PrimeCuts

PrimeCuts – This Week in the Journals

October 16, 2017

By Christian Torres, MD

Peer Reviewed

It’s another week, which means there’s been another attempt by President Trump to undermine Obamacare. On Thursday, Trump signed an executive order that would cut subsidies to insurers providing coverage to low-income individuals [1]. It’s already drawn swift criticism from the American Medical Association, among other health care groups [2]. We’ll see in the coming days if there’s any effort by Congress to keep the subsidies going. Meanwhile, we’ll keep going with a recap of the latest research.

Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis

Romosozumab,  a monoclonal antibody that inhibits sclerostin, is a monthly subcutaneous injection that both promotes bone formation and decreases bone resorption. First-line options for the management of osteoporosis may change based on a recent study in the NEJM of Romosozumab[3]. Researchers compared Romosozumab to alendronate in a randomized, controlled trial of more than 4000 postmenopausal women with osteoporosis and a history of vertebral or femoral fractures. Participants received either alendronate or Romosozumab for 1 year, followed by alendronate in the second year. All patients received calcium and vitamin D supplementation.

Primary endpoints for the study were the incidences of new vertebral and clinical fractures (symptomatic, vertebral or otherwise) after 24 months. Patients who received the monoclonal antibody had a 48% and 27% risk reduction, respectively, compared to alendronate alone. Both were statistically significant. Safety profiles were similar, but there was a higher incidence of cardiac ischemia and cerebrovascular events with Romosuzamab.

This comparative-effectiveness trial shows promise for Romosozumab, but as an accompanying editorial [4] notes, the cardiovascular effects of Romosozumab may require further study before alendronate gives way to a new first-line.

Association of Public Health Initiatives With Outcomes for Out-of-Hospital Cardiac Arrest at Home and in Public Locations

When we think of patient education, CPR might not be at the top of the list, but it may be worth at least a second thought. This study of out-of-hospital cardiac arrest in JAMA Cardiology found that a public health initiative in North Carolina was associated with increased rates of bystander CPR and positive outcomes post-arrest[5].

The initiative, called RACE [6], focused on improving cardiac arrest management from its onset on through hospitalization. It included outreach and training in CPR for the general public, along with a review of best practices for EMS and in-hospital providers. From 2010 to 2014, spanning over 8000 cardiac arrests, there were statistically significant increases in bystander CPR at home and in public, along with other positive changes such as an increase in home defibrillation. These interventions correlated with greater odds of survival to discharge.

The authors provide little information on the cost and coordination required to pull off this major initiative. Their work, however, at least shows that the “chain of survival,” as they describe it, can be strengthened by a concerted effort to involve the community in that chain.

Low Rates of Gastrointestinal and non-Gastrointestinal Complications for Screening or Surveillance Colonoscopies in a Population-based Study

Referral for a screening colonoscopy has become such a standard part of the primary care visit, that we might forget how these procedures aren’t necessarily benign. A study of more than 1.5 million screening colonoscopies done in California helps to clarify the risks[7]. Researchers found the post-procedure rate of lower GI bleeding was 5.3 per 10,000, while perforation was 2.9. They also found that among non-GI events, the rate of ischemic stroke (4.7 per 10,000) was higher than in the general population, though myocardial infarction (2.5 per 10,000) was not.

These rates were higher among colonoscopies in which there was an intervention such as a biopsy, and among non-screening colonoscopies. Adverse events were most common within 14 days of colonoscopy, and risk factors for events included Black race, low income, and public insurance.

Cigarette smoking and the risk of systemic lupus erythematosus

Previous research on smoking as a risk factor for SLE has had conflicting findings, but this prospective cohort study makes for yet another strong case against tobacco use[8]. Based on data from the Nurses Cohort Studies, current smokers had 1.86 times the risk of dsDNA-positive SLE compared to never-smokers. Risk was also increased (hazard ratio 1.60) among those who smoked more than 10 pack-years. These were both statistically significant findings, and interestingly, the association was not seen with dsDNA-negative SLE and SLE as a whole.

The researchers note these findings may help delineate the pathogenesis of autoantibodies involved in SLE. For our patients, however, it provides yet another stark example of the risks of smoking, and the importance of cessation. Among this cohort, past smokers appeared to approach the risk of never-smokers after just 5 years without cigarettes.

A few other studies from this week in Minicuts:

An enhanced discharge medication reconciliation process, with both pharmacists and prescribers collaborating, did not reduce 30-day hospital revisit rates in this study of nearly 10,000 patient admissions [9].

Also on the medication front, a Dutch study used a thorough, multidisciplinary approach to medication reconciliation in nursing homes and had more success reducing polypharmacy compared to usual care. It’s a small study, and also showed no difference in outcomes such as  number of falls and quality of life [10].

Lastly, please call, don’t text. A study found that patients were more likely to return their fecal immunochemical test (FITs) after a live phone call reminder than after a text reminder [11].

Dr. Christian Torres is a 2nd-year resident in internal medicine at NYU Langone Health

Peer reviewed by Ian Henderson, MD, contribution editor, Clinical Correlations and Chief Resident,  Internal Medicine, NYU Langone Health

Image referenced at:  https://www.nytimes.com/2017/10/12/us/politics/trump-obamacare-executive-order-health-insurance.html

References

  1. Pear R, Haberman M, Abelson R. Trump to Scrap Critical Health Care Subsidies, Hitting Obamacare Again. The New York Times. October 12, 2017.  https://www.nytimes.com/2017/10/12/us/politics/trump-obamacare-executive-order-health-insurance.html
  1. Schouten F. Trump’s move to end insurance subsidies jolts Washington. USA Today. October 14, 2017. https://www.usatoday.com/story/news/politics/2017/10/14/trump-move-end-insurance-subsidies-jolts-health-industry-washington/764673001/
  1. Saag KG, et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. NEJM. 2017;377:1417-1427. http://www.nejm.org/doi/full/10.1056/NEJMoa1708322
  1. Rosen, CJ. Romosozumab — Promising or Practice Changing? NEJM. 2017;377:1479-1480. http://www.nejm.org/doi/full/10.1056/NEJMe1711298
  1. Fordyce CB, et al. Association of Public Health Initiatives With Outcomes for Out-of-Hospital Cardiac Arrest at Home and in Public Locations. JAMA Cardiol. 2017. https://jamanetwork.com/journals/jamacardiology/article-abstract/2656353
  1. “Optimal Cardiac Arrest System Specification By Point Of Care Operations Manual; Version 3.0” http://racecars.dcri.org/wp-content/uploads/2014/08/RACE-ops-3.0.pdf
  1. Louise W, et al. Low Rates of Gastrointestinal and non-Gastrointestinal Complications for Screening or Surveillance Colonoscopies in a Population-based Study. Gastroenterology. 2017. http://www.gastrojournal.org/article/S0016-5085(17)36239-X/fulltext
  1. Barbhaiya M, et al. Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses’ Health Study cohorts. Ann Rheum Dis. 2017. http://ard.bmj.com/content/early/2017/10/07/annrheumdis-2017-211675 
  1. Baker M, et al. Do Combined Pharmacist and Prescriber Efforts on Medication Reconciliation Reduce Postdischarge Patient Emergency Department Visits and Hospital Readmissions? Journal of Hospital Medicine. 2017. http://www.journalofhospitalmedicine.com/jhospmed/article/148443/hospital-medicine/do-combined-pharmacist-and-prescriber-efforts-medication
  1. Wouters H, et al. Discontinuing Inappropriate Medication Use in Nursing Home Residents: A Cluster Randomized Controlled Trial. Ann Intern Med. 2017. http://annals.org/aim/article/2657164/discontinuing-inappropriate-medication-use-nursing-home-residents-cluster-randomized-controlled 
  1. Coronado GD, et al. Effect of Reminding Patients to Complete Fecal Immunochemical Testing: A Comparative Effectiveness Study of Automated and Live Approaches. J Gen Intern Med. 2017. https://link.springer.com/article/10.1007%2Fs11606-017-4184-x

 

Primecuts – This Week in the Journals

October 9, 2017

By Joanne Bruno, MD/PhD

Peer Reviewed 

There’s finally starting to be a bit more of a chill in the air, which can only mean one thing – pie season is finally here! While this time of year is rife with celebration and gluttony, it is also a time to give back to those in need. This is especially relevant this year given that Puerto Rico is still reeling from the devastation left by Hurricane Maria and Las Vegas just experienced one of the worst mass shootings in US history. Here are ways that we can help.[1 2] Now, let us turn to brighter news in the form of the recently published advancements in medicine in this week’s PrimeCuts.

Rituximab maintenance therapy prolongs disease-free and overall survival in patients with mantle cell lymphoma.

Mantle cell lymphoma has historically been categorized as an ultimately incurable cancer; although many patients temporarily achieve remission, they eventually relapse and become progressively less responsive to chemotherapy with each successive treatment regimen. While recent advances have been made in optimizing the chemotherapy cocktails used both prior and subsequent to patients undergoing autologous stem cell transplant, none of these ultimately resulted in prolongation of overall survival in these patients.[3] However, Le Gouill et al. hypothesized that treatment with rituximab, a monoclonal antibody against CD20, after transplantation may be useful in suppressing any tumor cells that remain and thereby inhibit disease progression.[4] In their randomized, prospective phase 3 trial published in NEJM this week, they show that patients randomized to receive rituximab maintenance therapy after autologous stem cell transplant experienced an increased rate of progression-free survival at 4 years (83% v. 64%, P<0.001) as well as an increased rate of overall survival (89% v. 80%, P=0.04) compared to those who only underwent observation post-transplantation. Thus, the number needed to treat to prevent one death during this time span is 11.1 patients. As is frequently the case with advancements in biomedical science, the findings from this study spurred even more questions. It will be interesting to see whether rituximab maintenance therapy has similar effects in those patients who receive alternative induction chemotherapy regimens, or whether its effect is specific to the regimen used in this study.  Additionally, in this study maintenance therapy was administered regardless of whether or not residual disease could be detected post-transplantation. It may be that there is a subset of patients whose response to the initial treatment is so robust that keeping them on maintenance therapy is superfluous. However, further work will need to be done to investigate this. 

Using lung recruitment and titrated PEEP strategies in patients with moderate to severe ARDS increases mortality compared to the conventional low PEEP strategy. 

Also in the vein of challenging medical dogma, a study published in JAMA this past week sought to oppose the low-PEEP strategy conventionally used for treatment of ARDS, comparing it with a lung recruitment maneuver that uses stepwise increases in PEEP to maximize respiratory system compliance[5]. This multicenter trial spanned 120 ICUs from 9 different countries, and randomized 1010 patients with moderate to severe ARDS requiring invasive mechanical ventilation to either the lung recruitment strategy (experimental) group or a low-PEEP strategy (control) group. Patients were excluded from the trial if they were on vasopressors, had contraindications to hypercapnia, or had a pneumothorax/pneumomediastinum. All patients received at least 3 hours of mechanical ventilation using a low-PEEP and low-tidal volume prior to randomization. The lung recruitment strategy was overwhelmingly inferior to the low-PEEP strategy, and was associated with increased mortality at 28 days (55.3% v. 49.3%, P=0.041), increased 6-month mortality (65.3% v. 59.9%, P=0.04), decreased ventilator-free days (5.3 v. 6.4, P= 0.03), increased risk of pneumothorax requiring chest tube placement (3.2% v. 1.2%, P=0.03), and risk of barotrauma (5.6% v. 1.6%, P=0.001). While these raw percentages may not seem strikingly different at face value, the number needed to harm for 6-month mortality with the lung recruitment strategy is only 18.5, which is significant given how relatively common ARDS is among critical care patients. 

Effective HCV treatment results in reduction of the risk of HCC except in those with established cirrhosis.                                                              

The advent of new direct-acting antiviral agents against hepatitis C has resulted in undetectable viral loads and what is essentially being called a cure for many patients. While it is intuitive that eradication of the hepatitis C virus stalls progression of disease to cirrhosis and liver failure, it has been unclear whether elevated risk of hepatocellular carcinoma (HCC) persists in these patients. A large cohort study published in Gastroenterology broaches this question by comparing the incidence of diagnosis of HCC in 22,500 HCV-positive patients in the Veterans Health Administration system with sustained viral response (SVR) after antiviral treatment to those who underwent treatment but did not achieve viral eradication[6]. The annual incidence of HCC diagnosis in those who achieved sustained viral response was 0.9 per 100 patient-years, compared to 3.45 per 100 patient-years in those with detectable viral load after treatment. Sustained viral response on the other hand was associated with a 76% decrease in the risk of HCC. The study also identified cirrhosis and alcohol use as factors that conferred a continued heightened risk of HCC despite viral clearance (1.82% v. 0.34% for cirrhotics and 1.01% v. 0.72% for alcohol users). While no causative associations can be made from this study, and there certainly could be confounding influences at play – for instance, perhaps those patients who were compliant with their treatment are likely also compliant with their other medications and in better health overall – these data clearly emphasize the importance of diagnosing our patients with hepatitis C early on in the course of their illness, and starting them on antiviral agents as quickly as possible.

Results from the Phase 1 trail for an Anti-Zika Virus Vaccine show that the DNA vaccine is capable of eliciting anti-Zika virus immune responses. 

Although Zika virus was first discovered in 1947, it has only begun to plague human populations in recent years. Zika infection can be transmitted by mosquitoes or via exchange of bodily fluids between individuals. In most humans, infection with Zika appears to be relatively benign with the majority of those infected experiencing vague symptoms similar to that of the common cold. However, infection with Zika during pregnancy can have severe consequences for fetal brain development resulting in microcephaly [7]. Preclinical studies have confirmed the immunogenicity of a DNA vaccine against the ZIKA premembrane and envelope proteins, as well as its effectiveness in protecting against Zika infection in mice and primates [8]. However, further studies have been necessary to confirm its safety and efficacy in humans. To this end, a phase 1, open-label clinical trial recently published in the New England Journal of Medicine is suggestive of vaccine safety with 0 of the 40 participants experiencing any serious adverse events. The participants received three doses of the vaccine with detectable antibody development against Zika virus in all participants at two weeks after administration of the third dose. Additionally, application of the serum from Zika-vaccinated individuals was protective against Zika infection in both tissue culture and murine models. While it still remains to be seen whether the vaccine will be efficacious in conferring immunity against Zika virus in humans, these initial studies are certainly promising and a step in the right direction.

Other interesting reads this week in Minicuts….

In a randomized trial of patients undergoing orthopedic surgery, using genotype to guide warfarin dosing rather than conventional clinical guidance reduced the rate of major bleed, VTE, supratherapeutic INR, and death.[9]

Whole genome sequencing on patients with idiopathic pulmonary hypertension identifies a cohort of patients with biallelic mutations in the EIF2AK4 gene who have a younger age of diagnosis with negative CT findings. Patients who fit these criteria would likely benefit from genetic testing, which could allow for less time to diagnosis and earlier referral to lung transplant.[10]

Rapid antigen tests that more accurately distinguish Zika virus from dengue viruses may be on the horizon.[11]

Finally, there is now proof that increased physical activity diminishes genetic susceptibility to weight gain.[12]

Dr. Joanne Bruno is a 1st year internal medicine resident at NYU Langone Health 

Peer reviewed by Amar Parikh, MD, associate editor of Clinical Correlations and chief resident of internal medicine at NYU Langone Health

References: 

  1. J H. How you can help hurricane victims in Puerto Rico. Secondary How you can help hurricane victims in Puerto Rico 2017. http://www.pbs.org/newshour/rundown/can-help-hurricane-victims-puerto-rico/.
  2. John T. How you can help the victims of the mass shooting in Las Vegas. Secondary How you can help the victims of the mass shooting in Las Vegas. 2017. http://time.com/money/4964866/las-vegas-shooting-how-to-help-victims/.
  3. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 2016;388(10044):565-75 doi: 10.1016/S0140-6736(16)00739-X[published Online First: Epub Date]|.
  4. Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma. N Engl J Med 2017;377(13):1250-60 doi: 10.1056/NEJMoa1701769[published Online First: Epub Date]|.
  5. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial I. Effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: A randomized clinical trial. JAMA 2017 doi: 10.1001/jama.2017.14171[published Online First: Epub Date]|.
  6. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology 2017;153(4):996-1005 e1 doi: 10.1053/j.gastro.2017.06.012[published Online First: Epub Date]|.
  7. Mlakar J, Korva M, Tul N, et al. Zika Virus Associated with Microcephaly. N Engl J Med 2016;374(10):951-8 doi: 10.1056/NEJMoa1600651[published Online First: Epub Date]|.
  8. Larocca RA, Abbink P, Peron JP, et al. Vaccine protection against Zika virus from Brazil. Nature 2016;536(7617):474-8 doi: 10.1038/nature18952[published Online First: Epub Date]|.
  9. Gage BF, Bass AR, Lin H, et al. Effect of genotype-guided warfarin dosing on clinical events and anticoagulation control among patients undergoing hip or knee arthroplasty: The gift randomized clinical trial. JAMA 2017;318(12):1115-24 doi: 10.1001/jama.2017.11469[published Online First: Epub Date]|.
  10. Hadinnapola C, Bleda M, Haimel M, et al. Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension. Circulation 2017 doi: 10.1161/circulationaha.117.028351[published Online First: Epub Date]|.
  11. Bosch I, de Puig H, Hiley M, et al. Rapid antigen tests for dengue virus serotypes and Zika virus in patient serum. Sci Transl Med 2017;9(409) doi: 10.1126/scitranslmed.aan1589[published Online First: Epub Date]|.
  12. Wang T, Huang T, Heianza Y, et al. Genetic Susceptibility, Change in Physical Activity, and Long-term Weight Gain. Diabetes 2017;66(10):2704-12 doi: 10.2337/db17-0071[published Online First: Epub Date]|.

 

Primecuts – This Week in the Journals

October 2, 2017

pumpkinsBy Kumar Vasudevan, MD

Peer Reviewed

With October beginning and the weather starting to change, the season for apple picking, Pumpkin Spice Lattes, and football also commences. However, with all the joys of fall, we also begin flu season and prepare for all the complications that it brings.  With this in mind, we turn to the medical literature which searches for novel treatments for this deadly illness.

Oseltamivir, Amantadine and Ribavirin Combination Antiviral Therapy versus Oseltamivir Monotherapy for the Treatment of Influenza

The flu is a very costly and dramatic illness, and the new seasonal vaccine is just coming out. Oseltamivir is our only line of defense after disease onset, and it reduces the typical one to two-week disease course by approximately one day if given properly [1]. There have also been some studies showing it reduces the risk of acquiring other lower respiratory tract infections and other hospital complications [2]. While those results are somewhat promising there is still much to be desired for such a common and costly disease. Many other viruses have been targeted with combination antiviral therapy.  Previously, the combination of amantadine, oseltamivir and ribavirin has shown increased antiviral activity (maximizing effective drug concentration) of each of these drugs in vitro compared to each of the drugs independently. Additionally, this combination can be used even if treatment is delayed for 72 hours compared to the 24-48 hour window recommended for oseltamivir monotherapy.

So, with hopes of finding a better treatment solution for influenza, a randomized double-blind phase 2 study was conducted on 560 patients across 5 countries [3] comparing combination amantadine, oseltamivir and ribavirin versus oseltamivir monotherapy. The study showed a 10% absolute reduction in viral shedding on day 3 as well as significant viral load reduction with combination therapy. By day 7, viral shedding was similar in combination versus monotherapy. Most importantly, and to the dismay of researchers, there was no significant clinical benefit in terms of fevers, myalgia, respiratory symptoms, etc. when comparing the two groups. The combination group did however experience more serious adverse events (GI and respiratory), though it is unclear if that can be contributed to the therapy.  In preclinical trials, a decreased viral load and shedding has been associated with decreased symptoms but only in animal models, and the combination therapy shows decreased shedding compared to monotherapy. However, the US Food and Drug Administration does not believe this should be considered as it does not appropriately assess how well a patient “feels, functions or survives.” With decreased viral load and thus, viral shedding, may come other benefits like decreased resistance and decreased infectivity. Ultimately, the search for a symptomatic resolution for influenza continues, and whether it will be a combination or a novel medication remains to be seen. In the meantime, make sure to get vaccinated.

Continuous Glucose Monitoring versus Usual Care in Patients with Type 2 Diabetes

Recently, continuous glucose monitoring (CGM) has been popular in treating Type 1 diabetes. It sends glucose values to patients’ cell phones every 5 minutes. A sensor is placed in subcutaneous fat, and measures glucose in interstitial fluid.  Patients can observe how their body is responding to insulin and assess what foods or activities help keep their diabetes under control. Studies have shown CGM can reduce A1C by about 0.6% points compared to regular care (over 24 weeks), and it has been suggested that it can be helpful in monitoring hypoglycemia as well [4]. This is fairly impressive given that no medication is required and it also gives patients autonomy over their glucose levels.

However, CGM has not been studied with Type 2 diabetes, thus a 24-week trial across North America was conducted to do so [5].  The study initially enrolled 254 participants, but lost 93 of them to withdrawal and ineligibility. Half of the participants were given the CGM system and training on how to use the CGM as an adjunct to regular blood glucose monitoring. The control group did not receive a CGM device, but were asked to monitor blood glucose 4 times daily with adjustments to medications being left to the discretion of patients’ individual providers. Biochemical hypoglycemia was infrequent across both groups. Mean HbA1C reduction was 0.8% in CGM vs. 0.5% in control, with an improvement of 0.3% (95% CI of 0.5 to 0.0). This improvement is less than what was seen in Type 1 diabetics, and it is postulated that patients with Type 2 diabetes have less advanced diabetes management skills (carb counting and experience since youth) which limits the value of CGM, but these findings do suggest that CGM could be useful. Though the paper suggests beginning to use CGM now, another study of a larger sample size may be appropriate to better assess the benefit and also obtain satisfaction data to assess if patients felt the CGM offered a greater feeling of control on their diabetes management.

IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia

Heparin Induced Thrombocytopenia (HIT) is a common and frightening concern when a patient receiving heparin experiences a drop in platelets. Unfortunately, repleting platelets can be dangerous (can double rates of mortality [6]) and finding an alternative anticoagulant is dangerous as patients are already thrombocytopenic, but we cannot ignore the possibility of DVTs, strokes, CAD and other embolic complications. With such high mortality and no great solution, further research is warranted to search for creative options.

A recent paper published in Chest [7] reported on three patients with severe HIT refractory to standard therapy but who had sustained response to IVIG. One patient, a 47-year-old man, had a PE and right atrial thrombus 13 days after heparin administration. He received argatroban, thrombectomy and multiple platelet transfusions along with dexamethasone and bivalirudin, but he maintained severely thrombocytopenic for 2.5 weeks until being given 1g/kg per day on 2 consecutive days. He remained free of thrombocytopenia for 8 months following this period. A second patient, 9 days after receiving heparin for CABG, became thrombocytopenic and suffered from a pulmonary embolus. This patient remained thrombocytopenic for 3 weeks despite platelet transfusion and therapeutic plasma exchange. He also was given IVIG and remained free of thrombosis and thrombocytopenia for 7 months. The third patient also had persistently low platelets and DVTs 5 days after CABG and heparin exposure, and for 2 weeks he remained thrombocytopenic despite normal care. With IVIG, he too improved. In these cases, the timeline between sustained response and complementary laboratory data “leave little doubt” that there is some causal relationship between the IVIG and clinical improvement.  The figure below shows these patients’ platelet response to IVIG. There may be some patients with particular genotypes that lend resistance to IVIG usage, but for the most part the study suggests implementing the use of IVIG for HIT response. This data warrants prospective trials to better assess the utility of IVIG for those with refractory HIT. Importantly though, IVIG can be procoagulable for certain patients [8] and more data is needed to ensure this could be a safe solution to a very complex problem of HIT.

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Weight and Metabolic Outcomes 12 years after Gastric Bypass

Obesity is a costly epidemic in our country. A recent study suggested even healthy obese people in this country can amount to tens of thousands of dollars in healthcare costs solely for their risk of developing more significant disease [9]. Surgery and gastric bypass have been effective in maintaining weight-loss and improving type 2 diabetes, but there is little comprehensive data on long-term follow-up of Roux-en-Y bypasses.

An observational prospective study was initiated in July 2000 through March 2016 involving 1156 patients [10] where ultimately 835 patients were followed, and about half (418) had surgery while the other 417 did not. There was also a population-based sample of 321 adults who were recruited separately but had not undergone surgery or been seen at the surgical center (i.e. not seeking surgery). The study compared these three groups, looking at weight lost, remission rates of Type 2 diabetes, hypertension and dyslipidemia 12 years after surgery. The mean percentage weight loss was persistent at 12 years (26.9%) for the surgical group as compared with 0.9-2% mean percentage weight loss in the non-surgery groups. Type 2 diabetes remission was 75% at 2 years, 62% at 6 years and 51% at 12 years in this study in the surgical group. However, in subgroup analysis, this benefit was weaker in patients who had initiated insulin therapy before receiving their bypass. This indicates a less significant impact if Type 2 Diabetes is more advanced prior to surgery. Similar results were seen in a Swedish study.

Of note, there were 7 deaths by suicide (5 in the surgery group and 2 in the non-surgery group). It is unclear why those suicides occurred and whether it is related to the surgery and the lifestyle that follows. More studies need to be conducted to evaluate and determine the need for close mental health follow-up for patients receiving bariatric surgery. Despite the low risk (<2%) for suicide compared to general population, it does appear that bariatric surgery has substantial health benefits in the way of diabetes and weight loss that are sustained for at least 12 years.

On that note, we will go to some MiniCuts:

Turns out exercise is good for your body. The PURE study looked at the exercise patterns of 130,000 people. People who exercise intensely have 13% less mortality and 9.5% less major CAD events which is better than most medication [11].

JAMA looked at the associations between healthcare costs and being on Supplemental Nutrition Assistance Programs (SNAP). They found savings of approximately $1400 in healthcare per year in regards to ED visits compared to patients with similar socioeconomic statuses (200% below the poverty level) who did not receive SNAP  [12]. For even more intensive information on the parallels between social spending and health care costs, check out the book, The American Health Care Paradox by Elizabeth Bradley.

A study in Gastroenterology investigated Proton Pump Inhibitors (PPIs) and their association with CKD development [13]. They found that PPI users had a Hazard Ratio of 1.26 (95% CI of 1.05 to 1.51) in developing CKD with higher degrees of ESRD and AKI compared to H2 Blocker users. These were modest results, but continue to add more reasons to reduce the use of chronic PPI use.

Dr. Kumar Vasudevan, a 2nd year Internal Medicine Resident at NYU Langone Health

Peer reviewed by Dana Zalkin, MD, 3rd year Internal Medicine Resident, NYU Langone Health

Image courtesy of Wikimedia Commons

References:

  1. Cooper Nicola J, Sutton Alexander J, Abrams Keith R, Wailoo Allan, Turner David, Nicholson Karl G et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomized controlled trialsBMJ 2003; 326 :1235 http://www.bmj.com/content/326/7401/1235.long
  1. Hernán MA, Lipsitch M. Oseltamivir and Risk of Lower Respiratory Tract Complications in Patients with Flu Symptoms: A Meta-analysis of Eleven Randomized Clinical Trials. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 2011; 53(3):277-279. https://www-ncbi-nlm-nih-gov/pmc/articles/PMC3137795/
  1. Beigel, John et al. Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomized phase 2 trial. Lancet. 2017. thelancet.com/journals/laninf/article/PIIS1473-3099(17)30476-0/fulltext
  1. Beck RW, Riddlesworth T, Ruedy K, Ahmann A, Bergenstal R, Haller S, et al DIAMOND Study Group Effect of continuous glucose monitoring on glycemic control in adults with type 1 diabetes using insulin injections: the DIAMOND randomized clinical trial.JAMA2017317371378 http://jamanetwork.com.ezproxy.med.nyu.edu/journals/jama/fullarticle/2598770
  2. Beck RW, Riddlesworth TD, Ruedy K, Ahmann A, Haller S, Kruger D, et al. Continuous Glucose Monitoring Versus Usual Care in Patients With Type 2 Diabetes Receiving Multiple Daily Insulin Injections: A Randomized Trial. Ann Intern Med. 2017; 167:365–374.doi: 10.7326/M16-2855. http://annals.org/aim/article/2649297/continuous-glucose-monitoring-versus-usual-care-patients-type-2-diabetes
  1. Goel R, Ness PM, Takemoto CM, et al. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood 2015; 125:1470. http://www.bloodjournal.org/content/125/9/1470.long?sso-checked=true
  1. Padmanabhan A, Jones C, et al. IVIG for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. Vol 152 Is 3. September 2017. p 478 – 485. https://www-sciencedirect-com/science/article/pii/S0012369217307249#bib40
  1. M. Ammann, M.P. Jones, B.K. Link, et al. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy Blood, 127 (2) (2015), pp. 200-207 http://www.bloodjournal.org/content/127/2/200.long?sso-checked=true
  1. Norton, Amy. US pays high price for Obesity. CBS News. September 2017. https://www.cbsnews.com/news/us-pays-high-price-for-obesity/
  1. Adams T, Davidson L, Litwin S et al. Weight and Metabolic Outcomes 12 Years after Gastric Bypass. New England Journal of Medicine. September 21, 2017. 377:1143-1155. http://www.nejm.org/doi/full/10.1056/NEJMoa1700459#t=article
  1. Lear S, Hu W, Rangarajan S et al. The effect of physical activity on mortality and cardiovascular disease in 130 000 people from 17 high-income, middle-income, and low-income countries: the PURE study. The Lancet. September 2017. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31634-3/fulltext
  1. Berkowitz SA, Seligman HK, Rigdon J, Meigs JB, Basu S. Supplemental Nutrition Assistance Program (SNAP) Participation and Health Care Expenditures Among Low-Income Adults. JAMA Intern Med.Published online September 25, 2017. doi:10.1001/jamainternmed.2017.4841 http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2653910?amp;utm_source=JAMA%20Intern%20MedPublishAheadofPrint&utm_campaign=25-09-2017
  1. Klatte DCF, Gasparini A, Xu H et al. Association between Proton Pump Inhibitor Use and Risk of Progression of Chronic Kidney Disease. Gastroenterology. Vol 153 Issue 3. September 2017 p 638-640. https://www-sciencedirect-com/science/article/pii/S0016508517356883

 

 

 

Primecuts – This Week in the Journals

September 18, 2017

floodsBy Alvaro F. Vargas P. M.D

Peer Reviewed

As the world and the United States recover from disasters such as storms the size of a country [1], record-breaking earthquakes [2], and hundreds of millions of data breaches [3], let us force ourselves to turn our attention to the comforts of data with this week’s Primecuts.

SPRINT re-revisited: intensive BP control increases CKD events but still saves lives

The well-referenced SPRINT trial (5), continues to be prominently featured in the literature. Three weeks ago a NEJM article reported in PrimeCuts [6] showed that the intensive systolic blood-pressure (SBP) control group (<120 mmHg)  had similar physical and mental wellbeing outcomes compared to the standard SBP control group (<140 mmHg). Last week, the Annals of Internal Medicine published a subgroup analysis of the trial looking specifically at new events of chronic kidney disease (defined as a decrease in eGFR >30% with at least one value below 60mL/min/1.73m2) [7]. From the 9,361 original trial participants, 6,662 of them had normal kidney function prior to randomization to intensive or standard SBP control. At 3-years, 4.2% of participants in the intensive group and 1.1% of participants in the standard group had a CKD event (HR, 3.54 [CI, 2.50 to 5.02]; P < 0.001). All these cases were asymptomatic, a significant number recovered (25% in the intensive group, 10% in the standard group), and no participant progressed to end-stage renal disease. While the number needed to harm to produce a new CKD event was low at 38, the number needed to prevent a cardiovascular event or an all-cause death was close at 48, which led the authors to conclude that the benefits of intensive SBP control still outweighs its risks. Despite the limitation of a relatively short follow-up window, these data intensify the pressure (no pun intended) on the not-so-few SPRINT trial skeptics [8].

Supplemental oxygen offers no benefit in patients with suspected MI without hypoxemia

As you develop chest pain due to the anxiety of waiting for even more SPRINT trial data, don’t panic if there is not supplemental oxygen available, as it probably will not make much of a difference – or at least that is the conclusion from the Determination of the Role of Oxygen in Suspected Acute Myocardial Infarction (DETO2X-AMI) trial [9]. In this Swedish, registry-based, open-label clinical trial recently published in the NEJM, 6,629 normoxemic patients (O2 saturation of 90% or above) with suspected or confirmed myocardial infarction (MI) were randomized to 6 liters/minute of supplemental oxygen or ambient air. Patients were at least 30 years old and suspected MI was defined as chest pain or shortness of breath for less than 6 hours, in addition to EKG changes suggesting ischemia or an increased troponin. At 1-year registry-based follow-up, there were no differences among groups in all-cause mortality (5% vs. 5.1%) and MI rehospitalization (3.8 vs. 3.3%, P=0.33). Researchers noted that while these results are in line with a Cochrane meta-analyses [10], the Air Versus Oxygen in ST-Elevation Myocardial infarction (AVOID) trial [11] showed larger infarcts with supplemental oxygen use, a finding that is not supported by the DETO2X-AMI data. It is important to note that this was a registry-based study with its associated limitations, and that the final diagnosis was not MI in 24.4% of participants. Nonetheless, these data further argue against the reflexive use of supplemental oxygen in normoxemic patients with suspected MI.

Adoption of evidence-based care processes are associated with decreased mortality in S. Aureus bacteremia 

If this title caused you to meet SIRS criteria (or should I say qSOFA?), wait until you learn more about this large Veterans Affairs study published in JAMA internal medicine [12]. In this retrospective, observational cohort study which included 124 hospitals and 36,868 patients with a documented Staphylococcus aureus bacteremia (SAB) between the years 2003 and 2014, researchers compared the implementation of specific evidence-based processes and all-cause 30-day mortality. Mortality in SAB decreased from 25.7% in 2003 to 16.5% in 2014 (P < .001 for trend).  Specifically, the use of echocardiography to identify endocarditis, appropriate antibiotic prescribing, and infectious disease (ID) consultation all increased significantly (echocardiography to 72.8% from 33.8%; appropriate antibiotics to 78.9% from 66.4%; ID consultation to 68% from 37.4%; all also P < .001 for trend). The use of these three care processes was associated with lower 30-day mortality in a dose-response fashion. By recycled predictions methods, researchers approximated that implementation of these evidence-based care processes was responsible for 57.3% of the mortality improvement observed. And while a causal relationship cannot be concluded by this observational study, the strength of the associations should strongly motivate us to continue to develop and implement evidence-based processes to guide our systems-based and individual practices.

Colonoscopy outreach better than fecal immunochemical test outreach and usual care for CRC screening process completion   

Make sure you prep well for MiniCuts with this JAMA-published clinical trial exploring different strategies to improve colorectal cancer (CRC) screening completion in a safety-net health system [13]. CRC screening process completion rates continue to be suboptimal nationwide. In some groups, more than 50% of patients do not initiate screening or follow up with results [14]. This study attempted to address this issue by randomizing 5,999 (yes, I know) active primary care patients between 50 and 64 years of age to receive either usual care (office-based screening), fecal immunochemical test (FIT) outreach, or colposcopy outreach. Participants were then followed for three years for screening process completion (screening initiation and follow-up). The outreach strategy included a mailed letter with information on CRC risk and screening, and either a FIT test kit with instructions or a phone number to schedule a colonoscopy. Results showed that screening process completion was successful in 10.7% (95% CI, 9.1% to 12.6%) in the usual-care group, 28% (95% CI, 26.2% to 29.8%) in the FIT outreach group, and 38.4%(95% CI, 36.5% to 40.4%) in the colonoscopy outreach group (P < .001 for all group comparisons). While the study’s primary outcome, screening process completion, is a better indicator than 1-time screening, authors noted no mortality or early CRC detection conclusions can be drawn from these data due to lack of statistical power. We will have to patiently wait for the final results from the CONFIRM and COLONPREV trials for hard-outcomes comparison between FIT and colonoscopy, but based on this recent study, outreach colonoscopy strategies appear to be the most effective option to increase CRC screening process completion in our safety-net populations.

And…time for MiniCuts!

In a small (n=75) randomized controlled trial (DIAMOND) [16] exploring the benefit of insulin pump therapy in type 1 diabetes patients on continuous glucose monitoring, insulin pump therapy was found to significantly improve glycemic control compared to multiple daily injections.

In a slightly bigger prospective study including more than 100,000 patients with a +20-year follow-up [17], never-smoker participants with early asthma had similar respiratory and non-respiratory infection rates compared to patients with diabetes.

And finally, to allow all the dog-lovers among us to fully rest after dissecting dense medical literature, a prospective first-of-its-kind study [18] suggested that human sleep does not seem to be disturbed by sharing the room with one adult dog.

Dr. Alvaro F. Vargas P. M.D, is a 1st year resident at NYU Langone Health

Peer reviewed by Daniel Taupin, MD, contributing editor, Clincial Correlations

Image courtesy of Wikimedia Commons

References

  1. Corkery C. Hurricane Irma turns Barbuda to ‘rubble’ as storm the size of France churns through the Caribbean. The National. September 7, 2017. https://www.thenational.ae/world/the-americas/hurricane-irma-turns-barbuda-to-rubble-as-storm-the-size-of-france-churns-through-the-caribbean-1.626488
  2. Berlinger J, Castillo M, Sanchez R. Mexico’s strongest earthquake in a century leaves dozens dead. CNN. September 8, 20017. http://www.cnn.com/2017/09/08/americas/earthquake-hits-off-the-coast-of-southern-mexico/index.html
  3. Lanktree G. Could You Be Affected By The Equifax Data Breach That Hit 143M American? Newsweek. September 8, 2017. http://www.newsweek.com/could-you-be-affected-equifax-data-breach-hit-143m-americans-661618
  4. Thomas, L. Juan Martin del Potro’s Beautiful Upset of Roger Federer at the U.S. Open. The New Yorker. September 7, 2017. https://www.newyorker.com/news/sporting-scene/juan-martin-del-potros-beautiful-upset-of-roger-federer-at-the-us-open
  5. Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015; 373:2103-16.[PMID: 26551272] doi:10.1056/NEJMoa1511939
  6. Berlowitz DR, Foy CG, Kazis LE, et al. Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes. N Engl J Med 2017; 377:733-744. Published online August 24, 2017. DOI: 10.1056/NEJMoa1611179  http://www.nejm.org/toc/nejm/377/8/
  7. Beddhu S, Rocco MV, Toto R, Craven TE, Greene T, Bhatt U, et al. Effects of Intensive Systolic Blood Pressure Control on Kidney and Cardiovascular Outcomes in Persons Without Kidney Disease: A Secondary Analysis of a Randomized Trial. Ann Intern Med. [Epub ahead of print 5 September 2017] doi: 10.7326/M16-2966
  8. Husten L. Cardiologists: Thumbs Down To SPRINT. Cardio Brief. August 30, 2016. http://www.cardiobrief.org/2016/08/28/cardiologists-thumbs-down-to-sprint/
  9. Hofmann R, James SK, Jernberg T, et al. Oxygen Therapy in Suspected Acute Myocardial Infarction. N Engl J Med. 2017. Published online August 28, 2017
  10. Cabello JB, Burls A, Emparanza JI, Bayliss SE, Quinn T. Oxygen therapy for acute myocardial infarction. Cochrane Database Syst Rev 2016; 12: CD007160.
  11. Stub D, Smith K, Bernard S, et al. Air versus oxygen in ST-segment-elevation myocardial infarction. Circulation 2015; 131: 2143-50.
  12. Goto M, Schweizer ML, Vaughan-Sarrazin MS, Perencevich EN, Livorsi DJ, Diekema DJ, Richardson KK, Beck BF, Alexander B, Ohl ME. Association of Evidence-Based Care Processes With Mortality in Staphylococcus aureus Bacteremia at Veterans Health Administration Hospitals, 2003-2014. JAMA Intern Med.Published online September 05, 2017. doi:10.1001/jamainternmed.2017.3958
  13. Singal AG, Gupta S, Skinner CS, Ahn C, Santini NO, Agrawal D, Mayorga CA, Murphy C, Tiro JA, McCallister K, Sanders JM, Bishop WP, Loewen AC, Halm EA. Effect of Colonoscopy Outreach vs Fecal Immunochemical Test Outreach on Colorectal Cancer Screening CompletionA Randomized Clinical Trial. 2017;318(9):806–815. doi:10.1001/jama.2017.11389
  14. White A, Thompson TD, White MC, et al. Cancer screening test use—United States, 2015. MMWR Morb Mortal Wkly Rep. 2017;66(8):201-206.
  15. Quintero E, Castells A, Bujanda L, et al; COLONPREV Study Investigators. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N Engl J Med. 2012; 366(8):697-706.
  16. Beck RW, Riddlesworth TD, Ruedy KJ, et al. Effect of initiating use of an insulin pump in adults with type 1 diabetes using multiple daily insulin injections and continuous glucose monitoring (DIAMOND): a multicentre, randomised controlled trial. The Lancet Diabetes & Endocrinology. 2017; 5(9): 700-708.
  17. Helby J, Nordestgaard BG, Benfield T, Bojesen SE. Asthma, other atopic conditions and risk of infections in 105,519 general population never and ever smokers. Journal of Internal Medicine. 2017; 282(3): 254-267.
  18. Patel SI, Miller BW, Kosiorek HE, Parish JM, Lyng PJ, Krahn LE. The Effect of Dogs on Human Sleep in the Home Sleep Environment. Mayo Clinic Proceedings. 2017; 92(9):1368-1372.

 

 

 

 

Primecuts – This Week in the Journals

September 6, 2017

AtherosclerosisBy Rushad Dordi, MD

Peer Reviewed

This week’s Primecuts details four examples of novel methodologies for treating common diseases. We begin first with a study repurposing an anti-inflammatory therapeutic for the treatment of atherosclerosis, and move onto a new targeted gene therapy for malignant mesothelioma. Finally, we touch on using probiotics to modify peanut allergies, based on a novel understanding of immunogenicity, and using the immune system to assist regulation in type 1-diabetes. Together, these studies show the power of creative thinking in the scientific process, and how even well characterized pathologies can benefit from new approaches.

1) Anti-inflammatory Therapy with Canakinumab for Atherosclerotic Disease

Atherosclerosis is well documented to be, at least in part, an inflammatory process (1). The inflammatory response is a critical part of healing after vascular injury, and in the long run likely plays a role in thrombosis and plaque instability (2). However, no purely anti-inflammatory drugs are used for treatment of atherosclerotic disease, and even drugs with anti-inflammatory effects, such as aspirin, are thought to exert their benefit via non-inflammatory mechanisms.

In a recent paper (CANTOS), Ridker and colleagues explore the potential for canakinumab, a monocolonal antibody targeting interleukin-1B, in the treatment of atherosclerotic cardiovascular disease (3). The authors randomly assigned 10,061 patients with previous myocardial infarction and elevated C-reactive protein levels to either one of three doses of canakinumab (50mg, 150mg, 300mg) or placebo. The primary endpoint of this 5 year study was a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. The incidence rate for the primary endpoint was 4.50 events per 100 person-years in the placebo group, 4.11 (HR 0.93 [0.80-1.07], p=0.30) in the 50mg group, 3.86 (HR 0.85 [0.74-0.98] p=0.021) in the 150mg group, and 3.90 (HR 0.86 [0.75-0.99] p=0.031) events in the 300mg group. Significantly more infection related deaths occurred in the experimental group.

CANTOS has helped elucidate the inflammatory hypothesis of atherosclerotic cardiovascular disease. However, more studies on the nature of the benefit are needed: statistical significance on the primary composite endpoint was driven by a lower incidence of myocardial infarction alone. And, given that the drug currently costs about $200,000 a year, more efforts are needed to stratify patients for those who may be better responders especially with such a small absolute risk reduction. Nevertheless, with intriguing CANTOS results, the door is open for further studies on anti-inflammatory agents for treatment of atherosclerosis.

2) Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomized double-blind placebo-controlled trial

Food allergies have become increasingly common in the past few decades, with deleterious effects on health and quality of life (4). Research shows that children with allergies have a quality of life worse than those with diabetes, and that accidental ingestion of peanuts in those with allergy is the leading cause of anaphylaxis (5, 6).

This week, Tang et al. published 4 year follow-up results from their initial study using a combined probiotic and peanut oral immunotherapy (PPOIT) to desensitize children with peanut allergy. The original trial randomized children into two groups: one with PPOIT with increasing amounts of peanut protein, and the other to placebo. The trial ran for 18 months and found that 82 percent of children in the experimental group became desensitized to peanut, as compared to just 4 percent in the placebo group (tolerance defined by mg of peanut ingestion).

Children from the original study were invited to participate in the extension study, which assessed peanut consumption habits over the last 4 years. The follow-up showed that participants from the PPOIT group were significantly more likely than those from the placebo group to continue eating peanut (16 of 24 (67%) patients versus one of 24 (4%), p=0.001), and had smaller wheals in peanut skin prick tests (5.2m [10.3, 0.0]).

Despite not having any particular guidelines during the follow-up period, treated children were still able to maintain their tolerant state. The trial suggests that continuous, small interventions, can have significant effects for this widely prevalent pathology.

3) Rivaroxaban with or without aspirin in stable cardiovascular disease

Aspirin and if necessary, dual anti-platelet therapy (DAPT) are currently standard of care for secondary prevention in cardiovascular disease. Yet with this regimen, nearly 10% of patients each year have recurrent events (7). In light of this, studies have attempted other means of anti-coagulation, but were met with limited success. Treatment with warfarin, for example, alone or in combination with aspirin, is superior to aspirin alone but leads to a significantly higher rate of intracranial bleeding (8).

Yusuf and colleagues this week reported the results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, which used the factor Xa inhibitor rivaroxban in secondary prevention (9). This trial randomized 27,395 patients into either low dose aspirin monotherapy (control group), low dose (5mg twice daily) rivaroxaban alone, or aspirin plus very low-dose rivaraoxaban (2.5mg twice daily). The primary endpoint was the rate of a composite endpoint of cardiovascular death, myocardial infarction, or stroke.

The results were compelling. The primary outcome occurred in 4.1% of patients with combination therapy, 4.9% of patients with rivaroxban alone, and 5.4% of patients with aspirin alone (HR of combination therapy vs aspirin alone was 0.76 [0.66, 0.86], p<0.001). Though the rates of major bleeding were significantly higher in the rivaroxaban groups than in the aspirin alone group, there was a net clinical benefit of adding rivaroxaban, and the trial was stopped early for efficacy.

Though the results are compelling, it is noteworthy that the inclusion criteria did not specify that patients be on maximal medical therapy prior to enrollment. This risks the notion that these patients may have been predisposed to a higher rate of events, in comparison to those patients on standard of care for cardiovascular disease. Nevertheless, the trial represents an important step in the field of thrombo-cardiology.

4) Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes 

Type 1 diabetes, which affects over 1 million people in the US, is an autoimmune disorder in which the body’s T-cells mistakenly attack the insulin producing cells in the pancreas (10). Despite the knowledge that type 1 diabetes is an immune mediated disease, few studies have tested the potential merit of immunotherapy in this condition.

Ali and colleagues this week reported the results of a placebo controlled study to determine whether a proinsulin peptide could modify T-cells in patients recently diagnosed with type 1 diabetes (11). 24 patients with the HLA-DRB1*0401 subtype of type 1 diabetes were randomized to either intradermal injections of proinsulin peptide every 2 or 4 weeks, or to placebo. The endpoint of the study was the change in required insulin use over 1 year, and in the serum levels of C-peptide. While the placebo group’s daily insulin use increased by 50% over 12 months,  the experimental group remained unchanged. Placebo subjects similarly showed a significant decline in C-peptide versus baseline, whereas no change was seen in those patients on immunotherapy. There was no evidence of toxic side effects, and pancreatic beta cells were not impaired as a result of the therapy.

Though the trial was not powered for efficacy, the results are compelling. The clean safety profile of the immunotherapy provides strong rationale for a subsequent study to more robustly test efficacy, and potentially lead to a new mechanism for treatment of this chronic, prevalent disease.

Minicuts 

Natriuretic peptide in congestive heart failure

Natriuretic peptides are biochemical markers of heart failure severity and predictors of adverse outcomes. Results published this week in JAMA showed however that a strategy of titrating standard therapy with natriuretic peptide levels did not significantly improve time to first hospitalization or mortality in heart failure patients (12).

A monoclonal antibody for hemophilia A

Emicuzamab is a monoclonal antibody which functions to bring together clotting factors IX and X, to restore to the function of factor VIII. Results of a phase 3 trial using emicuzamab as prophylaxis in hemophilia A were published, which showed significant benefits in annualized bleeding, as compared to patients receiving standard of care (13).

Selective internal radiotherapy in colorectal cancer

Results from a meta-analysis of three randomized trials using first-line chemotherapy with selective internal radiation therapy (SIRT) in patients with metastatic colorectal cancer with liver metastases was published in The Lancet (14). The data showed that the addition of SIRT to first line chemotherapy did not improve overall survival compared to chemotherapy alone.

Dr. Rushad Dordi is a 1st year resident at NYU Langone Health

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

Image courtesy of Wikimedia Commons

References

  1. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340(2):115-26. http://www.nejm.org/doi/full/10.1056/NEJM199901143400207
  2. Libby P, Ridker PM, Hansson GK, Leducq Transatlantic Network on A. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54(23):2129-38. https://www.ncbi.nlm.nih.gov/pubmed/19942084
  3. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1707914
  4. Osborne NJ, Koplin JJ, Martin PE, Gurrin LC, Lowe AJ, Matheson MC, et al. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J Allergy Clin Immunol. 2011;127(3):668-76 e1-2. https://www.ncbi.nlm.nih.gov/pubmed/21377036
  5. Prescott SL, Pawankar R, Allen KJ, Campbell DE, Sinn J, Fiocchi A, et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ J. 2013;6(1):21.
  6. Sicherer SH, Sampson HA. Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133(2):291-307; quiz 8.
  7. Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304(12):1350-7.  https://www.ncbi.nlm.nih.gov/pubmed/20805624
  8. Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol. 2003;41(4 Suppl S):62S-9S.
  9. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017.
  10. Patterson CC, Gyurus E, Rosenbauer J, Cinek O, Neu A, Schober E, et al. Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase. Diabetologia. 2012;55(8):2142-7. https://www.ncbi.nlm.nih.gov/pubmed/22638547
  11. Alhadj Ali M, Liu YF, Arif S, Tatovic D, Shariff H, Gibson VB, et al. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Sci Transl Med. 2017;9(402). https://www.ncbi.nlm.nih.gov/pubmed/28794283
  12. Felker GM, Anstrom KJ, Adams KF, Ezekowitz JA, Fiuzat M, Houston-Miller N, et al. Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2017;318(8):713-20.
  13. Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017;377(9):809-18. https://www.ncbi.nlm.nih.gov/pubmed/28691557
  14. Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017. https://www.ncbi.nlm.nih.gov/pubmed/28781171

 

Primecuts – This Week in the Journals

August 29, 2017

eclipse 2By Scarlett Murphy, MD

Peer Reviewed

American attention shifted away from challenging national conversations in the wake of Charlottesville towards the sky this past Monday, when a total solar eclipse traversed the entire US mainland for the first time since 1918 (1).  Although we missed out on the breath-taking experience of totality, New Yorkers still enjoyed a 72% partial eclipse (2).

President Trump held a special rally in Arizona, where he criticized the media for propagating his comments about Charlottesville that seemed to some to equate terrorist actions wielded by white supremacists with the largely peaceful resistance of counter protestors (3).  At this rally, the president threatened a government shutdown if Congress would not allocate funding for a border-wall with Mexico. Shortly afterwards, Trump pardoned Former Sheriff Joe Arpaio, drawing bipartisan criticism including a public denouncement from Arizona Senator John McCain (4) Arpaio was previously found to be guilty of criminal contempt of court for actively defying a federal district court order to stop detaining immigrants solely on the suspicion that they were undocumented (5).

Just days after Secretary of State Rex Tillerson praised North Korea for holding off on additional nuclear testing since July’s ICBM launch, North Korea fired three short range ballistic missiles off of it’s east coast (6).  Some analysts believe this was in response to Ulchi Freedom Guardian drills, an annual event held between the US and South Korea (6).

While most of the news remains far from uplifting, promising medical developments unfold everyday.  In this week’s Primecuts, we’ll focus on new updates addressing concerns with the 2015 SPRINT trial, examine if continuous glucose monitoring confers benefit in type II diabetes, learn about the role of steroids in acute lower respiratory tract infection, and revisit an affirmed association between HIV and HSV-2. 

SPRINT revisited: Effect of Intensive Blood-Pressure Treatment

on Patient-Reported Outcomes

We are all familiar with the SPRINT trial, the 2015 randomized control trial demonstrating that intensive systolic blood pressure (SBP) control in patients without diabetes lowered overall risk of fatal and non-fatal cardiovascular events as well as all-cause mortality (7).  Initial results were so compelling that the trial was halted after three of the five planned years (7). However, adoption of intensive control in clinical practice has lagged behind the data, with pervasive concerns among providers including increased weakness, impaired cognition, and lower quality of life in patients already burdened by multiple medical comorbidities.

Holding strong to their original thesis, the authors of SPRINT published new findings in the New England Journal this week addressing concerns about how intensive SBP control impacts overall quality of life. As part of the original SPRINT trial design, participants randomly assigned to an SBP target of 120mmHg or 140mmHg also completed multiple surveys at baseline and then at 12 and 24 months. Administered surveys included the physical component summary (PCS) and mental health component summary (MCS) of the Veterans RAND 12-Item Health survey, PHQ-9 surveys, and study-specific surveys regarding overall satisfaction with blood pressure care and medication adherence (8).

No significant differences were found between PCS, MCS and PHQ-9 scores between the two study arms over three years of follow-up.  Patients in the high-intensity arm on average received one additional medication with an overall average SBP reduction of 14.8 mmHg. Medication adherence did not differ between the study arms. Patients even reported slightly higher overall satisfaction with blood pressure care in the high-intensity arm, although the researchers graciously acknowledge the differences’ statistical but not clinical signification (88.6% vs 88.2%) (8).

            While offering reassurance about overall physical and mental well being, this study doesn’t explicitly examine a prominent concern:  possible increased instances of orthostasis or dizziness. However, it’s possible that such episodes implicitly factor into how patients evaluate their overall quality of life. Another possible limitation, acknowledged by the authors, includes a lack of evaluation in the first six months, in which many adverse events or functional status declines may have occurred (8).

Although cognitive function, medication adherence and quality of life were on-average unchanged during the three years of follow-up, I anticipate continued resistance to adding second or third line agents, as many embrace concerns about polypharmacy in the elderly as dogma (9). It will be interesting to see if the dissemination of these findings sways skeptics into intensifying control of their patients with high cardiovascular risk.

No Benefit to Glucocorticoids in Acute Lower Respiratory Tract Infection

In attempt to curtail the rampant misuse of antibiotics in the primary care setting, many providers have been offering oral corticosteroids to patients without asthma who present with acute lower respiratory infections (LRTI).  Acute LRTIs present with the same symptomatology as acute asthma exacerbations, and are associated with similar underlying bronchial epithelial changes (10).  One study reported usage in 15% of LRTI cases, despite a paucity of evidence supporting its use (11).  A new study published in this week’s JAMA examined the efficacy of steroid regimens in symptom reduction of LRTIs in patients without asthma.

In this randomized control trial across 54 family practice locations throughout the UK, 401 adults without a history of asthma presenting with acute LRTI symptoms were randomly assigned to receive a 5-day course of twice daily prednisolone (20 mg) or a placebo pill for the same duration.  Primary outcomes assessed variation between study arms for duration of cough and mean symptom severity scores on days 2-4 (10).

No difference was observed between the prednisolone and placebo arms for median cough duration (5 days in both arms). There was a non-statistically significant reduction in symptom severity scores (adjusted difference -0.2, relative reduction 9.3%) for the prednisolone group. No significant effects were observed for secondary outcomes including duration of non-cough symptoms, duration of abnormal peak flow, antibiotic use, or other adverse events (10).

This study addressed a novel question, as previous trials have evaluated inhaled but not oral corticosteroids for this condition. Limitations include a low recruitment rate (possibly signifying biased patient selection), and the potential to have unwittingly included patients with chronic or post-infectious cough who may have responded more favorably to steroids. The scope of the study did not address the efficacy of steroids in patients presenting with an infection severe enough to warrant initial antibiotics (10).

Acute LRTIs cause significant distress to patients. Exploring pharmacologic options that have shown efficacy in similar conditions is tempting given the dire need to curb inappropriate antibiotic use. However, oral corticosteroids don’t affect cough duration or severity in LRTIs, and this study’s authors actively recommend against their usage in patients who don’t have asthma or COPD (10).  For now, patients should be advised to stick to their grandma’s chicken soup.

Continuous Glucose Monitoring in Type II diabetes

The use of continuous blood glucose monitors (CGM) has provided individuals with type 1 diabetes (T1DM) more robust data for optimized glycemic control, with randomized trials showing significant reductions in HbA1c and reduced blood glucose variability. Previous trials on whether CGM could offer similar benefit in individuals with type II diabetes (T2DM) have shown mixed results.  In this week’s Annals of Internal Medicine, a new study demonstrated improved glycemic control with CGM in individuals with T2DM receiving multiple daily insulin (MDI) injections (12).

In this randomized clinical trial, 158 patients who met selection criteria throughout 25 endocrinology clinics were randomized either to the CGM experimental arm or the control arm, in which they monitored blood glucose four times daily using a traditional monitor (12).

Patients were assessed at follow-up visits at 4, 12 and 24 weeks.  Adjustments were made to insulin regimen based on the provider’s clinical judgment rather than a specific protocol.  Primary outcome was HbA1c reduction at 24 weeks (12).

At the end of the 24-week period, HbA1c reduction in the CGM arm was significantly greater than in the control group, although both groups attained HbA1c reduction (8.5% to 7.5% vs. 8.5% to 7.9%). Individuals in the CGM arm gained 1.3 kg over the 24-week period, whereas individuals in the control arm on average did not gain weight.  Episodes of severe hypoglycemia, DKA or HHS were not observed in either arm (12).

Acknowledged limitations to this study include the fact that follow-up was limited to six months, although the authors were optimistic about the high level of participation throughout the trial duration. The study was funded through the CGM device manufacturer, although they did not have approval authority over the final manuscript (12).

The reduction of HbA1c in both arms without significant pharmacologic adjustments may indicate that more frequent glucose monitoring alone improves glycemic control.  It is also worthwhile to note that reductions in HbA1c in CGM arm, while statistically significant, were also moderate at best (0.4% difference).  Weight gain experienced in the CGM arm is consistent with developments in other studies aiming for tighter glycemic control, and is an unfortunate complication that may limit overall macrovascular benefit to intensive treatment (12). A study of another CGM device that required patients to actively scan the system did not exhibit beneficial reduction in HbA1c, supporting both the idea that processes that require less patient input are more likely to aid in patient success but also muddling our ability to draw solid conclusions about the potential benefits of CGM in this population (13).  In a world with ever-advancing technology, it is essential to continually evaluate new developments, including CGM, that may benefit management of a highly prevalent illness associated with devastating morbidity when poorly managed.

HSV-2 incidence increases the likelihood of HIV acquisition

Herpes simplex 2 (HSV-2) and HIV infections are associated with major morbidity and mortality worldwide, with the burden of disease falling predominately on lower-income nations. A co-infection syndrome between HSV-2 and HIV has been previously described in literature, however, supporting data stems from small meta-analyses now over a decade old. A new WHO-funded meta-analysis of over 57 longitudinal studies published this week in the Lancet examined whether this purported association remained strong after considering a substantial amount of new research (14).

Researchers comprehensively reviewed available literature to identify appropriate cohort studies, case-controlled studies and controlled trials that assess the effect of pre-existing HSV-2 infection on HIV acquisition. Using data from these studies and previous meta-analyses, they estimated the association between HIV seroconversion with HSV-2 infection incidence or prevalence. They examined whether sex or membership in a general risk or higher risk pool (female sex workers, men who have sex with men, serodiscordant couples, and STD clinic patients) affected this relationship (14).

In this study, the incidence of new HIV was triple the baseline rate in general populations with high HSV-2 prevalence, and double the baseline in higher risk populations with similarly elevated HSV-2 prevalence. High incidence of new HSV-2 infections in general populations conferred an even higher risk than HSV-2 prevalence for new HIV acquisition (adjusted RR 2.7, 95% CI 2.2–3.4 vs RR 4.7, 95% CI 2.2–10.1) (14).

Because both infections are associated with the same body of risk factors, multiple opportunities for confounding are present, although the researchers believe they controlled for most instances.  Most of the populations categorized as general were African, which may have affected the generalizability of results to other world regions. As with all meta-analysis, publication bias may underlie many conclusions, although effects were believed to be minimal in this study (14).

Results from this study were largely consistent with previously published data, but novel in that they highlight a relationship between incident exposure and subsequent HIV acquisition (prior studies have only been able to link HSV-2 prevalence with HIV). Efforts are underway to develop an HSV-2 vaccine, and these results strengthen the idea that funding targeting HSV-2 reduction could have a beneficial effect on reducing not only HSV-2 but also HIV burden globally (14). 

Minicuts: 

Global Burden of Rheumatic Heart Disease

In the 2015 Global Burden of Disease Study, researchers examined worldwide prevalence and associated mortality of rheumatic heart disease over the past 25 years.  Results published in this week in the New England Journal cited an overall decline in global prevalence and mortality, but noted that rates remain high in vulnerable-low income countries, including South Asia, central sub-Saharan Africa and Oceania where an estimated 10-15 per 1000 persons are living with rheumatic heart disease (15).

Vitamin C and Leukemia in Murine Models

Researchers working with hematopoetic stem cells (HSC) in vivo in mice models discovered a relationship between systemic vitamin C depletion and reduced Tet2 tumor suppressor function, leading to increased HSC frequency and function and accelerated leukaemogenesis.  Increased dietary vitamin C consumption subsequently reversed this process, suggesting that accumulated ascorbate in cells leads to increased tumor suppressor gene expression, in turn suppressing HSC frequency, myelopoesis and leukamogenesis (16).

Older adults “on the move”

Older adults living in independent living facilities who participated in the “On the Move” exercise program as part of a randomized single intervention trial showed greater overall improvement in walking ability than those who participated in conventional senior exercise programs.  The “On the Move” program focuses on timing and movement coordination, whereas “usual care” exercise programs typically focus on seated strength, endurance and flexibility (17).

Dr. Scarlett Murphy is a 1st year resident at NYU Langone Health

Peer reviewed by David Kudlowitz, MD, NYU Internal Medicine Associates, NYU Langone Health

Image courtesy of Wikimedia Commons

References

1. Fountain H. A Total Solar Eclipse Leaves  a Nation in Awe. The New York Times. August 21 2017 https://www.nytimes.com/2017/08/21/science/total-solar-eclipse-day.html?mcubz=1

2. Wolfe J. New York Today: How to Watch the Solar Eclipse. The New York Times. August 21 2017 https://www.nytimes.com/2017/08/21/nyregion/new-york-today-how-to-watch-the-solar-eclipse.html?mcubz=1).

3. Wagner J, Johnson J, Paquette D. Trump threatens shutdown, suggests controversial pardon at Arizona rally.  The Washington Post. August 23rd 2017. https://www.washingtonpost.com/politics/trump-holds-campaign-style-rally-amid-large-protests-in-arizona/2017/08/22/dd7c83c0-8796-11e7-961d-2f373b3977ee_story.html?utm_term=.a98943d294a2

4.  Davis JH, Haberman M. Trump Pardons Joe Arpaio, Who Became Face of Crackdown on Illegal Immigration. The New York Times. August 25 2017. https://www.nytimes.com/2017/08/25/us/politics/joe-arpaio-trump-pardon-sheriff-arizona.html?mcubz=1

5. Perez-Pena R. Former Arizona Sheriff Joe Arpaio Is Convicted of Criminal Contempt.  The New York Times. July 31 2017. https://www.nytimes.com/2017/07/31/us/sheriff-joe-arpaio-convicted-arizona.html

6. Kim J, Stewart P. North Korea tests short-range missiles as South Korea, U.S. conduct drills.  Reuters. August 25 2017. https://ca.reuters.com/article/topNews/idCAKCN1B52Q2-OCATP 

7. Original Sprint Trial

8. Berlowitz DR, Foy CG, Kazis LE, et al. Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes. N Engl J Med 2017; 377:733-744. Published online August 24, 2017. DOI: 10.1056/NEJMoa1611179  http://www.nejm.org/toc/nejm/377/8/

9. Maher RL, Hanlon JT, Hajjar ER. Clinical Consequences of Polypharmacy in Elderly. Expert opinion on drug safety. 2014;13(1):10.1517/14740338.2013.827660. doi:10.1517/14740338.2013.827660.

10. Hay AD, Little P, Harnden A, Thompson M, Wang K, Kendrick D, Orton E, Brookes ST, Young GJ, May M, Hollinghurst S, Carroll FE, Downing H, Timmins D, Lafond N, El-Gohary M, Moore M. Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract InfectionA Randomized Clinical Trial. JAMA. 2017;318(8):721–730.

11. Ebell MHR, Radke T. Antibiotic use for viral acute respiratory tract infections remains common. Am J Manag Care. 2015;21(10):e567-e575. https://www.ncbi.nlm.nih.gov/pubmed/26619058

12.  Schwartz SS. Optimizing glycemic control and minimizing the risk of hypoglycemia in patients with type 2 diabetes. Drugs in Context. 2013;2013:212255. doi:10.7573/dic.212255. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884850/

13. Beck RW, Riddlesworth TD, Ruedy K, Ahman A, et al. Continuous Glucose Monitoring Versus Usual Care in Patients with Type 2 Diabetes Receiving Multiplde Daily Insulin Injections. Ann Intern Med. Published online Ausgust 22, 2017. doi:10.7326/M16-2855

14. Looker KJ, Elmes JAR, Gottleib SL, et al. Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis. Lancet Infect Dis. Published online August 23, 2017. http://dx.doi.org/10.1016/S1473-3099(17)30405-X

15. Watkins DA, Johnson CO, Colquhoun SM, et al. Global, regional, and national burden of rheumatic heart disease, 1990–2015. N Engl J Med 2017;377:713-722.

16. Agathacleous M, Meacham CE, Burgess RJ, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. Published online August 21, 2017. doi: 10.1038/nature23876

17. Brach JS, Perera S, Gilmore S, VanSwearingen JM, Brodine D, Nadkarni NK, Ricci E. Effectiveness of a Timing and Coordination Group Exercise Program to Improve Mobility in Community-Dwelling Older AdultsA Randomized Clinical Trial. JAMA Intern Med. Published online August 14, 2017. doi:10.1001/jamainternmed.2017.3609

 

Primecuts – This Week in the Journals

August 21, 2017

barcelonaBy Andrew Armanious, MD

Peer Reviewed

This past week, President Trump decided to part ways with White House Chief Strategist Steve Bannon (1). Bannon was a controversial and blunt-spoken political figure who influenced President Trump on many of his contentious campaign decisions. Bannon will be returning to his prior position of executive chairman of Breitbart News.

In world news, thousands of Spaniards in Barcelona assembled along La Rambla in an act of defiance against terrorism less than 24 hours after a van rammed into crowds of people in the same location (2). Participants commemorated the dead at makeshift memorials along the city’s ancient boulevard.

In this week’s edition of PrimeCuts, we will explore evolocumab’s effects on cognition, azithromycin use in asthma, alcohol’s effects on mortality, and detection of cancer using tumor DNA. 

Cognitive Function in a Randomized Trial of Evolocumab 

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are an exciting new frontier in cholesterol-lowering drug therapy. PCSK9 is an enzyme that binds and degrades the LDL receptor found on the surface of hepatocytes. By inhibiting PCSK9, higher quantities of LDL receptors are recycled and returned to the cell membrane, subsequently decreasing plasma LDL levels. Monoclonal antibodies to PCSK9, such as evolocumab, have been shown to reduce plasma LDL by up to 60 percent in patients on statin therapy (3).

The landmark FOURIER trial was a multi-national, randomized, placebo-controlled trial in which participants, aged 40 to 85 years with clinically evident atherosclerosis, had an LDL level of at least 70 on statin therapy (4). Evolocumab was compared to placebo in regards to several efficacy endpoints. It was shown that evolocumab reduced the risk of myocardial infarction, stroke, and coronary revascularization. However, there was no significant difference in cardiovascular death, death from all causes, or hospitalizations for unstable angina. While no mortality benefit was found in the FOURIER trial, a prior meta-analysis of 24 randomized trials found that PCSK9 inhibitors reduced both all-cause mortality and cardiovascular mortality (5).

In FOURIER and other PCSK9 inhibitor trials, a small percentage of patients reported adverse neurocognitive effects, raising concerns that either the drug itself and/or low LDL levels negatively impact cognition. In this week’s NEJM, investigators explored these concerns in the EBBINGHAUS study using neuropsychological testing in a subgroup of patients from the FOURIER trial (6).

The EBBINGHAUS study followed a total of 1204 patients enrolled in the FOURIER trial for a median of 19 months in order to demonstrate non-inferiority of evolocumab compared to placebo in terms of performance on the Cambridge Neuropsychological Test Automated Battery (CANTAB). Exclusion criteria were current or past diagnoses of mild cognitive impairment, dementia, or any condition or situation that would confound study results or interfere with participation.

The primary end point was the mean change from baseline over time of the raw score on the spatial working memory strategy index of executive function – one of the main components of CANTAB. The non-inferiority boundary was set at 20% of the standard deviation, estimated from observations in the placebo arm. In both arms, the baseline raw score was 17.8. The mean change from baseline in the evolocumab arm was -0.21 ± 2.62, compared to -0.29 ± 2.81 in the placebo arm (p < 0.001 for non-inferiority). Furthermore, exploratory analyses performed after stratification according to the lowest-attained LDL level after randomization did not find an association between LDL level and cognitive decline.

This study’s findings are promising for the future of the PCSK9 inhibitor class of LDL-lowering drugs. Limitations of the study include short follow-up relative to the decades of therapy that patients with high cholesterol typically undergo. In addition, because of the aforementioned exclusion criteria, conclusions cannot be drawn about the drug’s effects on cognition in patients with underlying dementia or mild cognitive impairment. Regardless, this study provides evidence that helps to ease concerns brought up by previous PCSK9 inhibitor trials.

Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial

Over 50 million people worldwide are estimated to have moderate-to-severe uncontrolled asthma. These patients often have severe exacerbations of their chronic disease despite treatment with inhaled corticosteroids and long-acting bronchodilators. Several add-on therapies have been studied in the treatment of persistent asthma. For instance, macrolide antibiotics have been shown to have antibacterial and antiviral effects; they also reduce airway inflammation in patients with refractory asthma (7).

While systematic reviews have shown improvement in asthma symptoms with macrolide therapy, endpoints such as number of asthma exacerbations have not been fully investigated. In the most recent edition of The Lancet, investigators sought to test the hypothesis that adding azithromycin therapy in patients with uncontrolled persistent asthma on inhaled maintenance therapy would reduce exacerbations and improve quality of life (8).

In the multi-center, randomized, double-blind, placebo-controlled AMAZES trial, 420 patients with persistent uncontrolled asthma despite maintenance therapy were assigned to either oral azithromycin 500mg three times weekly or placebo for 48 weeks. The ACQ6, a six-item symptom questionnaire, was used to define loss of asthma control (score ≥ 0.75). Exclusion criteria were recent exacerbations, infections, or changes in medication in the 4 weeks prior to study entry, active smoking, parenchymal lung disease, hearing impairment, and prolonged QTc.

The primary endpoints were total number of moderate and severe asthma exacerbations over 48 weeks and asthma quality of life (using the Asthma Quality of Life Questionnaire, or AQLQ). The azithromycin arm experienced 1.07 exacerbations per person-year (95% CI: 0.85-1.29), compared to 1.86 exacerbations in the control arm (95% CI: 1.54-2.18). The incidence rate ratio was 0.59 (95% CI: 0.47-0.74, p < 0.0001). Across all AQLQ domains, the azithromycin-treated group experienced improvement in quality of life with an adjusted mean difference of 0.36 (95% CI: 0.21-0.52, p = 0.001). There was no statistically significant difference in serious adverse effects between both groups; the azithromycin arm was significantly associated with higher rates of diarrhea.

This study used well-defined and patient-relevant endpoints to demonstrate that adding azithromycin to maintenance therapy in persistent uncontrolled asthma is safe and effective. One limitation of the study worth noting is antimicrobial resistance in the setting of add-on macrolide therapy. In fact, in the AMAZES trial, surveillance sputum cultures demonstrated an increase in azithromycin-resistant organisms in the azithromycin treatment arm. Although the increase was not statistically significant (p = 0.062), perhaps add-on azithromycin therapy should be restricted in terms of patient selection and duration of treatment so as to minimize future antimicrobial resistance.

Relationship of Alcohol Consumption to All-Cause, Cardiovascular, and

Cancer-Related Mortality in U.S. Adults

It has been well known that excessive alcohol consumption is directly linked to increased morbidity and mortality due to poisoning, liver disease, cancer, and other chronic diseases. On the other hand, several meta-analyses have found that the relationship between alcohol consumption and mortality is “J-shaped” (9). In this type of relationship, mortality initially decreases with increasing alcohol consumption before increasing again past baseline (abstinence) mortality.

However, prior cohort studies were found to have several biases, including “abstainer bias,” in which former drinkers were misclassified as abstainers. When these biases were controlled for, the results were not as consistent. In this week’s edition of JACC, investigators used the National Health Interview Survey (NHIS) in order to analyze the relationship between quantitative alcohol intake and all-cause, cardiovascular, and cancer mortality in 336,376 U.S. adults (10).

Using ICD-10 codes, study outcomes were defined as all-cause mortality as well as CVD, heart disease, cerebrovascular, and cancer specific mortality. Participants were categorized into six groups based on quantity of alcohol consumption. Light drinking was defined as < 3 drinks/week, while moderate drinkers consumed > 3 drinks/week to ≤ 14 drinks/week for men or > 3 drinks/week to ≤ 7 drinks/ week for women. Heavy drinkers consumed > 14 drinks/week for men or > 7 drinks/week for women.

After a median follow-up of 8.2 years, 34,754 participants died of all causes. Light or moderate drinkers had a lower risk for all-cause (light: −21%; moderate: −22%) and CVD mortality (light: −26%; moderate: −29%) compared to lifetime abstainers. In contrast, heavy drinking was associated with an 11% increased risk for all-cause mortality and a 27% increase in cancer-related mortality. This increase in all-cause and cancer-related mortality was also found in participants with binge drinking (5 or more drinks in one day) that occurred ≥ 1 day/week.

Hazard ratios were obtained after adjustment for the following: sex, age, race, ethnicity, education, marital status, BMI, physical activity, smoking, and physician-diagnosed diseases (hypertension, heart disease, stroke, cancer, and diabetes).

This study emphasizes the existence of the previously studied J-curve relationship between alcohol consumption and mortality. Strengths of this study include a large sample size and elimination of prior cohort studies’ biases by making the reference group only lifetime abstainers. Limitations include the fact that it is an observational study, although a long-term randomized controlled trial involving alcohol consumption may be difficult to complete.

Direct detection of early-stage cancers using circulating tumor DNA

Cancer is a highly prevalent and deadly disease that affects hundreds of millions of people worldwide. Each year, more than 8 million people die of cancer, and over 14 million people are newly diagnosed. It is well established that early detection of malignancy leads to increased effectiveness of therapies and higher rates of survival (11). Currently available biomarkers and screening methods have helped increase early detection, but they are limited to specific types of cancer and are sometimes more useful in monitoring rather than diagnosis.

Noninvasive liquid biopsy techniques have been developed using cell-free DNA (cfDNA), which has been shown to be elevated in patients with cancer (12).  Some of this cfDNA is tumor-derived and is termed circulating tumor DNA (ctDNA). In the most recent issue of Science Translational Medicine, investigators developed an approach to analyze sequence alterations in commonly altered cancer genes found in cfDNA (13). The sensitivity and specificity of the technique were evaluated in a cohort of 44 healthy individuals and a cohort of 194 patients with breast, colorectal, lung, or ovarian cancer. The cancer patients were untreated, and most were diagnosed at stages I and II.

Cancer patients were found to have higher concentrations of cfDNA (29ng/ml) compared to healthy individuals (7 ng/ml, p = 0.001). Using targeted error correction sequencing, investigators found that 67% of the cancer patients had detectable alterations in driver genes (with higher proportions of detected alterations in colorectal and ovarian cancer). Higher concentrations of both cfDNA and ctDNA were found in metastatic disease compared to earlier-stage disease among all cancer types.

The study also addressed the possible relationship between preoperative ctDNA and disease recurrence and survival in colorectal cancer. Patients with increased ctDNA had a shorter progression-free survival and overall survival compared to those with lower levels of ctDNA (p < 0.0001). When used as a continuous variable, the level of ctDNA also correlated with patient survival (p = 0.01).

The use of ctDNA for noninvasive detection of early stage cancer is an exciting new frontier in oncology. This study provides evidence that liquid biopsy analyses may be used in both quantitative and qualitative assessments of disease progression in common types of cancer. Because this technique directly identifies underlying populations of cells with identical mutations, it has the potential to have high specificity compared to other detection methods. Naturally, then, one of the limitations of this technique is its sensitivity, which raises questions about its utility as an effective screening method in the general population. Regardless, this study demonstrates that ctDNA detection could be a powerful tool in the fight against cancer. Further investigations are sure to come.

MiniCuts 

Effect of an Intensive Lifestyle Intervention

on Glycemic Control in Patients With Type 2 Diabetes 

A randomized clinical trial of 98 adults with non-insulin-dependent type 2 diabetes published in JAMA found that lifestyle interventions involving exercise and dietary plans resulted in a change in hemoglobin A1c in a direction consistent with benefit compared to standard care with counseling and target-driven medical therapy (14).

Benefits and safety of gabapentinoids in chronic low back pain:

A systematic review and meta-analysis of randomized controlled trials 

A systematic review and meta-analysis of eight randomized controlled trials reporting the use of gabapentinoid medications for chronic lower back pain published in PLOS Medicine showed minimal improvement in pain compared to other analgesics while creating significant risk of adverse effects (15).

Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes 

A retrospective cohort study published in the Annals of Internal Medicine involving 28,266 patients who experienced adverse reactions secondary to statin therapy found that continuing statin prescriptions after an adverse reaction was associated with a lower incidence of death and cardiovascular events (16). 

Dr.  Andrew Armanious is a 1st year resident at NYU Langone Health

Peer reviewed by Kevin Hauck, MD, attending physician, NYU Langone Health

Image courtesy of Wikimedia Commons 

References

  1. Press, T. (2017). Trump Ousts Bannon, His Influential, Divisive Strategist. https://www.nytimes.com/aponline/2017/08/18/us/politics/ap-us-trump-bannon.html
  1. NBC News. (2017). Scared but defiant, Barcelona marches to reclaim city from terrorists. http://www.nbcnews.com/news/world/scared-defiant-barcelona-marches-reclaim-city-terrorists-n793826
  1. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380(9858):2007-17.  https://www.ncbi.nlm.nih.gov/pubmed/23141813
  1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 http://www.nejm.org/doi/full/10.1056/NEJMoa1615664
  1. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163(1):40-51. https://www.ncbi.nlm.nih.gov/pubmed/25915661
  1. Giugliano RP, Mach F, Zavitz K, et al. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med. 2017;377(7):633-643.
  1. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177(2):148-55.
  1. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017 https://www.ncbi.nlm.nih.gov/pubmed/28687413
  1. Di Castelnuovo A, Costanzo S, Bagnardi V, et al. Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies. Arch Intern Med 2006;166: 2437–45.
  1. Xi B, Veeranki SP, Zhao M, Ma C, Yan Y, Mi J. Relationship of Alcohol Consumption to All-Cause, Cardiovascular, and Cancer-Related Mortality in U.S. Adults. J Am Coll Cardiol. 2017;70(8):913-922.
  1. World Health Organization, Guide to Cancer Early Diagnosis (World Health Organization, 2017).
  1. Stroun, P. Anker, J. Lyautey, C. Lederrey, P. A. Maurice, Isolation and characterization of DNA from the plasma of cancer patients. Eur. J. Cancer Clin. Oncol. 23, 707–712 (1987).  https://www.ncbi.nlm.nih.gov/pubmed/3653190
  1. Phallen J, Sausen M, Adleff V, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;9(403).
  1. Johansen MY, Macdonald CS, Hansen KB, et al. Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA. 2017;318(7):637-646.
  1. Shanthanna H, Gilron I, Rajarathinam M, AlAmri R, Kamath S, Thabane L, et al. (2017) Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta- analysis of randomized controlled trials. PLoS Med 14(8): e1002369. http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002369
  1. Zhang H, Plutzky J, Shubina M, Turchin A. Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study. Ann Intern Med. 2017;167(4):221-227.

Primecuts – This Week in the Journals

August 14, 2017

trainsBy Jonathan Whitehouse, MD

Peer Reviewed

In New York last week, Mayor de Blasio announced a plan to tax wealthy New Yorkers in order to raise funds for our enfeebled subway system.  It was seen by many as a direct political clash with Governor Cuomo over funding for the Metropolitan Transportation Authority, at a time when the subways are plagued by delays and cancellations, and when both politicians are preparing for elections (1). Other well-documented problems include an “antiquated signal system, severe overcrowding, and trains that are breaking down at a much higher rate than in the past” (2).   Local politicians recently participated in the two-day Riders Respond tour of the subways, interviewing and welcoming input from New York’s subway commuters.  The consistent theme from riders was dismay over the political posturing between the governor and mayor, as well as a plea to attenuate the intolerable summer heat of the subway platforms (3).

MTA’s sweltering platforms are unlikely to cool off anytime soon, at least without major policy changes by the federal government.  That’s the implication of a sweeping federal climate change report drafted by scientists from 13 federal agencies that reported that the average temperature in the United States has risen rapidly and drastically since 1980, concluding that that human activities, particularly greenhouse gas emissions, are primarily responsible for observed climate change.  The authors are awaiting permission from the Trump administration for official release of the report, although those involved would not be shocked if the report is changed or suppressed (4).

Speaking of shock, kicking off this edition of Primecuts we’ll be looking at a trial evaluating the use of angiotensin II in the treatment of vasodilatory shock, followed by studies on the effect of methylprednisolone in the treatment of IgA nephropathy, the effect of exenatide in the treatment of Parkinson’s disease, and the predictive role of bio-active adrenomedullin in sepsis.

Angiotensin II for the Treatment of Vasodilatory Shock 

The most common type of shock is vasodilatory shock, which is characterized by peripheral vasodilatation leading to reduced blood pressure in the setting of preserved cardiac output.  First line therapy to restore blood pressure is intravenous fluid resuscitation, followed by two classes of vasopressors: catecholamines and vasopressin. While effective, these medications have narrow therapeutic windows, as they can be toxic at higher doses.  Our bodies, however, also employ the renin-angiotensin-aldosterone system to increase blood pressure in vasodilatory shock.  In this week’s NEJM, investigators sought to determine whether the addition of angiotensin II would improve blood pressure in patients with vasodilatory shock refractory to standard therapies (5).

In this multi-national, double-blind, randomized, controlled trial, a total of 344 patients with vasodilatory shock already receiving conventional vasopressor support were assigned to either receive intravenous angiotensin II or placebo.  The primary endpoint was an increase in mean arterial pressure at 3 hours (either 10 mm Hg above baseline, or with an increase to at least 75 mm Hg); background vasopressors were not changed.

More patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) reached the primary endpoint; the odds ratio was 7.95 (95% CI, 4.76 to 13.3, p < 0.001). There was no statistically significant difference in the rate of adverse events between groups.

The study demonstrated that angiotensin II effectively raised blood pressure in patients with vasodilatory shock.  Limitations include a relatively small sample size, opening the possibly that clinically important side effects attributable to angiotensin may not have been detected.  Additionally, follow-up was limited to 28 days, prohibiting analysis of potential long-term effects of angiotensin II.  Finally, the study was not powered to demonstrate a difference in mortality.

The introduction of a new class of vasopressors is certainly exciting, especially one designed to mimic a natural physiological response to hypotension.  Will the addition of angiotensin II lead to better outcomes in vasodilatory shock?  The current evidence is at least promising, and further investigations and direct comparisons are certainly on the horizon.

Effect of Oral Methylprednisolone on Clinical Outcomes in Patients with IgA Nephropathy

The most prevalent primary glomerular disease is IgA nephropathy.  Patients with the disorder have an elevated risk of developing end stage renal disease (ESRD) and are typically treated with blockade of the renin-angiotensin-aldosterone system (RAAS) to prevent or slow disease progression.  Current guidelines also recommend a 6-month course of corticosteroids for patients with persistent proteinuria and reduced GFR, although this recommendation is based on low-quality evidence, and the benefit of corticosteroid therapy has been considered uncertain.  In the most recent edition of JAMA, investigators sought to evaluate the efficacy and safety of full-dose corticosteroid therapy (6).

The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multi-center, double-blind, randomized clinical trial that recruited 750 patients with IgA nephropathy. Those included had proteinuria greater than 1 g/d and an estimated glomerular filtration rate (eGFR) of 20-120 after at least 3 months of blood pressure control with RASS blockade.  Patients were randomized to either oral methylprednisolone (0.6 to 0.8 mg/kg/d) or to placebo for two months followed by a 4-6 month weaning period.  The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR.

Recruitment was discontinued after a median follow-up of 2.1 years, after observation of an increased rate of serious adverse events in the intervention group.  Serious events occurred in 20 participants in the methylprednisolone group (14.7%) vs 4 in the placebo group (3.2%; p <0.001). Most occurred in the first three months of treatment and were due to serious infections.

Over this time, the primary composite renal outcome occurred in 8 patients in the methylprednisolone group (5.9%) and 20 patients in the placebo group (15.9%; hazard ratio 0.37; p = 0.02).

While proteinuria and eGFR improved in participants randomized to receive methylprednisolone, the high rates infections suggests a need for reconsideration of current guidelines.  However, as IgA nephropathy is an immune-complex mediated disease, immune suppression with corticosteroids still holds promise as a valuable therapeutic option.  As these authors suggest, future research into the use of corticosteroids combined with prophylactic antibiotics seems an appropriate next investigatory step.

Exenatide once weekly versus placebo in Parkinson’s disease: a randomized, double-blind, placebo-controlled trial

The diabetes drug exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist which increases glucose-level-dependent insulin secretion, decreases glucagon secretion, and delays gastric emptying (7).  Previous Parkinson’s research in murine models has demonstrated that exenatide has led to improvements in motor performance, behavior, learning, and memory through unclear mechanisms.  In the most recent edition of The Lancet, investigators published a trial further studying the effects of exenatide on the motor-associated symptoms of Parkinson’s disease (7).

In a single-center, randomized double-blind, placebo-controlled trial, 62 patients with moderate Parkinson’s disease were randomly assigned to receive subcutaneous injections of exenatide or placebo weekly for 48 weeks in addition to their regular medication.  The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Motor Sub-scale (MDS-UPDRS) at 60 weeks.

In the exenatide group MDS-UPDRS scores improved by 1.0 point, and in the placebo group scores worsened by 2.1 points, an adjusted mean difference of -3.5 points (CI -6.7 to -0.3; p = 0.03).  There were not significant differences noted in assessments of cognition, mood, dyskinesia, non-motor symptoms, or quality of life.  Frequency and severity of adverse events also did not differ significantly between the two groups.

This trial is a milestone in Parkinson’s research.  Remarkably, exenatide leads to improvement in motor symptoms even 12 weeks after its last administration.  Whether this represents an enduring effect on disease progression is yet to be determined.   Regardless, this is an encouraging example of drug repurposing, a strategy which is increasingly being used by pharmaceutical companies.

Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis 

Adrenomedullin (ADM) is a 52-amino acid peptide that has been associated with several disease processes (8).  In addition to the increased circulating levels associated with myocardial injury, shock, cellular hypoxia, and oxidative stress, significantly increased levels of ADM have been reported in patients with sepsis.  Its exact role in sepsis is unclear.  In cell culture models, it’s been shown to reduce endothelial hyperpermeability and vascular leakage, and exogenous administration has been demonstrated as protective in animal models.  However, at higher levels of ADM are associated with worse patient outcomes, and administration of anti-ADM antibodies has mitigated sepsis-induced multi-organ failure in rodent models (8).

Until recently, ADM has been considered an unreliable biomarker, because several fragments of the precursor pro-hormone circulate which don’t necessarily reflect its activity.  However, an immunoassay that specially measures the biologically active form of ADM (bio-ADM) has been developed that has already been shown to be predictive of clinically relevant outcomes in acute heart failure.  In this month’s edition of CHEST, investigators sought to describe the relationship between bio-ADM and outcomes in patients with sepsis (8).

As a subset of the Albumin Italian Outcome Sepsis (ALBIOS) multi-center, open-label, randomized trial, 956 patients with severe sepsis or septic shock were recruited from 40 ICUs to participate in the bio-ADM study.  Venous blood was collected 1, 2, and 7 days after enrollment, or upon discharge.

As expected, authors found that plasma concentration of bio-ADM was high, particularly in patients with septic shock.  Interestingly, higher bio-ADM levels predicted the degree of hemodynamic support treatments, organ failure and shock.  The trend of bio-ADM levels during the first week of treatment predicted 90-day mortality (HR [95% CI], 1.3 [1.2-1.4]; P < .0001), and its reduction below 110 pg/mL on the 7th day was associated with reduced 90-day mortality.

Will physicians in our ICUs be ordering bio-ADM levels on our septic patients in the future?  While this study didn’t elucidate the mechanistic roles of ADM in sepsis, it clearly has a significant role in the pathophysiology of severe sepsis and septic shock.  However, additional studies will be necessary to demonstrate whether it has a role individualizing therapies.

Minicuts: 

Childhood intelligence and adult disease 

A cohort study with a 68-year follow-up published in the BMJ found that higher scores on a childhood intelligence test were associated with lower risk of mortality ascribed to coronary heart disease and stroke, cancers related to smoking, respiratory diseases, digestive diseases, injury, and dementia (9).

Expanding the role of non-specialists in Hepatitis C treatment

A non-randomized clinical trial published in the Annals of Internal Medicine found that Hepatitis C treatment with ledipasvir-sofosbuvir by non-specialist providers was as safe and effective as that provided by specialists, suggesting that PCPs and NPs could substantially expand the availability of community-based provision of Hepatitis C therapy (10).

Neuroimaging and borderline personality disorder 

A cohort study published in JAMA Psychiatry last week examined the use of 2-person neuroimaging to compare neural coupling (a stereotypical activation of cortical areas which occurs during face to face interactions) between pairs of healthy controls and patients with borderline personality disorder (BPD).  Neuro coupling between the pairs that included a participant with BPD was significantly lower than in the healthy pairs, suggesting a role for new quantifiable markers in the study of a disorder that’s been historically difficult to measure and treat (11).

Dr. Jonathan Whitehouse is a  NYU Langone Health

Peer Reviewed by Dr. Daniel Taupin, Inpatient Chief Resident, NYU Internal Medicine Residency Program at NYU Langone Health

Image courtesy of Wikimedia Commons 

References

  1. Goodman D. De Blasio’s Push for Tax on Wealthy Helps Put Pressure on Cuomo. The New York Times. August 7 2017, pg A18. https://www.nytimes.com/2017/08/07/nyregion/de-blasio-push-tax-on-wealthy-fix-subway.html?rref=collection%2Fsectioncollection%2Fnyregion&action=click&contentCollection=nyregion&region=rank&module=package&version=highlights&contentPlacement=5&pgtype=sectionfront
  1. Fessenden F, Fitzsimmons E, Lai R, Pearce A. New York’s Subway Are Not Just Delayed. Some Trains Don’t Run at All.  The New York Times, August 7, 2017. https://www.nytimes.com/interactive/2017/08/07/nyregion/new-yorks-subways-are-not-just-delayed-some-trains-dont-run-at-all.html?rref=collection%2Fsectioncollection%2Fnyregion&action=click&contentCollection=nyregion®ion=rank&module=package&version=highlights&contentPlacement=1&pgtype=sectionfront
  1. Nessen, S. All aboard the 24-Hour Subway Listening Tour. WYNC Radio, August 3, 2017.  http://www.wnyc.org/story/24-hour-subway-listening-tour/
  1. Friedman, L. Government Report Finds Drastic Impact of Climate Change in the U.S. The New York Times, August 8th, 2017, Page A1. https://www.nytimes.com/2017/08/07/climate/climate-change-drastic-warming-trump.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=first-column-region&region=top-news&WT.nav=top-news
  1. Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. New England Journal of Medicine 2017;377:419-30. http://www.nejm.org/doi/full/10.1056/NEJMoa1704154
  1. Lv J, Zhang H, Wong M, et al. Effect of oral methylprednisolone on clinical outcomes in patients with iga nephropathy: The testing randomized clinical trial. JAMA 2017;318:432-42. http://jamanetwork.com/journals/jama/article-abstract/2646717
  1. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. The Lancet 2017; pii: S0140-6736(17)31585-4. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31585-4/fulltext 
  1. Caironi P, Latini R, Struck J, et al. Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis. Chest 2017;152:312-20. http://journal.chestnet.org/article/S0012-3692(17)30704-3/fulltext
  1. Calvin CM, Batty GD, Der G, et al. Childhood intelligence in relation to major causes of death in 68 year follow-up: prospective population study. BMJ (Clinical research ed) 2017;357:j2708. http://www.bmj.com/content/357/bmj.j2708
  1. Kattakuzhy S, Gross C, Emmanuel B, et al. Expansion of Treatment for Hepatitis C Virus Infection by Task Shifting to Community-Based Nonspecialist Providers: A Nonrandomized Clinical Trial. Annals of internal medicine 2017. [Epub ahead of print 8 August 2017] http://annals.org/aim/article/2647669/expansion-treatment-hepatitis-c-virus-infection-task-shifting-community-based
  1. Bilek E, Stossel G, Schafer A, et al. State-Dependent Cross-Brain Information Flow in Borderline Personality Disorder. JAMA psychiatry 2017. [Epub ahead of print 2 August 2017] http://jamanetwork.com/journals/jamapsychiatry/article-abstract/2646393

 

Can I Safely Use Anticoagulants in my Patient with a Brain Tumor?

August 3, 2017

Brain tumorBy Christopher Sonne, MD

Peer Reviewed

It is the last admission of your admitting night shift. You are called to assess a pleasant, oriented 65-year-old man with lung cancer and metastases to the bone, liver, and brain. You review his history along with his admission labs and imaging, and you quickly feel confident in your diagnosis of a lobar pneumonia. Relieved, tired, the sun peaking through the call window, you begin to put in his orders. Finally, your last task is to choose adequate venous thromboembolism (VTE) prophylaxis—you hesitate. You know that his current metastatic disease makes him especially susceptible to VTE. But what about his brain metastasis? Is he at an increased risk of spontaneous intracranial bleed? How do you weigh protecting him from VTE against the devastation of intracranial hemorrhage?

ASCO guidelines give a 1A recommendation, for thromboprophylaxis in bed-bound inpatients who have cancer [1]. The incidence of deep vein thrombosis (DVT) or pulmonary embolism in these patients is 10-30%, leading to a nearly 47-fold increase in mortality from VTE compared to the general population [2]. The common choice for prophylaxis in these patients is a low-molecular-weight heparin (LMWH) like enoxaparin, based on extrapolations from data in the ENOXACAN and the CLOT trials [3,4]. However, in brain tumors, should we feel comfortable with these extrapolations? On the one hand, brain tumors are included in a short list of malignancies that are particularly prone to VTE, along with gastrointestinal, lung, gynecological, renal, and hematological cancers [1]. Rates of VTE in high-grade gliomas (the most common primary brain tumor) can range from 15-30%, and as high as 60% post-operatively [2,5,6]. On the other hand, only 27 of 676 patients with primary brain tumors were included in the CLOT trial, and no bleeding data for this specific subgroup was given [3].

You then consider what kind of brain tumor your patient has and its propensity to bleed. In this case, the patient has metastatic lung adenocarcinoma. Brain metastases from melanoma, thyroid cancer, renal cell carcinoma, and choriocarcinoma are traditionally known to pose the greatest baseline risk for spontaneous intracranial bleeding [7]. For your patient, rate of spontaneous intracranial hemorrhage (ICH) from metastatic lung adenocarcinoma appears to be comparatively low [8]. You breathe a little easier.

You then consider alternatives to anticoagulation. Pooled data using varied patient populations with malignancy shows a statistically significant decrease in deep vein thrombosis with the use of mechanical prophylaxis alone. However, this benefit does not extend to a significant reduction in the risk for pulmonary embolism [1]. In several small prospective studies, IVC filters have effectively shown neither a decrease in intracranial bleeds nor improved overall survival [5,6,12] and ACCP guidelines recommend against prophylactic IVC filters. No easy solution there.

You pull up some guidelines. National Comprehensive Cancer Network guidelines state that “intracranial or spinal lesions at high risk for bleeding” are an absolute contraindication to prophylactic or therapeutic anticoagulation. However, there are no further discussions, definitions, or citations on which this recommendation is based [11]. The American Society of Clinical Oncology (ASCO) guidelines meanwhile state that “the presence of an intracranial tumor or brain metastases without evidence of active bleeding is not an absolute contraindication to anticoagulation” [1].

The fact is that limited data exists on the risks and benefits of VTE prophylaxis in the setting of known brain tumors. You are forced to look for related data to help you make your own clinical decision. The question is not unfamiliar. Several small retrospective studies have demonstrated the effectiveness of unfractionated heparin and warfarin as secondary prophylaxis in patients with primary and metastatic brain tumors. Among these is a 1993 study looking at 49 patients with intracranial malignancy and concurrent VTE. Of the 49 patients, only 15 were treated with anticoagulation, and none of those 15 resulted in ICH or other major bleeds [10]. Another retrospective study of 49 patients with primary and metastatic brain tumors matched by malignancy type and location of VTE were divided between two groups based on whether they received anticoagulation or an IVC filter. The two groups had statistically equivalent rates of intracranial bleeds and mortality at 8 weeks [12]. These results seem to indicate that the rate of bleeding on anticoagulation was equivalent to the rate of spontaneous bleeding off anticoagulation. However, the study was limited by size and its retrospective design. Perhaps those chosen for IVC filters were deemed to be at greater clinical risk for ICH to begin with. And again, these studies were all conducted with the question of secondary prophylaxis in patients with VTE.

The randomized placebo-controlled PRODIGE trial was initiated to look specifically at primary VTE prophylaxis in patients with malignant gliomas using the LMWH dalteparin versus placebo for 6 months after initial surgery. Development of objective DVT or PE was the primary endpoint. By 6 months, 11% in the LMWH group versus 17% in the placebo group developed VTE. Though this difference favored prophylaxis with LMWH, it was not statistically significant. Major bleeds were a secondary end-point. All bleeds in this trial ended up being intracranial bleeds, with 5 patients (5%) suffering intracranial bleeds in the LMWH group compared to 1 patient (1.2%) in the placebo group. This difference was also not statistically significant. While the trial seems to show trends toward improved VTE prophylaxis at the cost of increased intracranial bleeds, this Pfizer funded study was ended early because of an “expiration of study medication [with] no further re-supply” [13].

Perhaps most helpful was a recent matched retrospective cohort study by Donato et al. The study compared rates of ICH in patients with metastatic brain tumors and VTE on therapeutic enoxaparin versus matched subjects without VTE not on enoxaparin. Patients on enoxaparin suffered ICH at a rate of 19%, compared to 21% of patients not on anticoagulation, demonstrating no increased risk of ICH for patients with brain tumors while on anticoagulation. Similar rates persisted regardless of whether or not the bleeds were symptomatic or just picked up on imaging. Subgroup analyses also looking at the incidence of ICH based on malignancy type, and demonstrated no difference between anticoagulated versus non-anticoagulated groups. Rather, in this subgroup analysis, rates of ICH in melanoma and renal cell carcinoma in both anticoagulated and non-anticoagulated groups were equal and substantially higher than other types of malignancies such as metastatic lung cancer (HR 3.98; P < 0.001) [8]. Though renal cell carcinoma and melanoma carry the highest risk of intratumoral bleeds, even these malignancies showed no increased risk of bleeding on anticoagulation.

For decades, clinicians have grappled with striking a balance between bleeding and thrombosis. Medicine is a science, replete with cohorts and p-values and confidence intervals. But in questions such as this, science is limited by practicalities that force us to take what sparse data may exist and treat to the best of our clinical intuition. Donato et al. may provide the best foothold to help make this clinical decision. Even therapeutic doses of anticoagulation may not increase the risk of an intracranial hemorrhage even in the malignancies most prone to do so. These findings most closely resemble the brief ASCO statement that “the presence of an intracranial tumor or brain metastases without evidence of active bleeding is not an absolute contraindication to anticoagulation.” But with that, in the early hours of a new morning, we are left to decide what is best for our patient.

Commentary by David Green, MD, PhD, Director Adult Coagulation Lab Bellevue and Tisch Hospitals

Anticoagulation in the cancer patient, and even more so with brain metastasis or primary brain tumors presents a classic Scylla versus Charybdis problem. Cancer patient are more thrombotic than non-cancer patients and also are more prone to bleeding. Despite the variation in patient specific risks, a universal approach has been adopted for VTE prophylaxis. ACCP recommends a formal strategy to reduce inpatient VTE which has been adopted by most hospitals. As this discussion highlights, there is also potential for harm. The field is now moving away from universal prophylaxis toward a risk adapted strategy for VTE prophylaxis in medical and surgical patients.

In this case, what if the brain MRI demonstrated evidence of microbleed (hemosiderin)? Should we alter our practice? These are the difficult questions we routinely face in real world practice.

Dr. Christopher Sonne is a 3rd year resident at NYU Langone Health

Peer Reviewed by David Green, MD, PhD, Clinical Assistant Professor, Division of Hematology/Oncology, Department of Medicine, NYU Langone Health

Image courtesy of Wikimedia Commons

References

 

  1. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25:5490.  https://www.ncbi.nlm.nih.gov/pubmed/17968019

 

  1. Weinstock, Matthew J., Erik J. Uhlmann, and Jeffrey I. Zwicker. “Intracranial hemorrhage in cancer patients treated with anticoagulation.” Thrombosis research 140 (2016): S60-S65. http://www.thrombosisresearch.com/article/S0049-3848(16)30100-1/fulltext

 

  1. Lee AY, et al. “Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer”. The New England Journal of Medicine. 2003. 349(2):146-53. http://www.nejm.org/doi/full/10.1056/NEJMoa025313#t=article

 

  1. Bergqvist, David. “Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment.” British Journal of Surgery 84.8 (1997): 1099-1103.

 

  1. Jo JT, Schif D, perry, JR. Thrombosis in brain tumors. Semin Thromb Hemost. 2014;40:325-31

 

  1. Yust-Katz S, Mandel JJ, Wu J, Yuan Y, Webre C, Pawar TA, et al. Venous thromboembolsim (VTE) and glioblastoma. J Neurooncol.2015;124:87-94

 

  1. Wen, Patrick Y., and J. S. Loeffler. “Management of brain metastases.” Oncology (Williston Park, NY) 13.7 (1999): 941-54. Accessed via http://www.cancernetwork.com/oncology-journal/management-brain-metastases. Jul 27 2016.

 

  1. Donato J, Campigotto F, Uhlmann EJ, et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood. 2015;126(4):494-499.

 

  1. Semrad TJ, O’Donnell R, Wun T, et al. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg. 2007;106(4):601-608.

 

  1. Levin, J. M., et al. “Complications of therapy for venous thromboembolic disease in patients with brain tumors.” Neurology 43.6 (1993): 1111-1111.

 

  1. NCCN Clinical Practice Guidelines in Oncology. Venous Thromboembolic Disease. Accessed via http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf. Jul 26 2016

 

  1. Olin JW, Young JR, Graor RA, et al: Treatment of deep vein thrombosis and pulmonary emboli in patients with primary and metastatic brain tumors: Anticoagulants or inferior vena cava filter? Arch Intern Med 147:2177-2179, 1987

 

  1. Perry, J. R., et al. “PRODIGE: a randomized placebo‐controlled trial of dalteparin low‐molecular‐weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma.” Journal of Thrombosis and Haemostasis8.9 (2010): 1959-1965.

 

Primecuts – This Week in the Journals

July 31, 2017

primecuts 7.31.17By Jiwoon Chang, MD

Peer Reviewed

This past week at the International AIDS Society Conference in Paris, investigators of the mosaic HIV vaccination trial called APPROACH shared their early findings of healthy adults developing immunological responses against HIV after vaccinations [1]. Results from this NIH-funded clinical trial are expected in late 2017, but the preliminary report provides a new hope to protect those at risk of acquiring HIV. This week, our first article evaluates enhanced antimicrobial prophylaxis for HIV patients with low CD4+ count. The second article reviews the duration of targeted temperature management in unconscious patients with out-of-hospital cardiac arrest. Next, we will explore the effects of E-cigarette use with smoking cessation in the current US population. Finally, we will discuss the use of idarucizumab to reverse the anticoagulation effect of dabigatran.

Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa

According to the World Health Organization, 36.7 million people lived with HIV/AIDS and 1.1 million people died of complications from AIDS worldwide in 2015 [2]. In sub-Saharan Africa, about 25% of patients with HIV have a CD4+ count of less than 100 cells per cubic millimeter, and 10% of these individuals die in the first 3 months of starting antiretroviral therapy (ART) [3,4].

In a NEJM study published this week, investigators of the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) conducted an open-label, randomized trial to compare enhanced antimicrobial prophylaxis and standard prophylaxis (5). The study included 1805 HIV-infected patients with CD4+ count of less than 100 cells per cubit millimeter in Africa without any previous ART. Patients were randomized to enhanced therapy with continuous trimethoprim-sulfamethoxazole, 12 weeks of isoniazid-pyridoxine, 12 weeks of fluconazole, 5 days of azithromycin, and 1 dose of albendazole, or standard therapy with continuous trimethoprim-sulfamethoxazole at the initiation of ART. The primary outcome included death at 24 weeks after enrollment. Other outcomes included death at 48 weeks, incidences of opportunistic infections, and serious adverse events from prophylactic drugs.

Investigators found that the rate of death at 24 weeks was significantly less with enhanced prophylaxis compared to standard prophylaxis (8.9% vs. 12.2%, p=0.03, CI 0.55-0.98). The enhanced prophylaxis group had a lower rate of death at 48 weeks as well (11.0% vs. 14.4%, p=0.04, CI 0.58-0.99). Notable findings in secondary outcomes include lower rates of new tuberculosis (7.1% vs. 10.2%, p=0.02, CI 0.49-0.93), cryptococcal infection (1.0% vs. 2.6%, p=0.01, CI 0.18-0.83) in enhanced prophylaxis group. There was no significant difference in the rate of presumed severe bacterial infections (4.6% vs. 3.7%, p=0.32, CI 0.80-1.99). The rate of adverse events due to prophylactic drugs did not differ significantly between the two groups (6.8% vs. 7.7%, p=0.50, CI 0.63-1.26).

In this study, enhanced prophylaxis resulted in lower rates of death at 24 and 48 weeks in severely immunocompromised patients with AIDS compared to standard prophylactic therapy. These findings advocate for enhanced prophylactic treatment to prevent tuberculosis and cryptococcal disease at the initiation of ART. Limitations of this trial included the lack of microbiologic analyses at participating centers, causing many bacterial infections to be diagnosed presumptively. Given limited screening test availability in many African regions, benefits of enhanced prophylactic treatment may outweigh harms of potential antimicrobial resistance in patients with AIDS, and guidelines for prophylactic antimicrobial regimen in AIDS patients may be updated for resource-limited areas.

Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest

To prevent a neurologic deficit and death in unconscious patients who had out-of-hospital cardiac arrest, current international guidelines recommend targeted temperature management (TTM) [6]. A clinical trial in 2013 showed similar benefits of TTM at 33°C and at 36°C, and investigators from the study recommended at least 24 hours of TTM, but the optimal duration of cooling is unclear [7].

A pragmatic, multicenter, randomized trial conducted in Europe was published this week in JAMA to address the question of whether or not TTM for 48 hours results in better neurologic outcome compared to 24-hour TTM. [8]. 355 adults between the age of 17 and 80 with out-of-hospital cardiac arrest who had sustained return of spontaneous circulation for more than 20 minutes and Glasgow Coma Scale score less than 8 were randomized to 24 or 48 hours of TTM at 33°C. The primary outcome was 6-month neurologic outcome, and secondary outcomes were 6-month mortality, adverse events, and ICU resource use.

Study authors found no significant difference in favorable functional neurologic outcome in 6 months between 24-hour and 48-hour groups (64% vs. 69%, p=0.33, CI 0.93-1.25). There was also no difference in mortality at 6 months (34% vs. 27%, p=0.19, CI 0.59-1.11). There was a modest but significant decrease in adverse events in the 24-hour cooling group compared to the 48-hour group (91% vs. 97%, p=0.03, CI 1.01-1.12). The median ICU length of stay was shorter in the 24-hour group compared to the 48-hour group (117 hours vs. 151 hours, p<0.001, CI 1.14-1.47). Authors concluded that there was no scientific evidence to support 48 hours of TTM compared to 24 hours, and longer TTM may cause more adverse events and a longer ICU stay. This study had limited power given a small number of subjects, and the 5% difference in 6-month neurologic outcome should be re-evaluated in a larger trial. While this trial addressed one variable of TTM, larger and more sophisticated studies are required to address the optimal temperature, duration, and onset of TTM for unconscious patients after cardiac arrest.

E-cigarette use and associated changes in population smoking cessation: evidence from US current population surveys
Use of electronic cigarettes has increased worldwide, but there is a debate regarding its utility for cigarette smoking cessation. Some countries like the United Kingdom allow e-cigarettes to be licensed for nicotine replacement therapy, whereas Australia does not allow the sale of nicotine-containing e-cigarettes. In a BMJ study published this week, a group of investigators from UCSD examined if the increase in use of e-cigarettes in the US was associated with a smoking cessation rate at the population level [9]. This study used the US Current Population Surveys about tobacco use supplement between 2001 and 2015 and included 161,054 respondents from the 2014-15 survey to analyze the prevalence of e-cigarette use. Measured outcomes included the number of current smokers and quitters, the rate of attempt to quit cigarette smoking, and the rate of successful quitting. Investigators found 22,548 active smokers and 2,136 recent quitters from the 161,054 people who completed the 2014-15 survey. 38.2% of active smokers and 49.3% of recent quitters had tried e-cigarettes in the past, and 11.5% and 19.0% of them reported active e-cigarette use. E-cigarette users were more likely to try to quit smoking (65.1% vs. 40.1%, change=25.0%, CI 23.2-26.9%) and more likely to succeed in quitting (8.2% vs. 4.8%, change=3.5%, CI 2.5-4.5%). This study shows a correlation between increased e-cigarette use and increased overall smoking cessation for the US population. Limitations include recall biases from self-reporting and absence of randomization. We should consider using e-cigarettes for smoking cessation in addition to other nicotine replacement therapy and varenicline. Future studies may examine the health impact of long-term e-cigarette use and initiation of e-cigarettes among teenagers to analyze the effect on public health.

Idarucizumab for Dabigatran Reversal — Full Cohort Analysis

Dabigatran is an oral anticoagulation that works by directly inhibiting thrombin. Idarucizumab is a monoclonal antibody fragment that binds dabigatran to reverse its anticoagulation effect, and it was approved by the FDA after interim analysis with the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study in 2015 [10].

This past week in NEJM, investigators reported the full cohort analysis of the RE-VERSE AD trial to validate the interim findings and assess the use of idarucizumab in patients with uncontrolled bleeding or those with an urgent procedure [11]. In this pragmatic, multicenter, prospective, single-cohort study, 301 patients received idarucizumab for uncontrolled bleeding, such as gastrointestinal bleeding and intracranial hemorrhage, and 202 patients received idarucizumab for urgent surgery or intervention. Primary outcome was the maximum percentage reversal of dabigatran’s anticoagulation effect, which was measured by the diluated thrombin time or the ecarin clotting time. Clinical outcomes such as thrombotic complications and mortality were also measured.

Investigators found that the median maximum percentage reversal at 4 hours after idarucizumab administration was 100% in all patients. Among patients who received idarucizumab for uncontrolled bleeding, 67.7% had bleeding cessation within 24 hours with the median time to hemostasis 2.5 hours after administration (CI 2.2 to 3.9). Authors reported that the rest of patients in this group did not have any evidence of bleeding on physical examination or imaging.
Among those who received idarucizumab prior to undergoing a procedure, 93.4% had periprocedural hemostasis. Thrombotic events at 90 days occurred in 6.3% in the uncontrolled bleeding group and 7.4% in the procedural group, and the mortality rate was 18.8% and 18.9%, respectively.

Although this study was conducted without a control group or randomization, this full cohort analysis validates the interim report of effective anticoagulation reversal of idarucizumab and advocates for its usage for patients on dabigatran who have uncontrolled bleeding or require urgent interventions. It is encouraging to see the effectiveness of idarucizumab as providers wait for the approval of monoclonal antibody fragments that reverse Factor Xa inhibitors, such as apixaban and rivaroxaban.

Minicuts
Sorafenib and TACE in Hepatocellular Carcinoma
Administration of Sorafenib with transarterial chemoembolization (TACE) did not improve progression-free survival in patients with unresectable hepatocellular carcinoma compared to TACE alone [12].

Calcium Correlation with Coronary Artery Disease
In a JAMA study published this week, investigators reported that a genetic predisposition to high serum calcium levels was associated with higher incidences of coronary artery disease and myocardial infarction [13].

Chronic Traumatic Encephalopathy in American Football Players
A case series of 202 American football players whose brains were donated for research showed that almost all of them had neuropathological evidence of chronic traumatic encephalopathy, or CTE [14]. This study also suggested that a high level of play might cause more extensive disease.

Dr. Jiwoon Chang is a 3rd year Internal Medicine Resident at NYU Langone Health

Peer reviewed by Amar Parikh, MD, Associate Editor, Clinical Correlations and Chief Resident in Internal Medicine at NYU Langone Health

Image courtesy of the National Institutes of Health

References

1. NIH News Releases. Experimental HIV vaccine regimen is well-tolerated, elicits immune responses. . National Institute on Health. https://www.nih.gov/news-events/news-releases/experimental-hiv-vaccine-regimen-well-tolerated-elicits-immune-responses. Published July 2017. Accessed July 28, 2017.

2. World Health Organization. Global Health Observatory (GHO) data. World Health Organization. http://www.who.int/gho/hiv/en/. Accessed July 28, 2017.

3. The IeDEA and ART Cohort Collaborations. Immunodeficiency at the start of combination antiretroviral therapy in low-, middle-, and high-income countries. J Acquir Immune Defic Syndr. 2014;65(1):e8-16. https://www.ncbi.nlm.nih.gov/pubmed/24419071

4. Boulle A, Schomaker M, May MT, et al. Mortality in patients with HIV-1 infection starting antiretroviral therapy in South Africa, Europe, or North America: a collaborative analysis of prospective studies. PLoS Med. 2014;11(9):e1001718.

5. Hakim J, Musiime V, Szubert AJ. Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa. NEJM. 2017;377:233-245. doi: 10.1056/NEJMoa1615822 https://www.ncbi.nlm.nih.gov/pubmed/28723333

6. Callaway CW, Donnino MW, Fink EL, et al. Part 8: post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18)(suppl 2):S465-S482. https://www.ncbi.nlm.nih.gov/pubmed/26472996

7. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C vs 36 degrees C after cardiac arrest. NEJM. 2013;369:2197-2206. http://www.nejm.org/doi/full/10.1056/NEJMoa1310519#t=article

8. Kirkegaard, H, Soreide, E, Haas, I. Targeted Temperature Management for 48 vs 24 hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A randomized clinical trial. JAMA. 2017;318(4):341-350. doi:10.1001/jama.2017.8978

9. Zhu, SH, Zhuang YL, Wong S, Cummins SE, Tedeschi GJ. E-cigarette use and associated changes in population smoking cessation: evidence from US current population surveys. BMJ. 2017;358. doi: https://doi.org/10.1136/bmj.j3262.

10. Pollack, CV, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. NEJM. 2015;373:511-520. https://www.ncbi.nlm.nih.gov/pubmed/26095746

11. Pollack, CV, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. NEJM. 2017. doi: 10.1056/NEJMoa1707278

12. Meyer T, Fox R, Ma YT et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2(8):565-575. doi: 10.1016/S2468-1253(17)30156-5. http://www.thelancet.com/pdfs/journals/langas/PIIS2468-1253(17)30156-5.pdf

13. Larsson SC, Burgess S, Michaëlsson K. Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction. JAMA. 2017;318(4):371-380. doi:10.1001/jama.2017.8981. http://paper.medlive.cn/literature/2630059

14. Mez J, Daneshvar DH, Kiernan PT. Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA. 2017;318(4):360-370. doi:10.1001/jama.2017.8334. file:///C:/Users/smitha11/Downloads/JOI170072supp1_prod.pdf

Primecuts – This Week in the Journals

July 25, 2017

50mgtramadolhclakymaKelsey Luoma, MD
Peer Reviewed

Opioid-related morbidity and mortality has reached crisis levels in the United States. According to the CDC, between 1999 and 2014 more than 165,000 people died due to opioid drug overdose [1]. This week, our first article questions whether a multicomponent primary care intervention can mitigate the risk of prescription opioid abuse, thereby potentially saving lives. Next, we’ll review a study on the effects of long-term inhaled corticosteroid use on fracture risk; we’ll compare various non-invasive testing strategies for workup of stable CAD; and, finally, we will address the age-old question of whether glucose self-monitoring in non-insulin-treated T2DM patients actually improves glycemic control. Most importantly, we’ll take a look at whether your coffee addiction—ahem, habit—is associated with mortality risk.

Improving Adherence to Long-term Opioid Therapy Guidelines to Reduce Opioid Misuse in Primary Care

In an effort to mitigate over-prescription of opioids, the CDC and other professional medical societies have published guidelines for medical providers regarding long term opioid prescription. Included in these guidelines are recommendations for patient-clinician agreements, urine drug testing, prescription drug monitoring programs and opioid assessment tools. Unfortunately, observational studies suggest prescriber compliance with these guidelines is poor.

In a JAMA study published online this week, a group of investigators affiliated with Boston Medical Center performed a cluster-randomized clinical trial to examine the effects of a multicomponent intervention on clinician adherence to opioid prescribing guidelines and opioid misuse risk [2]. The study included 53 primary care clinicians (PCCs) and 985 patients on opioid therapy for chronic pain. It was conducted in 4 safety-net primary care practices between January 2014 and March 2016. The multifaceted primary care intervention included nurse care management, electronic registry, academic detailing, and electronic decision tools. This was compared to a control of electronic decision tools alone. Primary outcomes were documentation of guideline-concordant care (both a patient-PCC agreement in the electronic health record and at least one urine drug test) over 12 months and 2 or more early opioid refills. Other outcomes included opioid dose reduction and opioid treatment discontinuation.

Study authors found that patients in the intervention group were significantly more likely to receive guideline-concordant care (65.9% vs 37.8%; P < .001; CI 3.6-10.2), to have a patient-PCC agreement (53.8% vs 6.0%; P < .001; CI 4.4-32.2) and to undergo at least 1 urine drug test (74.6% vs 57.9%; P < .001; CI 1.8-5.0) compared with controls. There was no difference in early opioid refills between groups (20.7% vs 20.1%; CI 0.7-1.8). With respect to secondary outcomes, primary care providers in the intervention group were more likely to discontinue opioid treatment (21.3% vs 16.8%; P = .04; CI 1.02-2.1), and to decrease opioid dose of patients remaining on therapy (32.8% vs 22.9%; P = .01; CI 1.1-2.4). In this study, a multifaceted primary care intervention resulted in improved adherence to established guidelines regarding opioid prescription. Although there was no significant difference in early opioid refill between intervention and control groups, rates of opioid discontinuation and opioid dose reduction were higher in the intervention group. These findings suggest that a comprehensive multidisciplinary approach can successfully mitigate opioid overuse, and similar interventions should be further studied. Long-term use of inhaled corticosteroids in COPD and the risk of fracture

Use of inhaled corticosteroids (ICS) for management of chronic obstructive pulmonary disease (COPD) is widespread and becoming increasingly common. These medications, however, are not without risk. Observational studies have shown that ICS use is correlated with decreased bone-mineral density in a dose-dependent fashion [3,4]. Whether or not this decrease in bone mineral density translates into fracture risk remains unclear as existing evidence has been conflicting.

To characterize fracture risk associated with long term ICS use in COPD patients, a group of researchers in Montreal, Quebec performed a nested case-control analysis with a cohort of 240,110 subjects aged 55 or older, who were newly treated for COPD between 1990 and 2005 [5]. During a mean follow-up of 5.3 years, 19,396 fracture cases were selected based on the occurrence of a first hip or upper extremity fracture. These were subsequently age- and sex-matched to 384,478 control person-moments. Study authors found a modest but significant increase in fracture risk with prolonged courses of high dose ICS. Specifically, for those treated with at least 1000 mcg in fluticasone-equivalents for a duration of greater than 4 years, there was a 10% increase in risk of hip or upper extremity fracture (RR 1.10; 95% CI 1.02-1.18). Fracture risk was not significantly increased with ICS treatment courses of < 4 years. Furthermore, the risk increase was not higher in post-menopausal women compared to men. This study adds to the existing literature which suggests that high doses of inhaled corticosteroids affects bone mineral density and can increase risk of fracture in our patients. This is an important lesson for all prescribers to internalize. While many reach to inhaled corticosteroids for treatment of COPD patients with hardly a second thought, this study reminds us to think twice, and perhaps double-check the guidelines for ICS therapy, before signing that script.
Comparison of Anatomic and Clinical Outcomes in Patients Undergoing Alternative Initial Noninvasive Testing Strategies for the Diagnosis of Stable Coronary Artery Disease

Multiple modalities exist for evaluation of suspected stable coronary artery disease. While American guidelines recommend the use of exercise stress test as first line when possible, European guidelines suggest that, in certain groups, stress imaging tests (myocardial perfusion imaging, stress echo) or coronary CTA may be preferred.

This week in the Journal of the American Heart Association (JAHA), a retrospective cohort study examined the relationship between initial non-invasive testing modality and obstructive CAD on invasive angiography [6]. This study used population data from health insurance claims in Ontario, Canada. Adults 20 years of age or older who had undergone one non-invasive test (exercise stress test, myocardial perfusion imaging, stress echo, or coronary CTA), followed by invasive angiography within 6 months, were included. The study’s primary outcome was presence of obstructive CAD on invasive angiography. As a secondary outcome, a composite end-point of all-cause mortality and hospitalization for acute myocardial infarction or unstable angina was evaluated. After a mean follow up of 1.89 years, neither outcome was found to be significantly different amongst the 4 initial testing strategies. Patients who had undergone myocardial perfusion imaging (OR 0.97; CI 0.91-1.04), coronary CTA (OR 1.31; CI 0.89-1.92) or stress echo (OR 0.92; CI 0.82-1.02) did not have significantly different odds of having obstructive CAD compared with subjects who had been initially evaluated with exercise stress test. Furthermore, adjusted analysis showed no statistically significant difference in the composite endpoint—all-cause mortality and hospitalization for MI or unstable angina—between the various initial testing strategies.

While this study certainly has limitations—lack of data on patients with negative non-invasive test results for example—its implications are important. With no statistically significant difference in real-world outcomes amongst various non-invasive testing modalities, these results do not support the routine use of stress imaging or coronary CTA in the workup of stable CAD. In other words, for now we should continue to rely on exercise stress test for initial workup of stable CAD, when possible, as recommended by current American guidelines.

Glucose Self-monitoring in Non-Insulin-Treated Patients with Type 2 Diabetes in Primary Care Settings: A Randomized Trial

There is disagreement on whether self-monitoring of blood glucose (SMBG) has value for patients with non-insulin treated type 2 diabetes mellitus (T2DM). Some trials have shown that SMBG improves glycemic control while others have shown no benefit.

In a randomized controlled trial published in JAMA this week, the authors addressed the question of whether or not SMBG effectively improves hemoglobin A1c levels or health-related quality of life in people with non-insulin-treated T2DM [7]. Three approaches of SMBG were compared in a pragmatic, open-label randomized trial conducted in 15 primary care practices in central North Carolina. 450 adult patients with T2DM with hemoglobin A1c (HbA1c) between 6.5 and 9.5% were randomized to either no SMBG, once-daily SMBG, and once-daily SMBG with enhanced patient feedback. Primary outcomes included HbA1c levels and health-related quality of life at 52 weeks. At the study’s end, there were no significant differences in HbA1c levels across all 3 groups (P = .74; estimated adjusted mean hemoglobin A1c difference, SMBG with messaging vs no SMBG, -0.09%; 95% CI -0.31% to 0.14%; SMBG vs no SMBG, -0.05%; 95% CI -0.27% to 0.17%). Additionally, there were no significant differences in health-related quality of life.

This study shows that, in a real-world setting, self monitoring of blood glucose did not result in improved glycemic control or health-related quality of life, even when done in conjunction with a telehealth intervention. Interestingly enough, however, in the early months of the intervention there did appear to be a statistically significant difference in hemoglobin A1c level between the three groups. As patient compliance fell off over time, the statistical significance was lost as well, suggesting that effectiveness of SMBG may depend on patient motivation. We can conclude that the decision to initiate SMBG should be made on a case-by-case basis, as some patients, especially those who are highly motivated to comply, may indeed benefit from it.

Minicuts

Palliative Care
We have all seen patients reap tremendous benefit from the expert care of our palliative care specialists. But what affect does palliative care referral really have on quality of life in patients with advanced illness? A systematic review and meta-analysis published in the British Medical Journal seeks to answer this intriguing question [8].

PPIs and Memory Loss?

It’s no secret that certain drugs have effects on memory and may be associated with risk of dementia (benzodiazepines and anticholinergic medications come to mind). But should we be concerned about the effects of proton pump inhibitors on risk of Alzheimer’s disease? A study published in the American Journal of Gastroenterology asks exactly that [9].

A Cup of Coffee a day…

Coffee—elixir of life or perfect poison? This week, a prospective cohort study spanning 10 European countries examines the effect of coffee consumption on all-cause and cause-specific mortality [10].

Dr. Kelsey Luoma is a 2nd year Internal Medicine Resident at NYU Langone Health

Peer Reviewed Ian Henderson, MD, Contributing Editor and a Chief Resident in Internal Medicine at NYU Langone Health

Image courtesy of Wikimedia Commons

References

1. CDC. Multiple cause of death data on CDC WONDER. Atlanta, GA: US Department of Health and Human Services, CDC; 2016. http://wonder.cdc.gov/mcd.html

2. Liebschutz JM, Xuan Z, Shanahan CW, et al. Improving Adherence to Long-term Opioid Therapy Guidelines to Reduce Opioid Misuse in Primary Care JAMA Intern Med. 2017 July 17 [Epub ahead of print]. Accessed July 20, 2017

3. Israel E, et al. Effects of inhaled glucocorticoids on bone density in premenopausal women. New England Journal of Medicine, 2001. http://www.nejm.org/doi/full/10.1056/NEJMoa002304#t=article

4. Wong CA, et al. Inhaled corticosteroid use and bone mineral density in patients with asthma. Lancet, 2000.

5. Gonzales AV, et al. Long-term use of inhaled corticosteroids in COPD and the risk of fracture. Chest. 2017 Jul 14 [Epub ahead of print]. Accessed July 20, 2017. http://journal.chestnet.org/article/S0012-3692(17)31243-6/pdf

6. Roifman I, et al. Comparison of Anatomic and Clinical Outcomes in Patients Undergoing Alternative Initial Noninvasive Testing Strategies for the Diagnosis of Stable Coronary Artery Disease. Journal of the American Heart Association. 2017 Jul 19. Accessed July 20, 2017.

7. Young LA, et alGlucose Self-monitoring in Non-Insulin-Treated Patients With Type 2 Diabetes in Primary Care Settings: A Randomized Trial. JAMA Intern Med 2017 Jul. Accessed July 24. http://www.mdedge.com/ccjm/clinical-edge/summary/diabetes/glucose-self-monitoring-non-insulin-treated-patients-t2d

8. Gaertner J, et al. Effect of specialist palliative care services on quality of life in adults with advanced incurable illness in hospital, hospice, or community settings: a systematic review and meta-analysis. BMJ 2017 July 4; 357:j2925. http://www.bmj.com/content/357/bmj.j2925

9. Taipale H, et al. No association between proton pump inhibitor use and risk of alzheimer’s disease. Am J Gastroenterol. 2017 July 11 [Epub ahead of print]. Accessed July 20, 2017.

10. Gunter MJ et al. Coffee Drinking and Mortality in 10 European Countries: A Multinational Cohort Study. Ann Intern Med. 2017 Jul 11. Accessed July 20, 2017. http://annals.org/aim/article/2643435/coffee-drinking-mortality-10-european-countries-multinational-cohort-study

Primecuts – This Week in the Journals

July 19, 2017

By Cesar Soria Jimenez, MD
Peer Reviewed

Obesity-waist_circumferenceIn this week’s Primecuts issue, we will be discussing topics related to obesity and its effects on the global population over the past quarter century (the effects are both surprising and worse than you likely imagine), a trial analyzing the potential for a blood serum biomarker to distinguish the infectious etiology of community acquired pneumonia and prevent unnecessary use of empiric antibiotics, and the characterization of a distinct phenotype of heart failure with ejection fraction, a condition that is becoming more common yet remains difficult to identify and treat.

1. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. [1]
Overweight and obesity prevalence continues to increase worldwide. Body mass index (BMI) has been identified as a risk factor for several chronic diseases, including but limited to cardiovascular diseases (CVD), diabetes mellitus (DM), chronic kidney disease (CKD), cancer, and musculoskeletal disorders. In order to develop treatments and prevention policies to ameliorate this trend and its sequelae, this article evaluated the trends in prevalence of overweight and obesity, including the patterns of death and disability-adjusted life-years related to high BMI, according to age and sex, in 195 countries.

Researchers used the comparative-risk-assessment approach from the Global Burden of Disease study to estimate the burden of disease related to high BMI from 1990 to 2015. To assess the global distribution of BMI, they searched Medline for studies providing nationally or subnationally representative estimates of BMI, overweight, obesity among adults and children. In addition, they estimated the effects of high BMI on health outcomes by using Bradford Hill’s criteria for causation and evidence-grading criteria of the World Cancer Research Fund to evaluate epidemiologic evidence supporting causal relationship between high BMI and several diseases. Finally, researchers used the most recent pooled analysis of prospective observational studies to determine the BMI associated with the lowest overall risk of death. The number of deaths and disability-adjusted life-years were computed in relation to high BMI for each country, according to age, sex, year and cause.

In 2015, 107.7 million children (uncertainty interval, 101.1-115.1) and 603.7 million adults (uncertainty interval, 592.9-615.6) were obese worldwide. Overall prevalence of obesity was 12.0% among adults and 5.0% among children. Notably, the prevalence of obesity was generally higher among women than men across all age brackets studied (5-year increment groups from 20 to 80+ years of age). There were no sex differences observed in obesity prevalence before the age of 20 years. Investigators also noted that in general, the prevalence of obesity among both men and women increased as socioeconomic index (SDI) – a measure of lag-distributed income per capita, average educational attainment among persons older than 15 years, and total fertility rate – increased. In children, the prevalence of obesity was greater in countries with higher SDI levels. At the national level, the prevalence of obesity among children and adults has doubled in 73 countries since 1980. Despite a lower prevalence of childhood obesity compared to adult obesity, the rate of increase in childhood obesity is outpacing that of adult obesity. Of note, the U.S. has the highest level of age-standardized childhood obesity (12.7%; 95% uncertainty interval, 12.2-13.2) and highest number of obese adults.

It was estimated that in 2015, a high BMI contributed to 4.0 million deaths (95% uncertainty interval, 2.7-5.3), and 120 million disability-adjusted life-years (95% uncertainty interval, 84-158). 70% of these deaths were related to CVD, sand 30% of deaths and 37% of disability-adjusted life-years occurred in adults with a BMI less than 30 (i.e. overweight). CVD was the leading cause of death and disability-adjusted life-years related to high BMI with 2.7 million deaths and 66.3 million disability-adjusted life-years. DM was the second leading cause of death with 0.6 million and 30.4 million disability-adjusted life-years. CKD was the second leading cause of disability-adjusted life-years; together with cancers, they accounted for less than 10% of all deaths. Globally, increases in BMI-related deaths and disability adjusted life-years were majorly offset by decreases in rates of death from CVD.

It is critical to note that the prevalence of obesity has increased despite national differences in income and wealth, pointing to changes in food environments and food systems as major drivers. Additionally, the rate of increase in BMI is outpacing the rate of related disease burden largely in part to improved clinical interventions that reduce this associated burden.

Some limitations of the study include: Using self-reported and measured data on height and weight; excluding studies that used the WHO definition of childhood overweight and obesity in order to apply a consistent definition from the International Obesity Task Force; limited availability of data for some locations; and not using other measures of adiposity such as waist circumference and wait-to-hip ratio. Nevertheless, this study addressed major limitations of previous studies by including more data sources and quantifying the prevalence of childhood obesity. Together, these results highlight the need for implementing multiple interventions to reduce the prevalence and disease burden of high BMI.

2. Procalcitonin as a Marker of Etiology in Adults Hospitalized With Community-Acquired Pneumonia. Clinical infectious Diseases. [2]

Pneumonia continues to be a major cause of morbidity and mortality in the country, with an estimated 63,000 deaths, 1.2 hospitalizations and 2.3 million emergency department visits a year. Management of community acquired pneumonia (CAP) includes empiric treatment with antibiotics targeting the most likely bacterial pathogen, however, recent studies suggest that viruses account for a large proportion of CAP cases in adults and children. If a viral etiology for CAP could be reliably distinguished from bacterial and mixed viral/bacterial infections, overuse of antibiotics could be prevented. Nevertheless, there is no available test that can rapidly and accurately differentiate between viral and bacterial respiratory infections. To this end, pro-calcitonin (PCT) has shown promise in discriminating between viral and bacterial infections.

In this study of 1735 adults hospitalized with CAP across 5 hospitals (3 academic, 1 county, and 1 community hospital), investigators evaluated the relationship between serum PCT concentration with etiology of pneumonia by performing systematic testing for viruses and bacteria, which included cultures, serology, urine antigen tests, and molecular detection.
Most notably, during the 2.5 years study period, pathogens were found in 645 (37%) of patients, of which 409 (24%) were viral, 67 (4%) atypical bacteria, 169 (10%) typical bacterial and 1% mycobacterial/fungal infections. The most common pathogens were rhinorvirus, M. pneumoniae, and S. pneumonia. Median PCT was lower in the viral group (0.09 ng/mL) compared to the typical (2.5 ng/mL) and atypical (0.20 ng/mL) bacterial group.

In distinguishing between 1) any bacterial CAP from viral CAP, a PCT threshold of ≥0.1 ng/mL resulted in a sensitivity of 80.9% and specificity of 51.6%; 2) a typical bacterial CAP from a viral/atypical CAP, this same PCT threshold had sensitivity of 87.6% and specificity of 49.3%; and 3) any bacterial CAP from a nonbacterial CAP, this threshold had a sensitivity of 80.9% and specificity of 46.2 %. As the PCT cut-point increased, sensitivity increased with a concomitant reduction in specificity.

Although there is limited applicability of this marker (no PCT threshold allowed for perfect discrimination between viral and bacterial etiologies, there were 62% of patients with no pathology detected, and no outpatient subjects were included) this study demonstrated that higher levels of serum PCT at hospital admission were strongly associated with increased probability of bacterial pathogen detection. This data suggest that serum PCT could be a helpful adjunct in assessing the etiology of patients’ CAP in the inpatient setting.

3. Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure with Preserved Ejection Fraction. [3]

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disorder caused or exacerbated by a variety of co-morbidities linked to both cardiac and extracardiac abnormalities. There have been no treatments identified that can improve the prognosis of patients with HFpEF, but phenotyping patients into pathophysioligcally homogenous groups may provide a better way of targeting treatments in the future. As the prevalence of obesity continues to increase (see Health Effects of Overweight and Obesity in 195 Countries over 25 Years above), HFpEF has become more common.

As it is known that obesity has several deleterious cardiovascular effect, this study hypothesized that obesity-related HFpEF may be a distinct clinical phenotype. To test this hypothesis, detailed characterization of cardiovascular structure, function, and reserve capacity in patients with HFpEF and class II or greater obesity was compared with nonobese HFpEF and control patients without HF by undergoing detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing. This was a single center, restrospective study analyzing consecutive patients with HFpEF undergoing invasive hemodynamic exercise testing between 2000 and 2014.

In comparison to nonobese patients with HFpEF and control patients, obese patients with HFpEF had larger plasma volume expansion (3907 mL vs 2772 mL and 2680 mL), more biventricular remodeling, grater right ventricular dilatation and dysfunctions, worse exercise capacity and hemodynamic restraints with exercise (peak oxygen consumption, 7.7±2.3 vs 10.0±3.4 and 12.9±4.0 mL/min•kg), and impaired pulmonary vasodilation.

Although this was a single-center study from a tertiary hospital and by nature is subject to selection and referral bial, this study provides a myriad of analytical evidence suggesting that obese patients with HFpEF have display a distinct phenotype and pathophysiology from nonobese HFpEF, opening the door for better targeting by novel treatments, and encourages other investigators to elucidate the cellular pathophysiology of this distinct phenotype.

Minicuts:

1. Immunochemical Faecal Occult Blood Testing to Screen for Colorectal Cancer: Can the Screening Interval be Extended? [4]

In a recently published article in BMJ, investigators explored alternative faecal immunochemical testing (FIT) strategies to screen for colorectal cancer. Since FIT is a quantitative test (in comparison to qualitative guaic-based faecal occult blood testing, gFOBT), it offers flexibility in selecting specific cut-off levels and screening intervals. The results found that alternative FIT strategies using a lower cut-off level and a longer screening interval were estimated to provide similar diagnostic ability compared to conventional FIT screening.

2. Effects of Physician-targeted Pay for Performance on Use of Spontaneous Breathing Trials in Mechanically Ventilated Patients. [5]

This study published in AJRCCM analyzes the effects of pay for performance, a common quality improvement strategy, on the rate of completion of daily spontaneous breathing trials (SBTs) in mechanically-ventilated patients. The results showed that paying physicians in this manner was associated with increasing trial completion rates in low-performing ICUs, however, improvements in patients outcomes were inconsistent.

3. Declining Risk of Sudden Death in Heart Failure. [6]

In this article published by NEJM, the change in risk of sudden death among patients with symptomatic heart failure with reduced ejection fraction (HFrEF) was analyzed. Investigators found that approx. 40,000 patients with HFrEF enrolled in 12 clinical trials spanning from 1995 to 2014 saw a 44% reduction in the rate of sudden death, attributed to the benefits of new pharmacotherapies over the last two decades.

Dr. Cesar Soria Jimenez is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Kevin Hauck, associate editor, Clinical Correlations

Image Courtesy of Wikimedia Commons

References

1. Afshin, A. et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med 377, 13–27 (2017). http://www.nejm.org/doi/full/10.1056/NEJMoa1614362#t=article

2. Self, W. H. et al. Procalcitonin as a Marker of Etiology in Adults Hospitalized with Community-Acquired Pneumonia. Clin Infect Dis (2017). doi:10.1093/cid/cix317 https://www.ncbi.nlm.nih.gov/pubmed/28407054

3. Obokata, M., Reddy, Y. N. V., Pislaru, S. V., Melenovsky, V. & Borlaug, B. A. Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction. Circulation 136, 6–19 (2017). http://paper.medlive.cn/literature/2449967

4. Haug, U., Grobbee, E. J., Lansdorp-Vogelaar, I., Spaander, M. C. W. & Kuipers, E. J. Immunochemical faecal occult blood testing to screen for colorectal cancer: can the screening interval be extended? Gut 66, 1262–1267 (2017). https://repub.eur.nl/pub/88904/

5. Barbash, I. J., Pike, F., Gunn, S. R., Seymour, C. W. & Kahn, J. M. Effects of Physician-targeted Pay for Performance on Use of Spontaneous Breathing Trials in Mechanically Ventilated Patients. Am J Respir Crit Care Med 196, 56–63 (2017). http://www.atsjournals.org/doi/abs/10.1164/rccm.201607-1505OC

6. Shen, L. et al. Declining Risk of Sudden Death in Heart Failure. N Engl J Med 377, 41–51 (2017). http://www.nejm.org/doi/full/10.1056/NEJMoa1609758