Primecuts – This Week In The Journals

September 30, 2013

By Darya Rudym, MD

Faculty Peer Reviewed

Lighter, faster, cheaper. This useful promo phrase applicable to almost all technological developments, was put forth by as they launched their new Kindle Fire this week. This came conveniently a day after Microsoft released the second generation of their much talked about Surface tablet. While the technology giants battled to appeal to the interests of a modern day reader, President Barack Obama endorsed democratic candidate Bill de Blasio for mayor of New York City. President Obama specifically supported de Blasio’s initiatives to improve affordable housing, finance pre-kindergarden classes and to preserve the community hospitals of NYC. The city’s attention this week is also on the New York Film Festival, which begins September 27th,and is promising to be a superb collection of movies this year.

So while you cozy up in front of TV with a new tablet in hand, pondering which candidate to support in the upcoming mayor race, here are a few noteworthy articles from the medical literature this week.

To start, JAMA published a study on the utility of repeat bone mineral density screening and it’s predictive value for osteoporotic fractures. [1] Bone mineral density (BMD) screening has long been the gold standard for assessing the risk of osteoporotic fractures and currently the USPSTF recommends routine screening for women 65 and older, waiting at least two years prior to a second examination. [2] Based on current literature, however, the benefit of repeat BMD testing is unclear. In this population-based analysis of 802 men and women from the Framingham Osteoporosis Study, the change in BMD from baseline was evaluated as a predictor for hip or major osteoporotic fracture (spine, forearm, or shoulder) during the follow up period. Participants underwent two BMD measures with mean time in between of 3.7 years and a subsequent mean follow-up time of 9.6 years. Patients in the original cohort were excluded if a hip fracture occurred prior to the second BMD test. The results demonstrated that while BMD change per standard deviation over the 3.7 years was independently associated with osteoporotic fractures, once examined over the 10 year follow-up, BMD change did not offer any additional information beyond what was already established by the baseline exam. The authors determined this by composing receiver operating characteristic (ROC) curves. After adjustments for multiple baseline characteristics including BMI, weight loss, and history of fracture, incorporating BMD change into the model did not significantly alter the area under the curve (AUC 0.71 vs 0.68). There was therefore no meaningful improvement in the predictive value of these tests for fracture risk. While this study has some limitations, including not adjusting for use of osteoporosis medications, it has a large sample size with substantial longitudinal follow-up. With costs of healthcare being a significant burden to the country, the clinical utility of testing must be evaluated and this study certainly calls into question that of repeat bone mineral density exams.

In anticoagulation news this week, NEJM brought forth the evaluation of dabigatran use in patients with mechanical heart valves. [3] In this prospective, randomized, open-label phase 2 dose-validation study, previously presented in the literature as RE-ALIGN [4], a total of 252 patients with aortic or mitral valve replacements were randomized to dabigatran or warfarin in a 2:1 ratio, with dosing of dabigatran based on renal function.. Patient data analysis was performed for two different cohorts, those who had undergone valve replacement in the previous 7 days and those within the past 3 months. For all dabigatran patients, doses were adjusted to maintain a trough plasma level of at least 50 ng/mL however warfarin patient’s doses were adjusted to maintain a therapeutic INR determined to be appropriate for thromboembolic risk. The primary outcome studied was the trough level of dabigatran, while clinical outcomes such as strokes, embolisms, TIAs and valve thrombosis were evaluated concomitantly. Unfortunately, the study had to be terminated prematurely as there was an excess of thromboembolic and bleeding events, especially in those patients whom had undergone replacement in the previous 7 days. The comparison clearly demonstrated that dabigatran is not only less effective than warfarin in thromboembolic prevention, but also comes with an increased risk of bleeding in patients with recent valve replacement surgery.

The attention of pulmonologists this week was on a Chest article examining the rates of cardiovascular events in COPD patients treated with roflumilast. [5] Roflumilast is a selective PDE-4 inhibitor recently shown to have very favorable effects on reducing the rates of exacerbation in patients with severe COPD. The study retrospectively pulled data from 14 placebo-controlled trials (of a minimum duration >12 weeks), and determined the rates of major adverse cardiovascular events (MACEs), which included cardiovascular death, nonfatal MI and stroke. With a total of 12,054 patients of similar baseline characteristics included, this study showed that compared with placebo, roflumilast was associated with a significantly reduced rate of MACEs (hazard ratio, 0.65; P=0.19), especially in patients with severe COPD. While the durations of the trials included were relatively short and the absolute risk reduction relatively modest, this novel medication has some impressive effects in a very sick population. With further analysis, the promising cardioprotective benefits of roflumilast can be further elucidated.

In the world of nephrology, JASN looked into galectin-3, a profibrotic mediator, as a possible novel biomarker to be implemented in predicting chronic kidney disease. [6] Galectin-3 has been shown to be strongly linked to renal fibrosis in animal models and to inversely correlate with GFR in previous human analyses. This retrospective study of 2450 Framingham Offspring patients evaluated galectin-3 levels with respect to GFR decline and albuminuria. With a mean follow up of 10.1 years, the results demonstrated that higher initial levels of galectin-3 are associated with an increased risk of incident CKD as well as a more rapid loss of renal function, but did not correlate with the level of albuminuria. When added to clinical predictiors from the Framingham Heart Study, galectin-3 did not alter risk predication in a clinically significant manner. Given that elevations in galectin-3 were noted years before overt kidney disease, these findings suggest that galectin-3 might play a role in identifying kidney damage earlier in the disease course than was previously capable. While these results are promising, they should be interpreted with caution as there is not enough data to prove causation versus correlation between galectin-3 and the development of CKD.

Other interesting reads this week…

1. DeSimone CV, Friedman PA, Asirvatham SJ, et al. Stroke or Transient Ischemic Attack in Patients With Transvenous Pacemaker or Defibrillator and Echocardiographically Detected Patent Foramen Ovale. Circ. 2013;128:1433-1441.

Those patients who have leads of cardiac implantable electronic devices in the right-sided cardiac chambers can develop thrombi with high risk of embolization. The study raises an important question of screening patients for PFO prior to device implantation as it was reported that presence of PFO on echo is associated with serious risk of embolic stroke or TIA.

2. Erickson KF, Cherlow GM, Goldhaber-Fiebert, JD. Cost-Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease. Annals of Internal Medicine. 2013;159:382-389.

As evidenced in the previously reported TEMPO study, Tolvaptan (antidiuretic hormone antagonist) was shown to have significant benefit in reduction of total kidney volume and preservation of GFR in patients with ADPKD. However, in this cost-benefit analysis, tolvaptan remains exceedingly expensive and, compared to other-commonly accepted medications, would be cost-effective to patients only if it’s current price was reduced by 93-95%.

3. Anthenelli RM, Morris C, Ramey TS, Dubrava SJ, Tsilkos K, Russ C, Yunis C. Effects of Varenicline on Smoking Cessation in Adults with Stably Treated Current or Past Major Depression. Annals of Internal Medicine. 2013;159;390-400.

This double-blinded randomized trial evaluated smoking cessation and changes in mood and anxiety in currently or previously depressed patients treated with varenicline compared to placebo. Patients on varenicline were reported not only to abstain from smoking longer but also to have stable moods without exacerbating depression or anxiety symptoms.

Dr. Darya Rudym is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Gregory Schrank, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


[1] Berry, SD, Samelson EJ, Pencina MJ, McLean RR, Cupples A, Broe EK, Kiel DP. Repeat Bone Mineral Density Screening and Prediction of Hip and Major Osteoporotic Fracture. JAMA. 2013; 310 (12):1256-1262.

[2] US Preventive Services Task Force. Screening for osteoporosis. Ann of Internal Medicine. 2011; 154 (5):356-364.

[3] Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Friedmann J, Van de Werf, F for the RE-ALIGN investigators. Dabigatran versus Warfarin in Patients with Mechanical Heart Valves. NEJM. 2013; 369 (13); 1206-1214.

[4] Van de Werf, F, Brueckmann M, Connolly SJ, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the Randomized Phase II Study to Evaluate the Safety and Pharmakokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN). Am Heart J. 2012; 163:931-7.

[5] White WB, Cooke GE, Kowey PR, Calverley PM, Bredenbroker D, Goehring UM, Rabe KF. Cardiovascular Safely in Patients Receiving Roflumilast for the Treatment of COPD. Chest. 2013; 144(3):758-765.

[6] O’Seaghdha CM, Hwang SJ, Ho JE, Vasan RS, Levy D, Fox CS. Elevated Galectin-3 Precedes the development of CKD. J Am Soc Nephrol. 2013; 24:1470-1477.