By: Josephine Ni, MD
Faculty Peer Reviewed
This week has been all about making progress and how one step forward is often accompanied by one step backwards. This was clearly illustrated as two particularly controversial pieces of legislation were voted on by the senate; Don’t Ask Don’t Tell was repealed as the DREAM act failed to pass. Like the political news, the medical articles that made headlines this week had both steps forwards and steps backwards.
First the steps backwards. Opioid analgesics are commonly prescribed medicines. In the last several years they have become even more popular as study after study highlighted troubling side effects of Non-steroidal anti-inflammatory drugs (NSAIDS). This culminated in the controversies surrounding the decision to remove rofecoxib (Vioxx) from the market when 2004 data showed an increase in cardiovascular events. Despite our shift towards opiodis, there is little comparable information about their safety profile. In the Archives of Internal Medicine this week, Solomon et al. sought to challenge conventional wisdom by presenting data from two observational studies that seek to investigate the relative safety of opiates versus NSAIDS) and COX-2 inhibitors (coxibs) [2. 3]. The first study is a prospective cohort study in which Medicare beneficiaries with osteoarthritis or rheumatoid arthritis from Pennsylvania and New Jersey who initiated therapy with an NSAID, a coxib, or an opioid were matched with controls based on propensity scores, which are estimated probabilities of receiving one treatment exposure versus another based on confounders that are pre-identified . Propensity score matching seeks to make treatment allocation the sole difference between treatment groups . The results of this study suggest that there are increased morbidity and mortality in patients in the opioid group, with the opioid group having an increased risk for cardiovascular events (Hazard Ratio (HR) 1.77, 95% Confidence Interval (CI) 1.39-2.24), fractures (HR 4.47, 95% CI 3.12-6.41) and even all-cause mortality (HR 1.87, 95% CI 1.39-2.53). Surprsingly, opioids and coxibs seemed to cause similar rates of gastrointestinal bleeding (HR 1.07 for opiods vs 0.6 for coxibs, both CI’s crossed 1).
In the second study, the authors used the same propensity score matching method described above to compare the safety profiles of five different opioids being used for nonmalignant pain . The study showed elevated risk of cardiovascular events for codeine compared with the reference hydrocodone after 180 days of exposure (RR 1.62, 95% CI 1.27-2.06), reduced risk of fracture for tramadol (RR 30 days 0.21, 95% CI 0.16-0.28) and propoxyphene (RR 30 days 0.54, 95% CI 0.44-0.66) after 30 days and 180 days, and an increased risk of all-cause mortality after 30 and 180 days for codeine (RR 180 days 2.53, 95% CI 1.70-3.76) and oxycodone (RR 180 days 2.25, 95% CI 1.52-3.34) . One wonders why codeine, as a low-potency opioid, would be less safe than other opioids. Certainly, both articles should prompt physicians to more carefully consider alternatives to opiates in elderly patients.
In a step forward, the NEJM published a multicenter, double-blind, randomized control study by Tang et. al that evaluated whether adding cardiac resynchronization therapy (CRT) to an ICD would decrease mortality for patients with New York Heart Association (NYHA) II or III heart failure, a wide QRS complex >120 msec, and left ventricular systolic dysfunction with EF<30% . 1798 of these patients were randomly assigned to receive either an ICD or ICD plus CRT. Patients were followed for an average of 3 years post-randomization, and the primary end-point was all-cause mortality or heart failure leading to hospitalization. Results show that the ICD-CRT group had both decreased mortality (HR 0.75, 95% CI 0.62-0.91) and fewer hospitalizations for heart failure (HR 0.68, 95% CI 0.56-0.83) than the ICD only group at 5 years post-randomization. It should be noted that the Kaplan-Meier all-cause mortality curves for the two groups did not diverge until 2 years after initiation of therapy, suggesting perhaps that CRT prevents long-term heart remodeling that is detrimental. In light of this trial, which confirms the results of the MADIT-CRT trial, it is likely that ICD-CRT will be increasingly considered in minimally symptomatic heart failure patients. Future cost-effecitve analyses should help guide us as significant funds would need committed to treat a very large patient pool
Speaking of progress, Science has their special “Insights into the Decade” issue this week highlighting advancements that have been made in the scientific community in the past 10 years., Science Translational Medicine also published an article suggesting a new way to assess PSA results: individualize healthy and high levels for each man based on genetic variants that affect PSA levels [6,7]. In this study, the genomes of about 16,000 men were scanned to identify places in the genome that modify the PSA level in blood, and six single-nucleotide polymorphisms (SNPs) were found: 5p15.33, 10q11, 10q26, 12q24, 17q12, and 19q13.33 . The authors then compared 5325 men with prostate cancer and 41,417 without to assess whether variants at the six sites modified PSA and prostate cancer risk, and found that SNPs at 10q26 and 12q24 were exclusively associated with elevated? PSA levels, whereas the other four loci also were associated with prostate cancer risk. Based on this, they propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
In conclusion, medical progress, like progress in the real world – is often cyclical. What is considered a step forward one day may easily be considered a mistake a few years down the road, and vice versa.
Dr. Josephine Ni is a second year internal medicine resident at NYU Langone Medical Center.
Peer reviewed by Neil Shapiro MD, Editor-in-Chief, Clinical Correlations
Image of Santa Claus on skies in Adelboden, Switzerland courtesy of Wikimedia Commons.
 Katz KA. Health hazards of “don’t ask, don’t tell”. N Engl J Med. 2010 Dec 16;363(25):2380-1. http://www.nejm.org/doi/full/10.1056/NEJMp1012496
 Solomon et. al. The comparative safety of analgesics in older adults with arthritis. Arch Intern Med. 2010 Dec 13;170(22):1968-78. http://archinte.ama-assn.org/cgi/content/full/170/22/1968
 Solomon et. al. The comparative safety of opioids for nonmalignant pain in older adults. Arch Intern Med. 2010 Dec 13;170(22):1979-86. http://archinte.ama-assn.org/cgi/content/full/170/22/1979
 Becker WC, O’Connor PG. The safety of opioid analgesics in the elderly: new data raise new concerns: comment on “the comparative safety of opioids for nonmalignant pain in older adults”. Arch Intern Med. 2010 Dec 13;170(22):1986-8. http://archinte.ama-assn.org/cgi/content/full/170/22/1986
 Tang et. al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010 Dec 16;363(25):2385-95. http://www.nejm.org/doi/full/10.1056/NEJMoa1009540
Couzin-Frankel J. Genetic Analysis Points the Way to Individualized PSA Tests. Science. 2010 Dec 17;330(6011):1602. http://www.sciencemag.org/content/330/6011/1602.full
Gudmundsson et. al. Genetic Correction of PSA Values Using Sequence Variants Associated with PSA Levels. Sci Tansl Med. 2010 Dec15;2(62):62ra92. http://stm.sciencemag.org/content/2/62/62ra92.full