Primecuts – This Week in the Journals

January 22, 2018

PrimeCuts 8 min read

By Scott Butler, MD 

Peer Reviewed

Could requiring Medicaid recipients to engage in community activities or work as a condition for eligibility improve health outcomes?  The Trump administration is planning to allow states to impose such requirements, much as they do for other programs such as food stamps and welfare1.  These conditions could be met by engaging in voluntary activities, attending school or caring for the elderly.  Given the recognized correlation between earnings and improved health outcomes, administration officials contend that the requirements themselves will foster better health.  Skeptics argue that providing insurance facilitates employment, not the other way around2.  It is certainly a debate to keep an eye on, but in the meantime, let’s recap recent developments in the medical journals. 

Predictors of Exacerbation Risk and Response to Budesonide in Patients with Chronic Obstructive Pulmonary Disease 

While the clinical benefits of treatments such as long-acting beta agonists (LABA) and inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) are well-established, recent data raise questions regarding the efficacy of ICS3,4.  Given the questionable benefit, as well concerns of potential risk including increased incidence of pneumonia5, a serum biomarker that predicts efficacy of ICS treatment in preventing exacerbations would be valuable in directing treatment.

A post-hoc analysis of three randomized control trials published in The Lancet Respiratory Medicine examined peripheral eosinophil count as a predictor of patient response to ICS for preventing COPD exacerbation6.  The three studies7,8,9 included patients over the age of 40 diagnosed with COPD with a smoking history of greater than 10 pack-years, with demonstrated airflow obstruction on pulmonary function tests (PFT).  Patients with a diagnosis of asthma were excluded.    These patients had experienced an exacerbation requiring oral corticosteroids or antibiotics within the prior 12 months.  This analysis compared the incidence of COPD exacerbation, defined as need for oral corticosteroids or hospital admission, for patients taking budesonide-formoterol or formoterol alone with varying serum eosinophil counts.

A total of 4,528 patients met the inclusion criteria and had available serum eosinophil data.  The incidence of COPD exacerbation increased with increasing degrees of peripheral eosinophilia.  Patients treated with formoterol alone with eosinophil counts <0.01×109 cells/L had 0.5 exacerbations annually, compared to 1.8 for those with eosinophil count >0.80×109 cells/L.  Notably, treatment effect in reducing exacerbations was detectable for budesonide-formoterol compared to formoterol alone only at eosinophil counts >0.10×109 cells/L.

These data demonstrate that COPD exacerbation frequency increases with eosinophil count for patients taking formoterol.  They also suggest that patients with eosinophil count >0.1×109 cells/L would benefit from combination ICS and LABA to prevent exacerbations.  That this study is a post-hoc analysis is a clear limitation, and its findings would be bolstered by a prospective follow-up study. 

Effect of Several Negative Rounds of Human Papillomavirus and Cytology Co-testing on Safety Against Cervical Cancer

Current guidelines recommend screening for cervical cancer by co-testing every 5 years, meaning combined high-risk human pappilomavirus (HPV) and cytologic testing10.  The underpinning of this recommendation is the concept that adding HPV testing to cytology reduces likelihood of developing subsequent invasive cervical cancer after initial negative screening11.  Despite this assumption, the majority of research on HPV-inclusive screening assesses only one round of cervical cancer screening.

An observational cohort study published in the Annals of Internal Medicine assessed the risk of developing cervical cancer after multiple negative co-tests performed at 3 year intervals12.  Women aged 30-64 receiving care at Kaiser Permanente Northern California were included in the study.  Subjects were required to have had one or more co-tests in the period from 2003-2014.  The risk of detection of invasive cervical malignancies were then assessed based on the number of prior negative co-tests.

The study included 990,013 women who met the inclusion criteria.  Each cycle of testing that was negative for invasive cervical cancer reduced the risk of future diagnosis, with the majority of the absolute decrease in risk occuring between the first and second round of testing.  The first negative round of testing corresponded to a 0.0064% 5-year risk, compared to 0.0015% after 3 rounds of negative screening.  No additional cases of invasive cervical cancer were diagnosed after a second negative co-test.

This study demonstrates that the risk of future development of invasive cervical cancer decreases considerably after more than one negative co-test, and that risk continues to decrease with each subsequent negative screening.  These data could be used to justify increasing the screening interval after one or two negative co-tests.   

Empagliflozin and Clinical Outcomes in Patients with Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease 

Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that acts at the proximal tubule of the kidney.  It has previously been demonstrated to reduce both morbidity and mortality among patients with known cardiovascular disease (CVD) and type II diabetes mellitus (DMII)13.  Because the mechanism of action is increased renal excretion of glucose, its efficacy is limited by renal function and its utility in patients with chronic kidney disease (CKD) has remained an open question14.

A study published in Circulation sought to clarify the role for empagliflozin in patients with CKD15.  Included patients had DMII, known CVD and estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min.  Patients were randomized to empagliflozin 10 mg, 25 mg, or placebo once daily, with continuation of standard care for their DMII.  The primary outcomes were cardiovascular death, heart failure exacerbation requiring hospitalization, all-cause hospitalization and all-cause mortality.

Of the 7020 patients randomized, 2250 had an eGFR<60 mL/min.  This subset of patients had a higher incidence of each primary outcome than their counterparts with eGFR>60 mL/min.  Among patients with an eGFR<60 mL/min, those treated with empagliflozin had an relative risk reduction of 29% for cardiovascular death compared to placebo (HR 0.71, 95% CI 0.42-0.87).  All-cause mortality was reduced by 24% (HR 0.76, 95%, CI 0.59-0.99), hospitalization for heart failure by 39% (HR 0.61, 95% CI 0.42-0.87) and hospitalization for any cause by 19% (HR 0.81, 95% CI 0.72-0.92).

These data demonstrate that the previously-published reductions in cardiovascular mortality, all-cause mortality and hospitalization afforded by empagliflozin for patients with DMII and CVD hold for patients with CKD.  Notably, this study excluded patients with an eGFR<30 mL/min, and additional investigation would be warranted for patients with more severe renal dysfunction. 

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients with Alzheimer Disease 

The 5-hydroxytryptamine-6 (5-HT6) receptor is an appealing target for the treatment of Alzheimer disease due to its proven role in learning and memory16, and animal studies have been promising in improving cognition17.  Currently, only cholinesterase inhibitors and N-methyl-D-aspartate-receptor antagonists are approved for treatment of Alzheimer disease.  Three randomized control trials were recently performed to assess idalopirdine, a 5-HT6 antagonist, as a complementary treatment for Alzheimer disease.

An analysis published in JAMA reported the results of the 3 randomized trials assessing the benefit of idalopirdine used in combination with cholinesterase inhibitors for the treatment of Alzheimer disease18.  Inclusion criteria included age over 50, diagnosis of Alzheimer disease meeting established criteria, and a history of at least 4 months taking a cholinesterase inhibitor.  Those taking memantine or having an additional diagnosis of an alternative form of dementia or severe central nervous system disease were excluded.  Patients were randomized to idalopirdine 10, 30 or 60 mg daily, or to placebo.  The primary outcome was change in Alzheimer’s Disease Assessment Scale (ADAS-Cog), a validated measure of cognition19.

Of the 2,525 patients included in the 3 trials, 2,254 were included in the final analysis.  In the first trial, the mean difference in change of ADAS-Cog score for idalopirdine compared to placebo was 0.05 (95% CI -0.88 to 0.98) for 60 mg, compared to 0.33 (95% CI -0.59 to 1.26) for 30 mg.  This non-significant relationship held for the second and third trials, nor were there any significant improvements in secondary measures, including an alternative Alzheimer disease cognition scale and a measure of activities of daily living.

These data show no improvement in measures of cognition for patients with Alzheimer disease treated with idalopirdine in addition to cholinesterase inhibitors.  These results contrast with a phase 2 study that had initially prompted optimism for a novel receptor target.  The variety of doses and large number of patients included in the study bolster the conclusion that idalopirdine does not represent a valuable new pharmacologic tool in the treatment of Alzheimer disease. 

MiniCuts:

A randomized control trial out of The Lancet found no difference in the risk of mortality or subsequent infections among critically ill patients given enteral vs parenteral nutrition within 24 hours of admission 20.

An analysis published in JAMA demonstrated the changes in mortality rate for breast cancers when stratified by molecular subtype from 2000-201221. The mortality rate for breast cancer in general has decreased by 37% over this time period.

A prospective cohort study in the BMJ looked at the effect of adherence to validated diets on long term weight changes among patients with a genetic predisposition for obesity. 22

Dr. Scott Butler is a 2nd year Internal Medicine Resident, NYU Langone Health

Peer reviewed by Ian Henderson, MD a Chief Resident in Internal Medicine, NYU Langone Health

References

  1. Pear R. Trump Administration Says States May Impose Work Requirements for Medicaid. The New York Times. https://www.nytimes.com/2018/01/11/us/politics/medicaid-work-requirements.html. Published 2018.
  2. Sanger-Katz M. Can Requiring People to Work Make Them Healthier? The New York Times2. https://www.nytimes.com/2018/01/11/upshot/medicaid-work-requirements-trump.html?rref=collection%2Fsectioncollection%2Fhealth&action=click&contentCollection=health&region=stream&module=stream_unit&version=latest&contentPlacement=3&pgtype=sectionfront. Published 2018.
  3. Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Inhaled corticosteroids vs placebo for preventing COPD exacerbations: a systematic review and metaregression of randomized controlled trials. Chest. 2010;137(2):318-325. doi:10.1378/chest.09-1305.
  4. Ernst P, Saad N, Suissa S. Inhaled corticosteroids in COPD: the clinical evidence. Eur Respir J. 2015;45(2):525-537. doi:10.1183/09031936.00128914.
  5. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036. doi:10.1136/thoraxjnl-2012-202872.
  6. Bafadhel M, Peterson S, De Blas MA, et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med. doi:https://doi.org/10.1016/S2213-2600(18)30006-7.
  7. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68(14):1975-2000.
  8. Rennard SI, Tashkin DP, McElhattan J, et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs. 2009;69(5):549-565. doi:10.2165/00003495-200969050-00004.
  9. Sharafkhaneh A, Southard JG, Goldman M, Uryniak T, Martin UJ. Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Respir Med. 2012;106(2):257-268. doi:10.1016/j.rmed.2011.07.020.
  10. ACOG Practice Bulletin Number 131: Screening for cervical cancer. Obstet Gynecol. 2012;120(5):1222-1238. doi:http://10.1097/AOG.0b013e318277c92a.
  11. Ronco G, Dillner J, Elfstrom KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet (London, England). 2014;383(9916):524-532. doi:10.1016/S0140-6736(13)62218-7.
  12. Castle PE, Kinney WK, Xue X, et al. Effect of Several Negative Rounds of Human Papillomavirus and Cytology Co-testing on Safety Against Cervical Cancer: An Observational Cohort Study. Ann Intern Med. 2018;168(1):20-29. doi:10.7326/M17-1609.
  13. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720.
  14. Macha S, Mattheus M, Halabi A, Pinnetti S, Woerle HJ, Broedl UC. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab. 2014;16(3):215-222. doi:10.1111/dom.12182.
  15. Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease. Circulation. 2018;137(2):119-129. doi:10.1161/CIRCULATIONAHA.117.028268.
  16. Geldenhuys WJ, Van der Schyf CJ. Role of serotonin in Alzheimer’s disease: a new therapeutic target? CNS Drugs. 2011;25(9):765-781. doi:10.2165/11590190-000000000-00000.
  17. Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics. 2008;5(3):458-469. doi:10.1016/j.nurt.2008.05.008.
  18. Atri A, Frolich L, Ballard C, et al. Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials. JAMA. 2018;319(2):130-142. doi:10.1001/jama.2017.20373.
  19. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984;141(11):1356-1364. doi:10.1176/ajp.141.11.1356.
  20. Reignier J, Boisrame-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet (London, England). November 2017. doi:10.1016/S0140-6736(17)32146-3.
  21. Plevritis SK, Munoz D, Kurian AW, et al. Association of Screening and Treatment With Breast Cancer Mortality by Molecular Subtype in US Women, 2000-2012. JAMA. 2018;319(2):154-164. doi:10.1001/jama.2017.19130.
  22. Wang T, Heianza Y, Sun D, et al. Improving adherence to healthy dietary patterns, genetic risk, and long term weight gain: gene-diet interaction analysis in two prospective cohort studies. BMJ. 2018;360. http://www.bmj.com/content/360/bmj.j5644.abstract.