Primecuts – This Week In The Journals

April 1, 2013

By Jiah Shin Teh, MD

Faculty Peer Reviewed

On behalf of Primecuts, happy belated Easter! We all hope that the days of special observance, no matter your faith, will help to refresh and recharge. For as we venture into the days of 2013, or post-12/21/12 for some out there, the world ever changes. Meteorites crashing down in spectacular Youtube-worthy fashion. North Korea’s wanton bluster reaching heights seldom seen that has got the world worried. And for us medical folks of course, the litany of new literature that has got us befuddled as always and scrambling to defibrillate ourselves. But Primecuts will hopefully stop you from pushing that button next to ‘charge’. Just a bit of tongue-in-cheek folks…Happy April’s Fools as well everybody…:)

Here are this week’s crème de la crème:

As per the 2007 National Health Statistics Report, since 2002 there has been a 68% increase in adults using chelation therapy for various forms of atherosclerotic disease. However, efficacy studies are lacking. In this week’s JAMA we find the Trial to Assess Chelation Therapy (TACT) trial [1], the first randomized trial powered to investigate the effect of a disodium EDTA chelation regimen on cardiovascular events in patients with previous MI. This double-blind, placebo-controlled trial coming out of 134 US and Canadian sites included 1708 patients who were fifty years or older with an MI at least 6 weeks prior and with serum creatinine levels of 2 mg/dL or less. They were randomized to a 2 x 2 group matrix: chelation infusion regimen (plus oral vitamin-mineral regimen to prevent depletion) versus placebo infusion (plus oral placebo). The intention-to-treat analysis with respect to the primary end point (composite total mortality, recurrent MI, stroke, coronary revascularization, OR hospitalization for angina) revealed fewer in the chelation group experienced the primary end point (hazard ratio (HR) 0.82, p=0.035). Further breakdown showed that the difference came from rates of coronary revascularization with total mortality not showing a statistically significant difference (HR 0.93 but with P=0.64). Subgroup analyses revealed statistically greater benefit of the chelation regimen in 2 subgroups: patients with anterior MI and those with diabetes. There were no statistical differences in terms of adverse events. While this evidence supports a moderate benefit of chelation regimen, particularly with revascularization rates, with no benefit towards mortality reduction the study does not support routine use in patients with MI.

Another trial creating some buzz is the Bronchiectasis and Low-dose Erythromycin Study (BLESS)[2] that investigated the efficacy of maintenance erythromycin in reducing pulmonary exacerbations in non-cystic fibrosis (CF) bronchiectasis patients. One hypothesis of the pathogenesis of non-CF bronchiectasis is that beyond the initial mucosa injury, persistent airway inflammation secondary to bacterial pathogens create a ‘vicious cycle’ of worsening damage and function of the mucosa and continued persistence of this bacterial load. Dovetailing the EMBRACE trial released last August in Lancet [3], cited in Primecuts August 20, 2012], which showed a benefit of maintenance azithromycin at reducing rates of pulmonary exacerbations, the Australian BLESS trial sought to verify whether the lower cost erythromycin truly provides a benefit in a longer twelve month study. This double-blind, placebo-controlled trial recruited 117 patients (nonsmoking for the duration of study, with a history of two or more pulmonary exacerbations in the preceding year) randomized to the erythromycin versus placebo arms. Results revealed that erythromycin did significantly reduce pulmonary exacerbations (incidence rate ratio 0.57, P=0.003), including for the pre-specified subgroup of patients with baseline Pseudomonas aeruginosa airway infection. It also positively influenced lung function decline assessed by changes in post-bronchodilator FEV1 measurements. The study also showed, not surprisingly, a significant increase in macrolide resistance as determined in commensal oropharyngeal streptococcal flora, arguing for a cautious approach to limit such maintenance therapy to patients with debilitating rates of exacerbations. Their findings were similar to the BAT (Bronchiectasis and Long-term Azithromycin Treatment) study[4] from Netherlands, also published in the same issue of JAMA.

Recommendations on hemoglobin thresholds for transfusion in various acute settings have been an extensively studied topic. In the non-acute setting, a double-blind, placebo-controlled trial published in the New England Journal of Medicine aimed to determine if there are any benefits to giving darbepoetin alfa to patients with systolic heart failure (LVEF of 40% or less) and mild-to-moderate anemia (hemoglobin level 9.0 to 12.0 g/dL) to achieve a hemoglobin target of 13 g/dL. The RED-HF (Reduction of Eventsby Darbepoetin Alfa in Heart Failure) trial[5] recruited a total of 2278 patients at 453 sites in 33 countries who were randomized to receive darbepoetin alfa versus placebo, and the primary outcome measure was a composite of all-cause mortality or hospitalization for worsening heart failure. The trial found that darbepoetin alfa did not improve primary outcome rates (50.7% in the treatment group and 49.5% in the placebo group, with no statistically significant differences in terms of all-cause mortality and hospitalizations for worsening heart failure). What the study did show was a higher, though not statistically significant, difference in the incidence of fatal or nonfatal stroke (hazard ratio 1.33, CI 0.83 to 2.12, P=0.23) as well as a significant increase in venous thromboembolic events. The use of darbepoetin alfa in this clinical setting is therefore not supported.

We now go onwards to a couple of articles relevant to our primary care practice. Published in the Online First segment of the Annals of Internal Medicine are the latest of recommendations from the U.S. Preventative Services Task Force (USPSTF) for vitaminD3 and calcium supplementation for postmenopausal women without a diagnosis of osteoporosis [6]. Based on 2 commissioned reviews of evidence and a meta-analysis, the USPSTF recommends against daily supplementation with 400 IU or less of vitamin vitamin D3 and 1000 mg or less of calcium for the primary prevention of fractures in non-institutionalized postmenopausal women, as evidence could not show the prevention of fractures (a D rating – click here for USPSTF rating scheme). In addition, the data shows potential downsides of supplementation, including an increased risk of renal stones. The Task Force also concluded that ‘the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1000 mg of calcium for the primary prevention of fractures in non-institutionalized postmenopausal women’.

Lastly, though not as exciting as March Madness, the matchup between chlorthalidone versus hydrochlorothiazide for the treatment of hypertension seems to tilt, at this present time that is, in favor of hydrochlorothiazide. An observational cohort study in Canada[7] followed a total of 29,873 patients on chlorthalidone versus hydrochlorothiazide for up to five years and measured a primary outcome of a composite of death or hospitalization for heart failure, stroke, or myocardial infarction. It found that, while no significant difference was found for the primary outcome, chlorthalidone was associated with more hospitalizations for hyponatremia and particularly hypokalemia. A weakness of the study was that the results could not be adjusted for differences in baseline clinical characteristics. However, the findings may prompt us to get a basic metabolic panel more frequently for our patients on chlorthalidone.

Other articles that may momentarily distract you from the Final Four this week:

1) Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies.BMJ 2013; 346 (Published 22 March 2013).

Use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia is associated with cardiovascular mortality at one year post episode, and the authors hypothesized a biological ischemic mechanism (e.g. activation of macrophages that my alter the progression of plaques).

2) Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial

The Lancet, Volume 381, Issue 9872, Pages 1107 – 1115, 30 March 2013

In patients taking oral anticoagulants,the need to undergo PCI warrants pre-procedural antiplatelet therapy but the risk of serious bleeding increases with when aspirin and clopidogrelare both onboard.Investigators found that clopiogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events.

3) HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease: A Cohort Study

Ann Intern Med. 26 February 2013 Online First

Investigators set out to determine if HIV accelerates HCV-related liver disease, and found that in their observational cohort study (2006-2011) patients with HIV/HCV co-infection did have liver cirrhosis stages similar to those without HIV who are nearly ten years older.

4) Blockade of receptor activator of nuclear factor-?B (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus.Nature Medicine19,358–363(2013)

The authors mentioned the strong evidence that activation of the transcription factor nuclear factor-?B (NF-?B) and downstream inflammatory signaling pathways particularly in the liver are key events in the etiology of hepatic insulin resistance and ?-cell dysfunction contributing to Type II Diabetes. They showed that blockade of receptor activator of nuclear factor-?B (RANKL) signaling in hepatocytes by genetic deletion of its receptor promotes greater insulin sensitivity in both a genetic and a nutritional model of type 2 diabetes.

Dr. Jiah Shin Teh is a 2nd year resident at NYU Langone Medical Center

Peer Reviewed by Danise Schiliro, MD, Internal Medicine Residency Program, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction  JAMA. 2013;309(12):1241-1250.

[2] Effect of Long-term, Low-Dose Erythromycin on Pulmonary Exacerbations Among Patients With Non–Cystic Fibrosis Bronchiectasis  JAMA. 2013;309(12):1260-1267.

[3] Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial.  Lancet. 2012 Aug 18;380(9842):660-7.

[4] Effect of Azithromycin Maintenance Treatment on Infectious Exacerbations Among Patients With Non–Cystic Fibrosis Bronchiectasis  JAMA. 2013;309(12):1251-1259.

[5] Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure  N Engl J Med 2013; 368:1210-1219, March 28, 2013.

[6] Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement  Ann Intern Med. 26 February 2013 Online First.

[7] ChlorthalidoneVersus Hydrochlorothiazide for the Treatment of Hypertension in Older Adults: A Population-Based Cohort Study.  Ann Intern Med. 19 March 2013;158(6):447-455