Primecuts – This Week In The Journals

January 24, 2017

PrimeCuts 8 min read
Lee,Chang W. - from camera serial number NYTCREDIT: Chang W. Lee/The New York Times

Lee,Chang W. – from camera serial number NYTCREDIT: Chang W. Lee/The New York Times

By Calvin Ngai, MD

Peer Reviewed

In former President Barack Obama’s last farewell speech, he asked all fellow Americans to continue to believe in our ability to create change. This past weekend, the day after Donald J. Trump was sworn into the presidential office and our country bid one last farewell to former President Obama, hundreds of thousands of women gathered in Washington D.C. (millions, including marches from all around the U.S. and the world) for the Women’s March to stand up, speak, and march for equality, human rights, feminism, science, and healthcare.

In this week’s Primecuts, we will highlight and summarize scientific articles (while avoiding alternative facts1).

Prime Cuts: 

1) Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus2

The US Preventive Services Task Force recommends low dose aspirin use for the primary prevention of cardiovascular disease.3 Nevertheless, there are patients who still experience a platelet-mediated ischemic event despite taking aspirin for its “anti-platelet” effect.  Additionally, previous studies of aspirin for primary prevention have not shown any differences in rates of cardiovascular death, non-fatal myocardial infarctions, and non-fatal stroke when compared to placebo.4, 5 Given these studies and controversy in the role of aspirin for primary prevention, the FDA does not endorse the use of aspirin in this setting.6 

There are many proposed mechanisms to explain why patients don’t clinically benefit from aspirin. Bhatt and colleagues sought to determine whether oral bioavailability of aspirin tablets plays a role in “aspirin resistance.” In a randomized, single-blinded, triple-crossover, pharmacokinetic, and pharmacodynamic study, they exposed individuals to three types of 325mg aspirin: 1) plain aspirin, 2) PL2200 (modified release lipid-based), and 3) enteric coated (EC) aspirin. Obese patients with T2DM were chosen as subjects because prior studies have suggested that weight and poor glycemic control were risk factors for poor aspirin pharmacokinetics. Aspirin non-responsiveness was defined as a residual serum thromboxane B2 (TXB2) level that was associated with elevated thrombotic risk (<99.0% inhibition or TXB2 > 3.1ng/mL). Results showed that the rate of aspirin non-responsiveness was 15.8%, 8.1%, and 52.8% respectively for plain aspirin, PL2200, and EC aspirin (p < 0.001 for comparisons vs. EC aspirin; p value not significant in between the other groups). When individuals receiving EC aspirin were crossed over to plain aspirin or PL2200, greater aspirin absorption and COX-1 inhibition were observed, thus the poor aspirin responsiveness seen in EC aspirin can be attributed to reduced bioavailability. However, this study was limited by the full dosing of aspirin, the enrollment of subjects without established cardiovascular disease, and the monitoring duration of aspirin responsiveness (only three days). Although this data provides an interesting pharmacologic reason behind why some patients may not respond to aspirin, it did not look into whether these different types of aspirin had an impact on patient outcomes.

2) Benefits and Harms of Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older: A Systematic Review and Meta-analysis7

In the elderly patient population (adults aged 60 years or older), guidelines have recommended a goal blood pressure (BP) of 150/90. In the Annals of Internal Medicine this past week, Weiss et al. published a systematic review and meta-analysis looking into the evidence behind this recommendation in light of recent data urging for tighter blood pressure control. Over 10,000 abstracts and 330 full-text articles were reviewed from multiple databases including MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews. The inclusion criteria were randomized trials of adults with a diagnosis of hypertension with a mean age of at least 60 years that directly compared different BP targets or more versus less intensive antihypertensive therapy. The primary outcomes were all-cause mortality, stroke, and cardiac events after at least 6 months of anti-hypertensive treatment. Sensitivity analyses were performed to address the heterogeneity of the study design and patient populations. Of the fifteen trials that were included in the meta-analysis, nine provided strong evidence that BP control to less than 150/90 decreases mortality (RR 0.90 [95% CI, 0.83 to 0.98]), cardiac events (RR 0.77 [CI, 0.68 to 0.89]), and stroke (RR 0.74 [CI, 0.65 to 0.84]). Six other trials using BP targets of 140/85 were associated with significant decreases in cardiac events (RR 0.82 [CI, 0.64 to 1.00]) and stroke (RR 0.79 [CI, 0.59 to 0.99]) but did not lead to significant reduction in mortality (RR 0.86 [CI, 0.69 to 1.06]).

Despite these findings, the controversy remains. The evidence for lower BP targets (systolic BP < than 120mmHg) has been inconsistent. This is mainly because two large trials, SPRINT8 and ACCORD9, have had contradictory results. In ACCORD, T2DM patients treated with aggressive blood pressure control (SBP <120) did not have improved outcomes when compared to the less intensive BP control group (SBP <140). In the SPRINT trial, non-diabetic patients had significantly better outcomes with tight BP control. It remains unclear whether these findings were due to the study populations or rather the study designs. In this study, it was difficult to look for treatment effects in diabetics versus non-diabetics because few studies included only T2DM patients (or excluded them) and there were major differences among these studies other than diabetes status. Therefore, more research is still warranted to determine the efficacy of strict BP control in diabetics. Of note in this meta-analysis, tighter BP control was associated with more short-term harms like hypotension and syncope but not with cognitive impairment, falls, or reduced quality of life. While guidelines exist for BP goals in the general population, anti-hypertensive treatment should be individualized and take into account each patient’s risk/benefit profile as well as comorbidities.

3) Reevaluation of Diagnosis in Adults With Physician-Diagnosed Asthma10

Symptoms of asthma are often non-specific, including wheezing, shortness of breath, chest tightness, and cough. The accurate diagnosis of asthma is made more difficult by its differing triggers, subtypes, and clinical courses. Ultimately, the diagnosis of asthma requires pulmonary function tests. However, many physicians choose to diagnose and treat patients empirically for asthma without having spirometry testing. In JAMA this past week, Aaron et al. sought to discover whether asthma diagnoses can be ruled out and asthma medications stopped in patients with physician-diagnosed asthma. This was a prospective, multicenter cohort study conducted in Canada from 1/2012 to 2/2015. Inclusion criteria were patients who were 18 years of age and had physician-diagnosed asthma established within the last 5 years. Patients were excluded if they were on long-term oral steroids, pregnant, breastfeeding, unable to perform spirometry, have contraindications to bronchial challenge test, or if they smoked for greater than 10 years (excluding possible COPD). The primary outcome was reached if a patient was determined to not have asthma. The diagnosis of asthma was ruled out in these patients if they did not have any evidence of acute worsening of asthma symptoms, reversible airflow obstruction on pulmonary function tests, or bronchial hyperresponsiveness after all asthma medications were tapered off. Additionally, a pulmonologist had to establish an alternative diagnosis. Out of 613 participants, the diagnosis of asthma was ruled out in 33% (95% CI, 29.4%-36.8%). In these participants whom asthma was ruled out, they were less likely to have undergone pulmonary function testing at the time of initial diagnosis as compared to participants whom asthma was confirmed (43.8% vs 55.6%, absolute difference 11.8%; 95% CI, 2.1%-21.5%). The alternative diagnoses that were given by the pulmonologist included GERD, cough due to ACE inhibitor, allergic rhinitis, but 12 patients had serious cardiorespiratory conditions including 4 individuals who had ischemic heart disease.

It is difficult to determine whether the 33% of patients in this study was due to initial misdiagnosis or spontaneous remission of asthma. In the future, clinicians should closely monitor patients with the diagnosis of asthma and actively try to titrate medications down as they achieve good asthma control. Additionally, reassessment of the asthma diagnosis may be warranted in patients who aren’t responding to traditional therapies by performing pulmonary function tests or referring to a pulmonologist.

4) Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: a Systematic Review and Meta-analysis11

Infectious enteritis, including bacterial (Campylobacter jejuni, E. coli O157:H7, etc.), viral (Norovirus), and protozoal (Giardia lamblia), have all been associated with development of irritable bowel syndrome (IBS). These food borne illnesses affect 15% of the U.S. population each year. In a systematic review and meta-analysis, Klem et al. (2017) sought to identify the risk factors and outcomes of IBS after infectious enteritis. The authors identified 45 studies via the Cochrane Database of Systematic Reviews, Ovid Medline, etc., which included more than 20,000 individuals with enteritis who were followed for at least 3 months to track the development of IBS. They found that the prevalence of IBS at 12 months after infectious enteritis was 10.1% (95% CI, 7.2-14.1). One out of nine individuals (95% CI, 7-13) exposed to food-borne illness and infectious enteritis may develop IBS—this is a 4 times higher risk than individuals who were not exposed. Interestingly, 42% of patients with protozoal enteritis developed IBS while only 14% with bacterial enteritis developed IBS. Additionally, results showed that the risk of IBS was significant higher in patients with antibiotic exposure (OR 1.7; 95% CI, 1.2-2.4), anxiety (OR 2; 95% CI, 1.3-2.9), depression (OR 1.5; 95% CI, 1.2-1.9), neuroticism (OR 3.3; 95% CI, 1.6-6.5), and in women (OR 2.2; 95% CI, 1.6-3.1). In the future, when patients present with chronic gastrointestinal discomfort after recent infectious enteritis, the diagnosis of irritable bowel syndrome must be considered, especially in those individuals who are at higher risk: women, individuals treated with antibiotics, and patients with anxiety/depression.

Minicuts:

1) “Zombie” Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York12

On July 12, 2016, multiple people were admitted to the hospital exhibiting “zombie-like” behavior after smoking a product called “AK-47 24 Karate Gold.” Extensive laboratory work-up including urine toxicology screening was unremarkable but it was later discovered that the product had contained AMB-FUBINACA, which is a potent short-acting synthetic cannabinoid with significant CNS depressant effects.

2) Transmission of Extensively Drug-Resistant Tuberculosis in South Africa13

Four hundred and four patients with extensively drug resistant Tuberculosis (XDR-TB) in South Africa underwent genotypic analysis in a prospective study performed by Shah et al. (2017). These authors found that the majority of the XDR TB cases were caused by transmission of the disease rather than acquired resistance from inadequate treatment of multidrug-resistant TB.

3) New Vaccines against Epidemic Infectious Diseases14

The World Health Organization regularly updates the list of pathogens that are most likely to cause outbreaks in the future (includes Zika, Chikungunya, etc.). In 2016, world leaders from different governments and organizations created the Coalition for Epidemic Preparedness Innovations (CEPI), with a goal to better promote the development of vaccines against these potential epidemics.

Dr. Calvin Ngai is a 1st year resident at NYU Langone Medical Center

Peer reviewed by David Kudlowitz, Chief Resident, NYU Langone Medical Center

Image courtesy of Change W. Lee, The New York Times

References:

  1. http://1.http://www.cnn.com/2017/01/22/politics/kellyanne-conway-alternative-facts/
  2. Bhatt DL, Grosser T, Dong JF, Logan D, Jeske W, Angiolillo DJ, Frelinger AL, Lei L, Liang J, Moore JE, Cryer B, Marathi U. Enteric coating and aspirin nonresponsiveness in patients with Type 2 Diabetes Mellitus. JACC. 2017 Jan 5. S0735-1097(16)37323-5. doi: 10.1016/j.jacc.2016.11.050. [Epub ahead of print]
  3. https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/aspirin-to-prevent-cardiovascular-disease-and-cancer
  4. de Gaetano G, Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomized trial in general practice. Lancet. 2001 Jan 13; 357(9250):89-95.
  5. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, Hennekens CH, Buring JE. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. NEJM. 2005; 352:1293-1304.
  6. http://6.http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm390539.htm
  7. Weiss J, Freeman M, Low A, Fu R, Kerfoot A, Paynter R, Motu’apuaka M, Kondo K, Kansagara D. Benefitis and harms of intensive blood pressure treatment in adults aged 60 years or older: a systematic review and meta-analysis. Ann Intern Med. 2017 Jan 17. doi: 10.7326/M16-1754 [Epub ahead of print]
  8. 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.
  9. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-85.
  10. Aaron SD, Vandemheen KL, Fitzgerald JM, et al. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA. 2017: 317(3):269-279.
  11. Klem F, Wadhwa A, Prokop L, Sundt W, Farrugia G, Camilleri M, Singh S, Grover M. Prevalence, risk factors, and outcomes of irritable bowel syndrome after infectious enteritis: A systematic review and meta-analysis. Gastroenterology. 2017 Jan 6. pii: S0016-5085(17)30008-2. doi: 10.1053/j.gastro.2016.12.039. [Epub ahead of print]
  12. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R. “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. NEJM. 2017; 376:235-242.
  13. Shah NS, Auld SC, Brust JCM, et al. Transmission of extensively drug-resistant tuberculosis in South Africa. NEJM. 2017; 376: 243-253.
  14. Rottigen JA, Gouglas D, Feinberg M, Plotkin S, Raghavan KV, Witty A, Draghia-Akli R, Stoffels P, Piot P. New vaccines against epidemic infectious diseases. NEJM. 2017 Jan 18. doi: 10.1056/NEJMp1613577. [Epub ahead of print]