Primecuts – This Week in the Journals

June 22, 2017

Vegas_Golden_Knights_logoBy David Pineles, MD
Peer Reviewed

In a major blow to the Democratic party, Republican Karen Handel won the special congressional election in Georgia, fending off Democrat Jon Ossoff [1]. While some see this as a victory for President Trump, others are viewing this as a win despite Mr. Trump’s actions [2]. In world news, Britain’s Prince Phillip, the 96-year old husband of Queen Elizabeth, spent his second night in King Edward VII Hospital for an unspecified infection [3]. In sporting news, the the National Hockey League held an expansion draft for the newly formed Las Vegas Golden Knights [4]. This will be the first major professional sporting team to reside in Las Vegas.

In this week’s Primecuts we will discuss utilizing the DAPT Score in post-PCI patients, treating recurrent C. diff infection with freeze-dried fecal transplant capsules, treating bronchiectasis with atorvastatin, and treating Barrett’s esophagus with low-grade dysplasia.

Use of the Dual-Antiplatelet Therapy (DAPT) Score to Guide Treatment Duration After PCI [5]

Use of dual-antiplatelet therapy with aspirin and an oral P2Y12 adenosine diphosphate receptor inhibitor following percutaneous coronary intervention (PCI) is an evidence based guideline. However, the duration of DAPT therapy remains somewhat controversial one year out from PCI, with guidelines recommending individualization of the treatment plan based on bleeding risk. The PRODIGY trial in 2012 was the first major trial to address this matter. The PRODIGY trial was a multicenter, randomized control trial reported in Circulation in 2012 [6]. This study randomized patients 30 days post-PCI (with stratification for bare-metal and drug eluting stents) to either 6 or 24 months of DAPT. They found that there was no significant difference in their primary end point (composite death of any cause) between the two groups. However, there were significantly more bleeding events in the 24-month of DAPT arm.

The DAPT score is a new clinical tool which aids in predicting benefit and harm (ie: cardiovascular events and bleeding) of DAPT beyond the one year mark. The DAPT score ranges from -2 to 10 and is calculated based on a set of criteria including: age, diabetes diagnosis, smoking status, prior PCI or MI, and history of CHF or left ventricular EF <30%. A score of

In the PRODIGY cohort, 45% of patients studied (884 participants) had a high DAPT score (≥2) and 55% (1086 participants) had a low score (<2). There was a significantly greater reduction in the primary efficacy outcome with 24 versus 6 months of DAPT in the patients with high scores than those with low scores [RD of -2.05 (95% CI, -5.04 to 0.95, p=0.30)]. There was also a significant increase in the primary safety outcome (major bleeding) with 24 versus 6 months in patients with low scores than those with high scores (RD 2.58, 95% CI, 0.71 to 4.46, p=0.046).

Although limited by the applicability of the DAPT score (can the scoring system be applied to the PRODIGY trial population?), the findings suggest that we should better stratify post-PCI patients in order to better assess their personalized benefit or harm from DAPT.

Successful Resolution of Recurrent C. Diff Infection Using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study [7]

With the widespread use and over prescribing of antibiotics by healthcare providers, there has
been a rise in incidence of Clostridium difficile infection (CDI). Standard treatment for this infection(ie: metronidazole and vancomycin) has good efficacy, however, these antibiotic treatments also suppress normal gut microbiota leaving patients vulnerable to recurrence. Fecal
microbiota transplant (FMT) has emerged as a potential tool to treat recurrent infections; however the logistics of FMT delivery remain problematic. This week in The American Journal of Gastroenterology the efficacy and safety of a freeze-dried, encapsulated fecal microbiota pill for patients with recurrent CDI were reported.

This was a single center, prospective study which enrolled 49 patients with recurrent C. difficile infection. Patients were included with at least 2 spontaneous recurrences of CDI following initial treatment and failure of at least one extended antibiotic regimen. Donor fecal material was obtained from two healthy male donors and the capsules were freeze-dried and categorized based on the number of bacteria in each capsule. The study protocol evolved over the course of the study. Initially, the protocol used ~2.5×1012 bacteria contained in 24–27 capsules in addition to a colon purgative before administration. However, due to limited number of FMT capsules, the authors had to decrease the dose in later stages of the trial and instead used ~2.1–2.5×1011 bacteria contained in a single dose of 2–3 capsules without a preceding colon emptying. At 2 months, there was an 87.8% (43/49) success rate in preventing CDI recurrence. No serious adverse events occurred during this time period.

Although this study does demonstrate strikingly positive results, there are numerous limitations that should be mentioned. First, the small sample size of 49 participants significantly limits the power of this study. Second, the trial was not randomized or controlled which allows for many possible confounding factors and biases to influence the results. Third, the fact that the investigators changed the protocol and altered the intervention mid-study raises questions in regards to standardization and confounding. Fourth, the study was only 2 months in duration which may not be long enough to capture all recurrences. Despite these limitations, this study highlights progress made in the delivery of FMT and its potential efficacy for recurrent CDI.

A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study [8]

Bronchiectasis is characterized by permanently damaged airways with excessive neutrophilic inflammation with ongoing bacterial colonization. Statins have been shown to have anti-inflammatory properties by modulating both the innate and adaptive immune systems. It was recently demonstrated in a randomized control trial that patients with moderately severe bronchiectasis treated with 6 months of atorvastatin 80 mg daily experienced reduced cough, enhanced sputum neutrophil apoptosis, and reduced serum IL-8 [9]. In a newly published article in Chest, investigators sought to investigate whether atorvastatin treatment in patients with more severe bronchiectasis and chronically infected with P. aeruginosa would result in similar effects.

Bedi et al. performed a single center, double blinded, randomized controlled trial of 32 adult patients with severe bronchiectasis and chronic infection with P. aeruginosa to receive 80 mg of atorvastatin daily or placebo for three months. The primary measured outcome was the perceived reduction in cough using the mean Leicester Cough Questionnaire (LCQ) score. The investigators found no significant difference in cough between the two groups, but did find a significant improvement in quality of life assessed by the St. George’s respiratory questionnaire (mean difference = -5.62, 95% CI [-10.13 to -1.13], p=0.016) in the high dose statin group. There was a significant difference in inflammatory markers between groups including serum IL-8 (p=0.04), TNF (p=0.01), and ICAM1 (p=0.04). No significant improvement in PFT’s or in the number of exacerbations was found in the atorvastatin group.

The study failed to meet its primary endpoint of improvement in cough and while the investigators did demonstrate an improvement in quality of life of these patients, this could not be explained by the addition of a high dose statin to the patient’s medical therapy. Given this study’s relatively small study cohort and short follow up period, its findings are limited. Overall, statin medications are not benign drugs and can have significant side effects to the patients taking them. As such, it does not appear that there is enough evidence here to change practice in this patient population and further trials need to be performed to better examine this topic.


Disease Progression in Barrett’s Low-Grade Dysplasia with Radiofrequency Ablation Compared with Surveillance: Systematic Review and Meta-Analysis [10]

The incidence of esophageal adenocarcinoma (EAC) has greatly increased over the past several years. Barrett’s esophagus (BE) is the only identifiable pre-malignant condition for EAC. Treatment options for BE depend on the degree of dysplasia. While the management for high-grade dysplastic BE and non-dysplastic BE remain clear, the management of BE with low-grade dysplasia remains controversial. In a recent study published in the American Journal of Gastroenterology, Qumseya et al. performed a meta-analysis to investigate the relative risk of disease progression among patients with BE with low-grade dysplasia treated with radiofrequency ablation compared with surveillance alone.

The investigators identified 19 eligible studies meeting their inclusion criteria which incorporated a total of 2,746 patients. The primary outcome was the relative risk of disease progression among patients with BE with low-grade dysplasia treated with RFA compared with those who underwent surveillance alone. They found a RR of disease progression in patients with BE-LGD treated with RFA compared with surveillance alone of 0.14% (95% CI, 0.04-0.45, p=0.001). This suggests an 86% reduction in the risk of disease progression in RFA compared with surveillance. Further, the authors found an absolute risk reduction from RFA compared with surveillance of 10.9% with a number needed to treat of 9.2.

Interestingly, as opposed to current guidelines which recommend surveillance endoscopy for BE-LGD, this meta-analysis demonstrates that RFA is associated with significant reduction in disease progression among patients with BE-LGD and is superior to surveillance alone. The limitations of this study include potential publication bias as alluded to by the authors in the not provided funnel plot. Additionally, as mentioned by the authors, significant inter- and intraobserver variability exists among pathologists with regard to ND-BE, indefinite for dysplasia, and LGD. As such this variability may affect data utilized in the meta-analysis. Despite these limitations, this article appears to put forward strong evidence to support a change in practice for a disease process with significant burden to the United States population.

Mini-Cuts:
1. CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis [11]
In a recently published article in Chest, investigators prospectively measured serum CA-125 levels in 241 LAM patients. Of note, multivariate analysis discovered that higher serum CA-125 levels correlated with lower FEV1 and pleural effusions (p<0.001) and decreased after sirolimus treatment (p=0.002). Although further larger trials need to be performed, these findings suggest CA-125 may be a biomarker for disease activity in this patient population.

2. A Trial of Itraconazole or ” Amphotericin B for HIV-Associated Talaromycosis [12]
In this newly published article in NEJM, authors performed a non-inferiority trial comparing amphotericin B and itraconazole for the treatment of T. marneffei infections, a rare but extremely fatal disease. The authors found that the mortality at 6 months was 11.3% in the amphotericin B group and 21.0% in the itraconazole group with an absolute risk difference of 9.7% (95% CI, 2.8 to 16.6, p=0.006). Overall, amphotericin was superior to itraconzole as initial treatment for this infection when comparing 6-month mortality and clinical response.

3. Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons [13]
This study published in JAMA prospectively analyzed cognitively normal individuals with elevated brain amyloid and found an increased risk of developing Alzheimer-related cognitive decline. Although the clinical significance of these findings remains unclear, these findings suggest a relationship between amyloid levels and cognitive decline that warrants further study.

References:

1. Martin, J., Fausset, R. “Karen Handel Wins Georgia Special Election, Fending Off Upstart Democrat.” The New York Times. 20 June 2017. https://www.nytimes.com/2017/06/20/us/politics/karen-handel-georgia-special-election.html?hp&action=click&pgtype=Homepage&clickSource=story-heading&module=first-column-region&region=top-news&WT.nav=top-news

2. Dionne Jr. E.J. “Karen Handel’s win was a victory for Republicans – but not for Trump.” The Waashington Post. 20 June 2017. https://www.washingtonpost.com/opinions/karen-handels-win-was-a-victory-republicans–but-not-for-trump/2017/06/21/e157fc00-56bc-11e7-b38e-35fd8e0c288f_story.html?utm_term=.77e40264508a

3. Costas, P. “Britain’s Prince Phillip to spend second night in hospital.” Reuters. 21 June 2017. http://www.reuters.com/article/us-britain-royals-idUSKBN19C16O?il=0

4. Elliott, H. “Vegas holds all the cards in NHL expansion draft.” The Los Angeles Times. 20 June 2017. http://www.latimes.com/sports/ducks/la-sp-nhl-expansion-draft-elliott-20170620-story.html
5. Piccolo R, Gargiulo G, Franzone A, et al. Use of the Dual-Antiplatelet Therapy Score to Guide Treatment Duration After Percutaneous Coronary Intervention. Ann Intern Med. 2017.

6. Kubbajeh M, Cavazza C, et al. Randomized comparison of 6- versus 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention: design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY). Am Heart J. 2010;160:804–811

7. Staley C, Hamilton MJ, Vaughn BP, et al. Successful Resolution of Recurrent Clostridium difficile Infection using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study. Am J Gastroenterol. 2017; https://www.ncbi.nlm.nih.gov/pubmed/28195180

8. Bedi P, Chalmers JD, Graham C, et al. A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study. Chest. 2017 https://www.ncbi.nlm.nih.gov/pubmed/28554732

9. Mandal P, Chalmers JD, Graham C, Harley et al. Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med. 2014 Jun;2(6):455-63.

10. Qumseya BJ, Wani S, Gendy S, Harnke B, Bergman JJ, Wolfsen H. Disease Progression in Barrett’s Low-Grade Dysplasia with Radiofrequency Ablation Compared With Surveillance: Systematic Review and Meta-Analysis. Am J Gastroenterol. 2017;112(6):849-865. https://www.ncbi.nlm.nih.gov/pubmed/28374819

11. Glasgow CG, Pacheco-rodriguez G, Steagall WK, et al. CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. Chest. 2017 https://www.ncbi.nlm.nih.gov/pubmed/28576630

12. Le T, Kinh NV, Cuc NTK, et al. A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis. N Engl J Med. 2017;376(24):2329-2340. https://www.ncbi.nlm.nih.gov/m/pubmed/28614691/

13. Donohue MC, Sperling RA, Petersen R, et al. Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons. JAMA. 2017;317(22):2305-2316. http://www.alzforum.org/papers/association-between-elevated-brain-amyloid-and-subsequent-cognitive-decline-among-cognitively

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