Primecuts – This Week In The Journals

September 10, 2012

By Anjali Varma Desai, M.D

Faculty Peer Reviewed

In the news this week, former US Open champion Andy Roddick ended his tennis career while Barack Obama sought to continue his presidential career. The Democratic National Convention, held last week in Charlotte, NC, featured speeches by President Obama and his wife, as well as former President Bill Clinton and Vice-President Joseph Biden. Many speeches addressed various aspects of Obama’s record, including his hotly-debated health care plan, with concrete references to the expected impact on the solvency of Medicare and Medicaid, the increase in the number of newly-insured Americans, and the plan’s overall effect on total health care costs. With health care again at the forefront of the nation’s collective consciousness, we peruse the current medical literature for salient and potentially practice-changing research.

One such study that appeared in The Lancet this week investigated whether chronic kidney disease should be considered a coronary heart disease risk equivalent.[1] The study used a large population-based cohort comprised of 5 distinct subgroups: patients with prior MI and four mutually exclusive groups defined by the presence or absence of diabetes and CKD. CKD was defined as an eGFR of 15–59.9 mL/min per 1.73 m2 (stage 3 or 4). DM was defined as HbA1c > 6.5%. The primary study outcome was the risk of hospitalization for MI. During a median follow-up of 48 months, the unadjusted rate of MI was highest in people with prior MI (18.5 per 1000 person-years, 95% CI 17.4–19.8). In patients without prior MI, the rate of MI was lower in those with DM without CKD (5.4 per 1000 person-years, 95% CI 5.2–5.7) than in those with CKD without DM (6.9 per 1000 person-years, 95% CI 6.6–7.2; p<0.0001). The rate of MI in patients with DM was substantially lower than for patients with eGFR < 45 mL/min per 1.73 m2 and severely increased proteinuria (6.6 per 1000 person-years, 95% CI 6.4–6.9 vs 12.4 per 1000 person-years, 95% CI 9.7–15.9). Overall, this study provides convincing evidence that CKD, particularly in the presence of severe proteinuria, may confer a risk similar to DM and other coronary heart disease risk equivalents.

Switching gears to the realm of infectious diseases, an article in the Annals of Internal Medicine explored the risks of the immune reconstitution inflammatory syndrome (IRIS) after antiretroviral therapy (ART) initiation in HIV patients co-infected with tuberculosis. [2] This randomized clinical trial of 642 patients with HIV and TB was conducted at an outpatient clinic in South Africa. Patients were randomly assigned to start ART within 4 weeks of TB treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of TB treatment (late integrated treatment group), or within 4 weeks after TB therapy completion (sequential treatment group). IRIS incidence was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; p< 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; p< 0.001) treatment groups. Patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; p = 0.007) and longer time to resolution (70.5 vs. 29.0 days; p = 0.001) than those in the other groups. The study illustrates that early initiation of ART during TB treatment confers an increased risk of IRIS and IRIS-related hospitalization. This finding, in conjunction with the SAPiT trial’s prior finding that early initiation of ART during TB treatment can reduce mortality by 56% in patients with CD4 + cell counts <500/mm3 [3], may influence practitioners to delay ART initiation in patients with higher CD4 counts.

Moving to the field of pulmonology, a study published in NEJM found that pulmonary artery (PA) enlargement was associated with acute COPD exacerbations.[4] In a multicenter, observational trial of current and former smokers with COPD, multivariate logistic regression analysis showed a significant association between PA enlargement (defined as a ratio of the diameter of the PA to the diameter of the aorta i.e. PA:A ratio >1 on CT) and a history of severe exacerbations at the time of enrollment in the trial (OR, 4.78; 95% confidence interval [CI], 3.43 to 6.65; p<0.001). A PA:A ratio > 1 was also independently associated with an increased risk of future severe exacerbations in the trial cohort (OR, 3.44; 95% CI, 2.78 to 4.25; p<0.001), as well as in an external validation cohort (OR, 2.80; 95% CI, 2.11 to 3.71; p<0.001). In both cohorts, a PA:A ratio > 1 had the strongest association with severe exacerbations, even more so than established risk factors including GERD, St. George’s Breathlessness Score, chronic bronchitis, and FEV1. Although this was an observational trial that cannot definitively prove causation, the PA:A ratio can be easily quantified and appears to hold a promise as a radiologic tool to identify patients who may be prone to future COPD exacerbations.

Lastly, some noteworthy news from the field of rheumatology: a review article that appeared in this week’s JAMA sought to quantify the risk of malignancies in patients with rheumatoid arthritis (RA) who are treated with biologic response modifiers (BRMs).[5] In a meta-analysis of 63 randomized clinical trials of at least 6-months duration evaluating BRMs (specifically abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab) in 29,423 RA patients, there was no statistically significant increased risk of malignancy compared to placebo or other disease-modifying anti-rheumatic drugs (DMARDs). The incidence rate for any malignancy during the first year of therapy was very low in the BRM plus methotrexate group (0.77%; 95% CI 0.65%-0.92%), the BRM monotherapy group (0.64%; 95% CI 0.42%-0.95%), and the controls (0.66%; 95% CI 0.52%-0.84%). In addition, no statistically significant risk was observed for specific cancer sites. The article provides reassuring evidence that the BRMs do not confer an enhanced risk of malignancy; however, it will be important to study malignancy risk in the longer term, as well as risk of cancer recurrence in RA patients with a prior history of cancer, as the authors suggest.

Below are a few additional articles that garnered media attention in the last week:

1) Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. http://www.iom.edu/Reports/2012/Best-Care-at-Lower-Cost-The-Path-to-Continuously-Learning-Health-Care-in-America.aspx

This Institute of Medicine report found that approximately one-third of US healthcare dollars in 2009 (about $750 billion) was not spent effectively. The report describes major categories of waste and provides a set of recommendations for enhancing patient care while simultaneously reducing costs.

2) An integrated encyclopedia of DNA elements in the human genome. http://www.nature.com/nature/journal/v489/n7414/full/nature11247.html

This is one of 6 papers published in this week’s issue of Nature that details the work of the ENCODE (Encyclopedia Of DNA Elements) project, a massive federal project which aimed to describe all functional elements in the human genome. ENCODE scientists were ultimately able to assign biochemical functions for 80% of the genome, especially outside of well-studied protein-coding regions; many of these newly identified regulatory elements seem to be implicated in a variety of human diseases, including multiple sclerosis, lupus, rheumatoid arthritis, Crohn’s disease, ulcerative colitis and celiac disease.

3) Intermittent androgen suppression for rising PSA level after radiotherapy. http://www.nejm.org/doi/full/10.1056/NEJMoa1201546

In this NEJM study, intermittent androgen deprivation in patients with rising PSA after radiotherapy was noninferior to continuous androgen deprivation in terms of overall survival. Intermittent therapy provided benefits in terms of physical function, fatigue, urinary problems, hot flashes, libido, and erectile function.

4) Association of Clopidogrel Treatment with Risk of Mortality and Cardiovascular

Events Following Myocardial Infarction in Patients with and without Diabetes http://jama.jamanetwork.com/article.aspx?articleid=1356353

The use of conventional clopidogrel treatment after MI was associated with a lower reduction in the risk of all-cause death and cardiovascular death among patients with diabetes compared to patients without diabetes.

Dr. Desai is a first year resident at NYU School of Medicine

Peer reviewed by Ishmeal Bradley, MD, Section Editor,  Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Tonelli M, Muntner P, Lloyd A, Manns BJ, Klarenbach S, Pannu N, James MT, Hemmelgarn BR. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. The Lancet 1 September 2012; 380 (9844): 807-814.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960572-8/fulltext

2. Naidoo K, Yende-Zuma N, Padayatchi N, Naidoo K, Jithoo N, Nair G, Bamber S, Gengiah S, El-Sadr WM, Friedland G, Abdool Karim S. The Immune Reconstitution Inflammatory Syndrome After Antiretroviral Therapy Initiation in Patients with Tuberculosis: Findings from the SAPiT trial. Annals of Internal Medicine 4 September 2012; 157(5): 313-324.  http://annals.org/article.aspx?articleid=1355683

3. Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray A, Gengiah T, Nair G, Bamber S, Singh A, Khan M, Pienaar J, El-Sadr W, Friedland G, Abdool Karim Q. Timing of initiation of antiretroviral drugs during tuberculosis therapy. New England Journal of Medicine 2010 Feb 25; 362(8): 697-706. http://www.nejm.org/doi/full/10.1056/NEJMoa0905848

4. Wells JM, Washko GR, Han MK, Abbas N, Nath H, Mamary AJ, Regan E, Bailey WC, Martinez FJ, Westfall E, Beaty TH, Curran-Everett D, Curtis JL, Hokanson JE, Lynch DA, Make BJ, Crapo JD, Silverman EK, Bowler RP, Dransfield MT. Pulmonary Arterial Enlargement and Acute Exacerbations of COPD. New England Journal of Medicine 2012 Sept 6; 367: 913-921.  http://www.nejm.org/doi/full/10.1056/NEJMoa1203830

5. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, Pollono EN, Cueto JP, Gonzalez-Crespo R, Fulton S, Suarez-Almazor ME. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: A meta-analysis. JAMA 2012 Sept 5; 308(9): 898-908.  http://jama.jamanetwork.com/article.aspx?articleid=1356358

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