Faculty Peer Reviewed
Most readers are probably familiar with the Nurses’ Health Study cohort which provided the data for a possible relationship between non-steroidal anti-inflammatory drug (NSAID) use and the incidence of inflammatory bowel disease (IBD) that was highlighted in the current issue of the Annals of Internal Medicine.  Participants self-reported NSAID and aspirin use every two years and were considered “regular users” if they took the medication at least twice per week. Forty-four percent were considered regular aspirin users and 37% regular NSAID users. Of the more than 76,000 responders, researchers found 240 confirmed cases of new Crohn’s disease (CD) and ulcerative colitis (UC). In the group of nurses who took NSAIDs at least 15 days in a month, there was an increased incidence of CD (hazard ratio 1.60 [95% CI: 0.99-2.58]) and UC (hazard ratio 1.87 [95% CI: 1.16-2.99]). Looked at another way, the association persisted for participants who took at least 5 NSAID tablets/week, with a hazard ratio of 1.71(95% CI: 1.05-2.77) for CD and 1.78 (95% CI: 1.10-2.89) for UC. Lastly, long-term NSAID use (>6 years) was positively associated with incidence of IBD, with hazard ratios of 2.83 (95% CI: 1.65-4.85) for CD and 2.00 (95% CI; 1.15-3.49) for UC. Aspirin use was not significantly associated with the development of IBD. The researchers hypothesized that the NSAIDS had a disruptive effect on the intestinal barrier, including cytoskeletal disruption and increased mucosal permeability. Although a positive association is a far cry from causation, these findings do raise interesting questions regarding prevention.
Speaking of preventive medicine, the Annals also published a very interesting study looking at primary care physicians’ understanding of cancer screening statistics.  Physicians were asked questions about a hypothetical cancer screening test described as noninvasive, free, and with potential therapeutic options. The authors presented the test results in two ways: first, as having a five-year survival benefit, secondly, as having a reduction in mortality. After answering these initial descriptions, the physicians were given more information about the cancer mortality, incidence, 5-year survival, and proportion of cancers detected at stage I (with a goal of looking for lead-time bias).
Overall, the researchers found that physicians showed “limited knowledge” about what evidence from cancer screening tests translates into decreased mortality (the clinically salient point). Almost half the participants (47%) reported that finding more cancer cases after screening was proof of saving lives. This could be the result of lead-time bias and over-diagnosis. While 81% of participants did agree that mortality data gave proof of saving lives, 76% also thought that survival data proved the same thing, which is not true. Given the option of recommending a test that improved 5-year survival from 68% to 99% and/or a test that reduced cancer mortality from 2 to 1.6 in 1,000 persons, physicians were three times as likely to opt for the former, although the latter is the one that validates the utility of the screening test. In an age where we as physicians are inundated with numbers, this serves as a serious reminder that statistics can be made to say almost anything, and that we need to be sure that we interpret the numbers carefully and thoughtfully, especially when it comes to making care decisions with our patients.
Now, let’s shift gears a little and focus on some data that came out regarding new options for old diseases. The New England Journal of Medicine published a study examining amantadine as a potential treatment adjunct for traumatic brain injury (TBI).  TBI results in brief neuronal hyperexcitability, followed by a long period of relatively neurotransmitter-deplete hypoexcitability. It is thought that amantadine may play a role here via indirect dopamine agonism. In this placebo-controlled, double-blind trial, 184 patients in an acute rehab facility aged 16-65yo, all with non-penetrating severe TBI resulting in a vegetative or minimally conscious state, were randomized to amantadine (titrated to 200mg twice daily for four weeks with subsequent taper) versus placebo.
The primary outcome was the change in Disability Rating Scale (DRS) score; the Coma Recovery Scale-Revised (CRS-R) was also used to define clinically significant findings (i.e. response to command, intelligible speech, and use of functional objects). Both groups showed improved DRS scores over time, though the change was significantly higher in the amantadine group (p=0.007). In general, those patients enrolled sooner after the injury and in a minimally conscious state recovered faster, but the effect of amantadine was still appreciated here. A greater percentage of the amantadine patients also reached more benchmarks on the CRS-R though this data was not statistically analyzed. Importantly, there was no evidence of increased seizures in the amantadine group. Although the follow-up time in this study was short, it does pave the way for huge potential treatment advances in an exciting area of medicine.
And lastly, we examine the phase I trial results of cardiac stem cell use post-myocardial infarction (MI).  CADUCEUS studied 25 patients with recent MI who had undergone percutaneous coronary intervention. Ninety-two percent of the patients had LAD or diagonal branch lesions with an average ejection fraction (EF) of 39% (study inclusion criteria 25-45%). Stem cells were harvested via endomyocardial biopsy and infused into a coronary artery five weeks later. In the treatment group, four patients received low-dose cells, one intermediate, and 12 high. Compared to the controls, as visualized on cardiac MRI, patients in the infusion group had decreased scar size (p=0.007 at 12 months) and more viable myocardium (p=0.01 at six months). Scar mass in the treated group decreased on average by 42% by 12 months. Lastly, these patients showed improved contractility (increase of 2.0% in treated patients versus a decrease of 1.5% in controls, p=0.009). There was only one adverse event in the treatment group, a STEMI, believed to be treatment related. Although this data is incredibly promising, we must remember that these results are not “hard” endpoints like mortality or even clinically significant change in EF. Still, the potential implications of this phase I trial are exciting with respect to future research.
Lakshmi Tummala, MD is a 3rd year resident at NYU Langone Medical Center
Peer reviewed by Ishmeal Bradley, MD, Section Editor, Clinical Correlations
Image courtesy of Wikimedia Commons
1. Ananthakrishnan, Ashwin et al. Aspirin, Nonsteroidal Anti-inflammatory Drug Use, and Risk for Crohn Disease and Ulcerative Colitis: A Cohort Study. Ann Intern Med. 2012;156:350-359. http://www.annals.org/content/156/5/350.full
2. Wegwarth, Odette et al. Do Physicians Understand Cancer Screening Statistics? A National Survey of Primary Care Physicians in the United States. Ann Intern Med. 2012;156:340-349.
3. Giacino, Joseph et al. Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury. N Engl J Med 2012; 366:819-826. http://www.nejm.org/doi/full/10.1056/NEJMoa1102609
4. Makkar, Raj et al. Intracoronary Cardiosphere-Derived Cells for Heart Regeneration after Myocardial Infarction (CADUCEUS): A Prospective, Randomised Phase 1 Trial. Lancet 2012; 379 (9819): 895 – 904. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60195-0/fulltext