-center study published in the New England Journal of Medicine [6] compared the efficacy of more intensive blood pressure lowering in the first 4.5 hours after symptom onset compared to standard practice.

The study included 1000 individuals with acute cerebral hemorrhage and a mean SBP of 200.6 +/- 27.0 mmHg. Inclusion criteria consisted of: symptom onset within 4.5 hours, Glasgow Coma Scale > 5, and hematoma size of less than 60 cm3 on initial head CT. A total of 500 patients were randomized to the intensive treatment group with goal SBP 110-139 mm Hg, while the other 500 patients were randomized to the standard treatment group with goal SBP 140-179 mm Hg.

The primary outcome was the proportion of patients with significant disability or death at 3 months. Secondary outcomes included quality of life scores at 3 months and the proportion of subjects with hematoma expansion of greater than or equal to 33% on CT 24 hours after presentation compared to CT on presentation. Significant death or disability occurred in 38.7% of those in the intensive treatment group compared to 37.7% in the standard treatment group (p=0.84). The study was discontinued due to futility prior to reaching target enrollment of 1280 participants.

Prior to conducting the study, the authors anticipated that the rate of death or disability would be 60% based on other published work. This suggests that the actual rate of 38% may have been artificially low due to study design. For example, because 56% of the study subjects had a baseline GCS score of 15, the potential effect of the study intervention may have been obscured by the subjects’ favorable baseline status. It is also possible that the increased level of standardization of medical care as a result of the study design inadvertently resulted in more positive outcomes, as this was a tightly monitored research study. Overall, these results suggest that intensive SBP reduction in acute cerebral hemorrhage is no more effective than standard SBP reduction with respect to associated disability and death. 

Association of Age at Onset of Menopause and Time since Onset of Menopause with Cardiovascular Outcomes, Intermediate Vascular Traits and All-Cause Mortality 

It has been shown that decreased endogenous estrogen synthesis and loss of ovarian function following menopause is associated with obesity, diabetes and hypertension. As a result, a recent systematic review and meta-analysis published in JAMA Cardiology [7] sought to evaluate whether early menopause is associated with worse cardiovascular outcomes. The analysis included 32 studies looking at age and/or time since onset of menopause in relation to risk of cardiovascular outcomes with a total of 310,329 women included.

The study compared cardiovascular disease (CVD) outcomes, CVD mortality, all-cause mortality and intermediate CVD end points between women who experienced menopause at less than 45 years old (considered premature) compared to those greater than 45 years old (control group). When compared to the control group, it was found that women with premature menopause had an increased risk of nonfatal coronary heart disease (relative risk 1.50, 95% confidence interval 1.28-1.76), fatal coronary heart disease (RR 1.11, CI 1.03-1.20) and CVD mortality (RR 1.19, CI 1.08-1.31). Notably, the relative risk of all-cause mortality was found to be 1.12 (CI 1.03-1.21) in those with premature menopause. With respect to cerebrovascular events, relative risks for overall stroke and for stroke mortality were not significantly different across groups.

The above results suggest that women who experience premature menopause have a greater risk of coronary heart disease, CVD, and all-cause mortality. The above trends were unchanged when the studies were grouped by location, type of menopause, adjustment for socioeconomic status and hormone replacement therapy. Based on this study, clinicians may approach this subgroup of patients with closer monitoring and more aggressive risk stratification in order to decrease the risk of adverse cardiovascular events.

Sugar Industry and Coronary Heart Disease Research 

A recent paper published in JAMA Internal Medicine [8] analyzed historical documents which highlighted the sugar industry’s historical involvement in downplaying the role of sucrose in coronary heart disease. Beginning in the 1960s, there were two conflicting views regarding CHD dietary risk factors: one identified fat and cholesterol as the main culprits, while a competing view suggested sugar was the primary culprit. However, by the 1980s most scientists focused on fat and cholesterol in CHD and denied an association between sugar and CHD.

This paper analyzed historical documents involving the Sugar Research Foundation (SRF) during the 1950s and 1960s including reports, internal communication, symposiums and statements to determine how this change in theory occurred. The SRF was involved in increasing the market share of sugar by promoting a low fat diet based upon the association between fat and cholesterol with atherosclerosis. This culminated in the SRF funding a review that was published in the New England Journal of Medicine in 1967 in which researchers stated that reduction of dietary cholesterol and the substitution of polyunsaturated fat for saturated fat were the only dietary interventions necessary to prevent CHD. The sugar industry subsequently continued to fund research on CHD.

It is important to note that these documents were limited and may not be reflective of all activities of the sugar industry. There were also no direct accounts provided, as the main individuals involved have died. In any case, the statements in this paper suggest that the role of sugar in CHD may have been perpetually and intentionally underestimated to influence federal policy and public opinion. Therefore, the role of sugar in CHD requires further attention and discussion in relation to dietary changes and primary prevention of CHD.

Mini-cuts:  

A systematic review and meta-analysis found that atrial fibrillation was associated with an increased risk of all-cause mortality, major cardiovascular mortality, major cardiovascular events, stroke, ischemic stroke, ischemic heart disease, sudden cardiac death, heart failure, chronic kidney disease and peripheral arterial disease. The highest absolute risk was for heart failure. [9]

A randomized control trial found that mild therapeutic hypothermia via rapid infusion of large volume cold normal saline during CPR in adults with out-of-hospital cardiac arrest was associated with decreased rate of return of spontaneous circulation in those with an initial shockable rhythm. [10]

The FDA voted to withdraw the black box warning on Varenicline (Chantix) which warned of serious neuropsychiatric risks, such as suicidal thoughts and hostility. [11]

Dr. Sara Stream is a 2nd year Internal Medicine resident at NYU Langone Medical Center

Peer reviewed by Jennifer S. Mulliken, MD, Associate Editor of Clinical Correlations and a Chief Resident at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

  1. Mele C, Baker A, and Barbaro M. Powerful Blast Injures at Least 29 in Manhattan; Second Device Found. New York Times. September 17, 2016. http://www.nytimes.com/2016/09/18/nyregion/chelsea-explosion-new-york-city.html?hp&clickSource=story-heading&WT.nav=top-news&_r=0&module=Endslate®ion=SlideShowTopBar&version=EndSlate&action=Click&contentCollection=N.Y.%20%2F%20Region&slideshowTitle=At%20Least%2029%20Injured%20in%20Explosion%20in%20Manhattan¤tSlide=Endslate&entrySlide=1&pgtype=imageslideshow
  2. Rosenberg E and Mele C. Chelsea Explosion: What We Know and Don’t know. New York Times. September 18, 2016. http://www.nytimes.com/2016/09/19/nyregion/chelsea-explosion-what-we-know-and-dont-know.html?ribbon-ad-idx=3&rref=homepage&module=Ribbon&version=origin&region=Header&action=click&contentCollection=Home%20Page&pgtype=article 
  3. Merica D. Clinton campaign releases new information. CNN. September 15, 2016. http://www.cnn.com/2016/09/14/politics/clinton-campaign-releases-new-health-information/
  4. Kopan T and Diamond J. Donald Trump campaign releases medical information, cites “stamina.” CNN. September 15, 2016. http://www.cnn.com/2016/09/15/politics/donald-trump-medical-details-stamina/ 
  5. Hamdy FC et al. ProtecT Study Group. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med. 2016 Sep 14. http://www.nejm.org/doi/full/10.1056/NEJMoa1606220#t=article  
  6. Qureshi AI et al. ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med. 2016 Sep 15;375(11):1033-1043. http://www.nejm.org/doi/full/10.1056/NEJMoa1603460
  7. Muka T, Oliver-Williams C, Kunutsor S, et al. Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality: A Systematic Review and Meta-analysis. JAMA Cardiol. Published online September 14, 2016. doi:10.1001/jamacardio.2016.2415. http://cardiology.jamanetwork.com/article.aspx?articleid=2551981
  8. Kearns CE, Schmidt LA, Glantz SA. Sugar Industry and Coronary Heart DiseaseResearch: A Historical Analysis of Internal Industry Documents. JAMA Intern Med. 2016 Sep 12. http://archinte.jamanetwork.com/article.aspx?articleid=2548255
  9. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. BMJ. 2016 Sep 6;354:i4482. http://www.bmj.com/content/354/bmj.i4482
  10. Bernard SA et al. Induction of Therapeutic Hypothermia During Out-of-Hospital Cardiac Arrest Using a Rapid Infusion of Cold Saline: The RINSE Trial (Rapid Infusion of Cold Normal Saline). Circulation. 2016 Sep 13;134(11):797-805. http://circ.ahajournals.org/content/134/11/797.long 
  11. Joint Meeting of the Psychopharmacological Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee. FDA Briefing Document. September 14, 2016: 1-564. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM520103.pdf 

 

 

 

 

Primecuts – This Week In The Journals

September 12, 2016

9-11_Memorial_NamesBy Katherine Lawrence, MD

Peer Reviewed

Yesterday marked the 15th anniversary of September 11, 2001. Fifteen years later, emotions are still strong; it was a day of memorials and memories, a celebration of those who gave their lives and reminder of the challenges that remain.

One of the many powerful legacies of 9/11 has been the chronicling of its health impacts. Both the city of New York and the federal government (including the Center for Disease Control and Prevention and the National Institute for Occupational Safety and Health) have established and maintained programs that collect data on 9/11 first responders and civilians, as well as providing medical care to those populations. The NYU School of Medicine is one of seven centers established by the James Zadroga 9/11 Health and Compensation Act of 2010. To date, 74,968 people have enrolled in one of these programs.

Fifteen years later, we are still discovering the health consequences of 9/11. On Saturday, New York Magazine wrote an article summarizing some of the things we have learned so far. Among the illnesses that the 9/11 fallout-exposed are at increased for are asthma, GERD, PTSD, and sarcoidosis. Cancer risks also appear to be increased, including prostate, thyroid, and breast, although the link is not definitive.

Just as important as a memorial for those who gave their lives, 9/11 is a tribute to those who served, survived, and are continually impacted by the events of that day. It is also a reminder to us in the medical community of the importance of occupational, environmental, and social determinants of health for our patients.

Here are reviews of other articles in medicine and health that made headlines this week:

Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes

Optimal imaging of pregnant women is a topic of continued discussion in the medical community. Magnetic resonance imaging during pregnancy is generally thought to be safe for the fetus, especially in the second or third trimester. Concerns about exposures in the first trimester, or exposures to gadolinium at any time during pregnancy, however, have resulted in recommendations to avoid these particular modalities, despite limited high-quality data regarding safety to the fetus.

A study in JAMA looked at the association between MRI exposure during pregnancy and fetal and childhood outcomes. A retrospective cohort study using universal health care databases in the province of Ontario, Canada was conducted at the Institute for Clinical Evaluative Sciences (ICES). Researchers identified all births of more than 20 weeks, from 2003-2015, to evaluate Magnetic resonance imaging exposure in the first trimester of pregnancy, or gadolinium MRI exposure at any time in pregnancy. Study outcomes for the first-trimester MRI cohort included stillbirth after 20 weeks’ gestation or neonatal death before 28 days after birth, congenital anomalies, neoplasm, vision loss, and hearing loss. Study outcomes for the gadolinium-enhanced MRI during pregnancy cohort included any diagnosed rheumatological, inflammatory, or infiltrative skin condition.

Among the first-trimester cohort, maternal MRI in the first trimester was not associated with a higher risk of stillbirth or neonatal death (adjusted RR of 1.68 (95%CI, 0.97 to 2.90)), congenital anomalies (HR of 1.16 (95% CI, 0.96 to 1.40), neoplasm, or hearing loss. The risk of vision loss was only seen in a subgroup analysis of MRI exposure at 5 to 10weeks’ gestation HR of 2.28(95%CI, 1.09-4.77). Among the gadolinium-exposed group, the study found gadolinium-enhanced MRI was associated increased risk of any rheumatological, inflammatory or infiltrative skin condition up to age 4 years (adjusted HR of 1.36 (95% CI, 1.09 to 1.69), and an almost four-fold risk of stillbirth or neonatal death (Adjusted RR 3.70 (95% CI, 1.55-8.85)), when compared to offspring of unexposed women.

The strengths of the study came from the large sample size (N = 1 420 188 in the first trimester cohort and N =1 418 848 in the gadolinium cohort) and the robustness of the data, having been derived from a centralized national database. Due to the relatively small numbers of exposed participants, however, many of the analyses conducted were underpowered to assess less common outcomes, resulting in less thorough evaluation of rare malformations. Additionally, follow-up was limited to four years, and therefore may not have captured later-onset disease in participants. Ultimately, this study provides an important contribution to peri-natal care, reinforcing that avoidance of gadolinium-enhanced MRIs in pregnancy should be recommended, and informing risk-benefit discussions with pregnant patients regarding possible congenital effects of imaging. 

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea 

Obstructive sleep apnea (OSA) affects 40-60% of Americans with cardiovascular disease, and is associated with adverse cardiovascular events, including hypertension and stroke. Continuous positive airway pressure (CPAP) is a commonly prescribed intervention for individuals who suffer from sleep apnea. In addition to improving breathing, CPAP has also been shown to lower systolic blood pressure, improve endothelial function, and increase insulin sensitivity, thereby having potential additional benefits for patients with cardiovascular disease.

A recent study in the NEJM evaluated the impact of continuous positive airway pressure (CPAP) on major cardiovascular events in patients with known cardiovascular disease and sleep apnea. The SAVE study was an international, multicenter, randomized, parallel-group, open-label trial, conducted under the supervision of The Adelaide Institute for Sleep Health of Flinders University of South Australia. The National Health and Medical Research Council of Australia and Philips Respironics funded the project, with Philips donating the CPAP equipment.

The study looked specifically at participants between 45 and 75 years, who held a diagnosis of coronary artery disease or cerebrovascular disease, as well as a diagnosis of moderate-to-severe obstructive sleep apnea (defined as an oxygen desaturation index >=12). After a 1-week sham CPAP trial, participants were randomly assigned to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). Anthropometric measurements were obtained at specific intervals, including blood pressure and heart rate, EKGs, as well as questionnaire data on OSA symptoms, health behaviors, and quality of life. The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.

In a blow to CPAP manufacturers, the study determined therapy with CPAP as compared with usual care did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. Results failed to show a significant difference in the primary outcome of death or hospitalization due to cardiovascular events between the experimental and control groups (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P = 0.34). The study did show, whoever, that CPAP decreased the mean apnea-hypopnea index (from 29.0 events per hour at baseline to 3.7 events per hour during follow-up), significantly reduced snoring and daytime sleepiness, and improved health-related quality of life and mood.

The results of this study are consistent with similar research in the area of CPAP and cardiovascular disease, which has shown no difference in outcomes. Limitations to the study included challenges in recruitment (5844 meeting eligibility criteria, 2687 were included in primary analysis and an additional 147 were lost to follow up). As is common in CPAP interventions, researchers also recognized substantial variation in adherence to the CPAP equipment. Finally, although the outcomes were not supportive of CPAP as a mechanism for improving cardiovascular events, potential bias remains in the funding of the project.

Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use

The FDA has issued a final rule on safety and effectiveness of consumer antiseptic products, banning 19 chemicals found in these products, including triclosan and triclocarban, from the US market. The FDA is issuing this final rule after considering the recommendations of the Nonprescription Drugs Advisory Committee (NDAC), and evaluating the data available on over-the-counter (OTC) consumer antiseptic wash products. This rule is an update of the consumer antiseptic wash proposed rule published in 2013 (known as ‘the 2013 Consumer Wash Proposed Rule’) and amends a 1994 rule for OTC antiseptic drug products.

‘Consumer antiseptic washes’ include a variety of personal care products, such as antibacterial soaps, hand washes, and antibacterial body washes, which are meant to be used as part of a washing-with-water routine. In the 2013 legislation, the FDA determined that the benefits of consumer anti-septic wash products (including hand washes and body washes) outweighed potential risks; these products were subsequently approved and brought to market as a variety of ‘anti-bacterial’ soaps, washes, and other goods. New information, however, has revealed that the costs of these products may actually outweigh the benefits. In its evaluation of the effectiveness of anti-bacterial products, the FDA found “insufficient evidence to demonstrate that there is any additional benefit from the use of these [ingredients] compared to non-antibacterial soap and water.” The organization also determined that there is insufficient data “to establish the safety of long-term, daily repeated exposure to these active ingredients used in consumer wash products”. A cost-benefit analysis of the new ruling estimated a total annualized cost of $23.6-27.6 million to reduce population exposure to antiseptic ingredients by roughly 2.2 million pound each year.

Importantly, the FDA ruling applies only to consumer antiseptics. It does not cover health care antiseptics or antiseptics identified as “first aid antiseptics”. It also does not include consumer antiseptic ‘rubs’ (products meant to be used without washing off, like hand sanitizer gel or spray) or antiseptics used by the food industry. Also, the FDA has deferred further rulemaking on three specific active ingredients used in these products, “to allow for the development and submission of new safety and effectiveness data”. The ingredients are benzalkonium chloride, benzethonium chloride, and chloroxylenol. More information is needed to determine the impact of these chemicals.

The rule becomes effective in September 2017, so it may be a while before we see the full impact of the decision reach the shelves.

Mini-cuts

In the wake of scandal involving surgeon Paolo Macchiarini, the Swedish government has fired the entire board of the prestigious Karolinska Institute, for their involvement in falsifying medical research on stem cell transplantation and endangering the lives of patients: http://www.bmj.com/content/354/bmj.i4894 

The CDC released a report at the beginning of this month documenting national estimates of marijuana use in the United States, from data collected by the National Survey on Drug Use and Health (NSDUH). The report suggests that there are roughly 7,000 new users every day: http://www.cdc.gov/mmwr/volumes/65/ss/ss6511a1.htm?s_cid=ss6511a1_w 

Last week, Mylan, the maker of the EpiPen auto-injector, announced a price-hike on their product right before the back to school rush: $600 for two pens, representing a 600% increase since the company bought the rights to the product in 2007. This has a resulted in public outrage, a media frenzy, and some important conversations on the state of our pharmaceutical markets: http://www.economist.com/news/business/21706347-row-over-mylans-epipen-allergy-medicine-raises-fresh-questions-about-how-drugs-are 

Dr. Katherine Lawrence is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Neha Jindal, MD, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

Brackbill R et al. Ten-year cancer incidence in rescue/recovery workers and civilians exposed to the September 11, 2001 terrorist attacks on the World Trade Center. Am J Ind Med. 2016 Sep;59(9):709-21. doi: 10.1002/ajim.22638.

Icitovic N et al. The association between body mass index and gastroesophageal reflux disease in the World Trade Center Health Program General Responder Cohort. Am J Ind Med. 2016 Sep;59(9):761-6. doi: 10.1002/ajim.22637.

Brackbill R et al. Asthma and Posttraumatic Stress Symptoms 5 to 6 Years Following Exposure to the World Trade Center Terrorist Attack. JAMA. 2009;302(5):502-516. doi:10.1001/jama.2009.1121.

NYU World Trade Center Program. http://www.wtc.med.nyu.edu/ Accessed 9/11/16.

FDA. Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use. https://www.federalregister.gov/documents/2016/09/06/2016-21337/safety-and-effectiveness-of-consumer-antiseptics-topical-antimicrobial-drug-products-for. Accessed 9/11/16.

Ray J et al. Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes. JAMA. 2016;316(9):952-961. doi:10.1001/jama.2016.12126

McEvoy D et al. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med 2016;375:919-31.