Primecuts – This Week in the Journals

December 4, 2017

By Margot Hedlin, MD

Peer Reviewed

It’s a brave new world – on Saturday the Senate approved a much-debated tax bill intended to cut $1.4 trillion from taxes, in part by lowering the corporate tax rate from 35% to 20% and repealing the individual health insurance mandate. The nonpartisan Congressional Budget Office estimates that 13 million fewer people will have health insurance by 2027, in part because as healthy individuals opt out of the market, rates will rise prohibitively for those who remain – an estimated 10% per year for individuals who have to buy their own insurance. The House and Senate will need to reconcile differences between their bills before the plan moves forward to the White House for final approval.

In a report that may fascinate and disgust New Yorkers of all stripes, a graduate student has released a report showing that rats have distinct “uptown” and “downtown” genetic populations, even showing granular differences between rats from different neighborhoods. The ostensible purpose of the study was to guide Mayor de Blasio’s proposed $32 million plan to manage the city’s rodent problem, though those who embrace the city’s unique ecosystem may take it as another reason for a bit of neighborhood pride.
And with that, let’s dive into the medical literature.

No Cuts for Old Men: Most Potentially Preventable Medicare Spending is incurred by Elderly Patients
With an ever-changing political climate that may signal cuts to the healthcare budget, investigations seeking to control growing healthcare costs seem ever more relevant. One such study in the Annals of Internal Medicine investigated potentially avoidable medical expenses in Medicare patients. The authors analyzed Medicare fee-for-service claims filed from 2011-2012, and studied the top 10% of the 6.1 million beneficiaries included in the sample.

They separated these high-cost users into 6 categories: frail elderly (46.2%), nonelderly disabled (14.3%), patients with major complex chronic medical conditions (11.1%), patients with minor complex chronic medical conditions (3.7%), patients with simple chronic medical conditions (2.0%), and relatively healthy patients (1.1%). In creating these categories, the authors found that high-cost patients in all groups had higher rates of mental illness and chronic medical conditions than non-high-cost patients. The authors then used two previously validated algorithms to identify potentially preventable hospitalizations and emergency room visits.

The authors found that 4.8% of the health care spending was potentially preventable, with high-cost patients incurring 73.8% of the expense and the remaining 90% of Medicare beneficiaries incurring the remaining 26.2%. Of note, high-cost elderly patients accounted for 43.9% of the potentially preventable spending – approximately $6593 per person – despite representing 4% of all Medicare beneficiaries. That group was followed by the nonelderly disabled, who incurred 14.8% of preventable spending ($3421 per person), and patients with major complex chronic medical conditions (11.2% of preventable spending, or $3327 per person). When the entire population of 6.1 million beneficiaries was analyzed, the frail elderly group (making up 8.6% of the population) represented the largest contribution to preventable spending at 51.2%.

When the data were further analyzed to understand the etiology of this potentially preventable spending in the frail elderly population, the majority of the expenses were incurred by hospital admissions for heart failure ($451 per person), bacterial pneumonia ($355), UTI ($289), COPD/asthma ($249), long-term complications of diabetes ($152), and dehydration ($121).

While this study largely highlights the need for further public health and quality improvement initiatives to address the needs of our geriatric patients, individual providers can take action on these studies as well. First, the US Preventative Task Force has several grade B recommendations for community-dwelling adults over 65: they recommend exercise, physical therapy, and vitamin D supplements for adults at increased risk for falls. Second, the study highlights the importance of pneumococcal vaccination in adults over 65. Third, providers may consider treating mental health issues more aggressively, and bringing high-risk patients in for more frequent visits for close monitoring of conditions such as heart failure.

Take it from the Top – Fecal Microbial Transplant by Oral Capsule is Non-Inferior to Colonoscopy for Recurrent C difficile Infection

Fecal microbial transplant (FMT) is the most effective treatment for recurrent Clostridium difficile infection (RCDI). Currently, FMT is primarily performed by colonoscopy as studies have indicated that direct delivery is more effective than oral delivery; however, colonoscopy is significantly more costly and invasive, and is a potential barrier to care for those with limited access.

Therefore, this study attempted to determine whether FMT performed by oral capsules is a viable alternative to FMT by colonoscopy, with a cutoff of -15% for noninferiority. This was an unblinded randomized trial, in which 116 adults were recruited from 3 academic centers in Alberta, Canada. Participants were included if they were age 18-90 and had at least 3 documented episodes of CDI, defined by a positive C diff test and >3 unformed bowel movements every 24 hours within 8 weeks of completing a course of treatment for C diff treatment. Patients were excluded if they had complicated CDI , chronic diarrhea, IBD with a flare within 3 months of starting the trial, active cancer treatment, colectomy/colostomy/ileostomy, or conditions requiring antibiotic treatment.

All patients were initially treated with 10 or more days of vancomycin at 125 mg four times daily until symptom resolution, followed by vancomycin 125 mg twice daily until 24 hours prior to FMT. All patients were prepped with 4L of GoLytely the night before receiving FMT. Subsequently, the 57 patients randomized to the oral capsule group swallowed 40 capsules containing a total of 200 mL of fecal slurry (a processed form of fecal material generated from 80-100 grams of donated stool), and the 59 patients in the colonoscopy group received 360 mL of fecal slurry in the cecum. Patients were then followed for 12 weeks. 89.5% of patients in the oral capsule group did not have recurrence, as compared to 96.6% of patients in the colonoscopy group, with a rate difference of -7.1% and 1-sided 95% confidence interval of -14.9% at p=0.048, which successfully qualifies oral capsule as noninferior to colonoscopy.

Patients were also asked to rate their experience, with significantly more patients in the capsule group rating their experience as “not at all unpleasant” (66% vs 44%). Minor adverse events occurred in 5.4% of the capsule group and 12.5% in the colonoscopy group. The cost for each patient in the colonoscopy group was $874 as compared to $308 in the capsule group, with the authors noting that this difference would likely be more pronounced in the US due to higher cost of colonoscopy.

This trial provides compelling evidence that oral capsule FMT is a good alternative to FMT by colonoscopy, which has not previously been demonstrated in the literature. The authors note that this study likely showed more benefit than previous trials because the capsule group received a larger inoculum of fecal material than is traditionally delivered (80-100g, as compared to previous studies providing 17-25g of fecal material). A major limitation of this study is the exclusion of patients with complicated CDI, patients who are arguably in greatest need of an effective and timely treatment for their condition. However, this study is promising as capsule delivery may be more convenient and cost-effective than colonoscopy, with the authors noting that FMT could be delivered in an office setting.

No Pain, No ‘graine: In phase 3 clinical trial, Fremanezumab Shows Promise for Patients with Chronic Migraine
A phase 3 trial of fremanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP), has shown promise as a preventative treatment for chronic migraine.

CGRP is a proinflammatory neuropeptide involved in the pathophysiology of migraine, causing vasodilation when released by trigeminal sensory neurons. Studies have shown that CGRP levels rise during a migraine, decrease when a triptan is administered, and that CGRP infused into migraineurs induces migraine. As such, compounds blocking CGRP’s effects have been under investigation.

This trial published in the New England Journal of Medicine was a 16 week double-blind study where 1130 participants were randomized into one of three groups: placebo, fremanezumab quarterly, fremanezumab monthly. Patients were recruited at 132 sites across 9 countries, and were included if they were age 18-70, had a history of migraine for at least one year, and if during the preintervention period they fulfilled criteria of chronic migraine by having a headache on >=15 days, with migraines on >=8 days.

Participants first had a 28 day pretrial period where they recorded incidence of headaches, migraines, and need for abortive therapies using an electronic headache diary. All participants received subcutaneous injections at 4 week intervals for a total of 12 weeks; patients in the fremanezumab quarterly group received 675 mg followed by placebo injections at subsequent visits, while patients in the fremanezumab monthly received the same initial 675 mg dose, followed by 225 mg doses at weeks 4 and 8. When the quarterly, monthly, and placebo groups were compared, there was a significant reduction in headache days per month (by 4.3±0.3 days, 4.6±0.3 days , and 2.5±0.3 days respectively, with a p<0.001), migraine days per month (4.9±0.4 days, 5.0±0.4 days, and 3.2±0.4 days respectively, with p<0.001), and number of days where patients used abortive therapies. (3.7±0.3 days, 4.2±0.3 days, and 1.9±0.3 days respectively, p<0.001). The only notable adverse events were injection site reactions such as erythema.

Another Reason to Mi-Grin: Erenumab for Episodic Migraine
While fremanezumab is effective for chronic migraine, patients with episodic migraine – an estimated 90% of patients with migraine – were not evaluated in the previously described trial. The STRIVE trial (Study to Evaluate the Efficacy and Safety of Erenumab in Migraine Prevention) was a phase 3 clinical trial that sought to determine whether erenumab, a fully human monoclonal antibody against the CGRP receptor, could help individuals who had fewer than 15 migraine or headache days per month.

955 patients were randomized to one of three groups: erenumab 70 mg monthly, erenumab 140 mg monthly, or placebo. Inclusion and exclusion criteria were largely the same as described previously, except patients were included if they had at least 4 but less than 15 migraine days per month. Patients underwent a 4 week baseline phase in which they recorded headache days and need for abortive medications, followed by a 24 week double-blind treatment phase, at which point patients received their assigned medication every 4 weeks.
When baseline headache data was compared to data collected from the final 3 months of the trial, both erenumab groups were found to reduce mean migraine days per month more than placebo (reduced by 3.2 days in 70 mg group, 3.7 days in 140 mg group, and 1.8 days in placebo group at p<0.001 for each dose versus placebo) and also reduced days in which patients used migraine-abortive medications (reduced by 1.1 days in 70 mg group, 1.6 days in 140 mg group, and 0.2 days in placebo group, for p<0.001 for each dose versus placebo). There were no significant differences between the groups in terms of frequency or severity of adverse events.

A major limitation of both erenumab and fremanezumab is that the trials excluded patients who, by several counts, are most seriously affected by migraine. Patients were excluded if they had failed at least 2 of the 4 classes of preventative therapies for migraine, if they had received botulinum injections within the last 4 months, if they had used interventions or devices (ie nerve blocks) in the 2 months prior to the study, or if they used opioids or barbiturates on >4 days during the preintervention period. Further study of these potentially promising treatments would need to investigate durability and safety of the medications, and would need to include patients with more severe migraines to ensure generalizability of results.

A study in the UK analyzed efficacy, safety, and cost-effectiveness of DOACs versus warfarin in patients with atrial fibrillation. They found that DOACs were at least as effective as warfarin at preventing stroke and had a decreased risk of major bleeding, with no significant difference in expected cost. Per their study, apixaban 5 mg twice daily has the most favorable profile as its reduced risk of major bleeding offsets its increased cost; followed by rivaroxaban 20 mg once daily.

A survey of surrogate decision-makers for hospitalized patients 65 and older investigated principles that surrogates use when making medical decisions for their loved ones. Our current ethical framework prioritizes patient autonomy over beneficence. However, the study found that surrogates are more likely to prioritize patients’ well-being (77.8%) over patient preferences (21.1%), though when advance directives are present surrogates are somewhat more likely to prioritize patient preferences.

Latent tuberculosis may not require directly observed therapy (DOT) for effective treatment. The iAdhere study was a 12-week phase 4 randomized clinical trial measuring adherence to a regimen of once-weekly isoniazid and rifampin for latent TB; 1002 patients were randomly assigned to DOT or self-administered therapy (SAT) with or without text message reminders. In the US population studied, SAT was found to be noninferior to DOT, with 85.4% completion in the DOT group, 77.9% completion in SAT group without text reminders, and 76.7% completion in the SAT-with-reminders group, and no statistically significant difference found with a noninferiority margin of 15%.

In local news, this marks the second year in a row that new HIV diagnoses have dropped in New York state, with a particularly impressive decline amongst non-white populations. This drop is thought to be attributable partly to the 2014 Ending the Epidemic campaign, which included initiatives such as needle exchanges and physician education on PrEP.

Dr. Margot Hedlin is a 1st year internal medicine resident at NYU Langone Health

Peer reviewed by Dana Zalkin, MD, 1st year resident at NYU Langone Health

Image Courtesy of Wikimedia Commons


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7. Complicated CDI was defined as 1 or more of the following: ICU admission, hypotension, fever≥38.5°C, ileus, significant abdominal distension, mental status changes, leukocytosis≥35,000 or <3,000, lactate >2.2 or end-organ damage, as outlined in Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M, Zuckerbraun BS. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013 Apr;108(4):478-98; quiz 499. doi: 10.1038/ajg.2013.4. Epub 2013 Feb 26. Review. PubMed [citation] PMID: 23439232

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