Faculty Peer Reviewed
This week’s edition of Primecuts begins with President Obama’s recent nomination of Elena Kagan, the current Solicitor General of the United States, as the 112th Supreme Court Justice. If confirmed, Kagan would join Ruth Bader Ginsburg and Sonia Sotomayor as the third female justice on the bench. Frank Sinatra once sang in his tribute to New York, “If I can make it there, I can make it anywhere…” And right he was. Interestingly, all three of these women, Ginsburg, Sotomayor, and Kagan, hail from New York – Brooklyn, the Bronx, and Manhattan, respectively (1). Although it is pure happenstance that New York was the past domicile of these three women, it is intriguing to attribute their successes to the diversity and ambitiousness that pervades the city of New York. While the life stories of these three women have received national attention, we should all take a moment and recognize the sacrifices and achievements of all women across the country, especially as this past Sunday was Mother’s Day.
We now turn to this week’s literature, where we find many articles pertinent to the general field of medicine. The Archives of Internal Medicine published an analysis on the prophylactic use of PPIs for nosocomial upper gastrointestinal bleeding (2). Many inpatient and outpatients are currently prescribed PPI’s prophylactically despite the lack of clear risk factors for upper gastrointestinal bleeding. Compounding this issue, we have learned about several significant adverse effects associated with the chronic use of PPIs: hip fractures due to calcium malabsorption, decreased effect of clopidgrel related to interactions with CYP2C19, and increased risk of Clostridium difficile infection as well as pneumonia. Given these significant adverse effects, Yachimski et al. developed a set of standardized guidelines by for physicians prescribing PPI prophylaxis to hospitalized patients: indicated in ICU patients with coagulopathy or patients on mechanical ventilation; may be considered in patients with history of peptic ulcer disease, especially if receiving NSAIDs or antiplatelets. The authors then looked at 942 patients, 458 were admitted prior to the implementation of the standardized guidelines and 484 were admitted following the development of the PPI prescribing guidelines. Interestingly, there was no statistically significant difference between the pre-guideline and post-guideline cohorts, in regards to patients receiving PPIs at admission (52% vs 46%, P=0.36) and discharge (42% vs 40%, P=0.97). However, in the subset of patients who were not on outpatient PPIs, significantly fewer patients in the post-guideline cohort compared to the pre-guideline cohort received prescriptions for PPIs on admission (27% vs 17%, P=0.001) and discharge (16% vs 10%, P=0.03). This study emphasizes the importance of analyzing the risks and benefits of any pharmacologic agents and confirms the necessity of determining whether it is appropriate to continue outpatient medications in a hospitalized patient.
The Archives of Internal Medicine also looked at gastric acid suppression,and the risk of the development of Clostridium difficile infection (3). Howell et al. analyzed prospective data on 101,796 discharges during a 5-year period. The primary exposure in this study was acid suppressive medications and the primary outcome was nosocomial C. difficile infection. The four acid suppression groups were no acid suppression, histamine2-receptor antagonists, daily PPIs, and more frequent than daily PPI use. Following adjustment for prescription of antibiotics, comorbidities, and age, the odds ratio of the development of a C. difficile infection significantly increased corresponding to the level of gastric acid suppression: OR of 1 (no acid suppression), 1.53 (95% CI, 1.12-2.10) for H2RA, 1.74 (95% CI, 1.39-2.18) for daily PPIs, 2.36 (95% CI, 1.79-3.11) for more frequent than daily PPI use. Furthermore, it was determined that compared to no acid suppressive therapy, daily PPI use was associated with a 70% increase in the odds of developing a C. difficile infection. Although this was an observational study, a randomized control trial might be considered unethical given that the hypothesis would be whether or not a therapy could induce harm, specifically C. difficile infection. This should make us all pause a second or third time before we write yet another ppi order.
A recent article in The Lancet featured an in depth analysis of the causality of triglycerides in coronary disease (4). Although the conventional wisdom is that hypertriglyceridemia is one of the etiologies of coronary disease, it is difficult for a study to control for HDL and LDL, and thus elucidate a causal effect of triglycerides. Therefore, Sarwar et al. analyzed the –1131T>C promoter polymorphism of the apolipoprotein A5 (APOA5) gene, one of the most important factors in the regulation of triglyceride levels. Patients found to have two C alleles had a 32.6% higher mean triglyceride level than did non-carriers. Furthermore, a dose-dependent relationship was identified with every C allele carrying a 16% higher mean triglyceride level (P=4.4×10-24). Although –1131T>C is strongly related to triglyceride levels, allowing for the adjustment for HDL and non-HDL cholesterol, patients with this polymorphism were found to have higher VLDL concentration, smaller HDL particle size, greater LDL concentration, and smaller LDL particle size. The odds ratio for coronary artery disease for each C allele was 1.18 (95% CI 1.11-1.26; P=2.6×10-7), with carriers of two C alleles having an OR of 1.40 (95% CI 1.12-1.75). This dose-dependent increase in coronary disease equates to approximately an 18% increased risk per C allele. Although these genetic analyses may appear to be on a very fundamental level, previous studies have attributed patient responses to statins and fibrates according to APOA5 –1131T>C status. Future studies are therefore necessary to develop a better understanding of the role of triglycerides in coronary disease, in order to elucidate optimal management strategies.
We end this week’s Primecuts with a discussion regarding An Entirely Subcutaneous Implantable Cardioverter-Defibrillator (5). This article was published in the New England Journal of Medicine and was subsequently featured in the New York Times (6). In the United States, approximately 10,000 patients per month receive a defibrillator. The complications of Implantable Cardioverter-Defibrillators (ICDs) are well-established and include pneumothorax, hemothorax, and cardiac tamponade, in the acute setting. Long-term complications of ICDs include inappropriate shocks, failed leads, and fractured leads. Given the significant morbidity and mortality that results from lead removal, there is an obvious benefit to an ICD that lacks a transvenous system. Bardy et al. conducted a small, non-randomized pilot trial of the implantation of subcutaneous ICDs in six patients, followed by a separate trial of 55 patients. The primary end point of this study was successful conversion of two consecutive episodes of induced ventricular fibrillation, each with a 65-J shock. Of the 55 patients enrolled in the European Clinical Trial, 53 were evaluated with defibrillation testing. The subcutaneous ICD detected and successfully converted 100% and 98%, respectively of the 137 episodes of induced ventricular fibrillation. At the end of 10 months follow-up, 98% of patients enrolled in the study were alive. The one death was reported to be due to renal failure. It is important to understand the limitations of this study, as the subcutaneous ICD is not indicated for all patients. The subcutaneous ICD was not designed to provide long-term pacing. Therefore, patients who require antibradycardia pacing are not candidates for this ICD. Furthermore, the subcutaneous ICDs are not able to treat patients with ventricular tachycardia rates less than 170 beats per minute. Consequently, although an entirely subcutaneous ICD is likely the wave of the future, long-term trials are still necessary for FDA approval and to ensure the safety of patients in whom an ICD is indicated.
Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations
1. Baum G, Susman T. Kagan would be high court’s third –New Yorker? LA Times. 2010 May 12. http://www.latimes.com/news/nationworld/nation/la-na-0512-kagan-ny-20100512,0,4228797,full.story
2. Yachimski PS, Farrell EA, Hunt DP, et al. Proton Pump Inhibitors for Prophylaxis of Nosocomial Upper Gastrointestinal Bleeding. Arch Intern Med. 2010 May 10;170(9):779-783. http://archinte.ama-assn.org/cgi/content/full/170/9/779
3. Howell MD, Novack V, Grgurich P, et al. Iatrogenic Gastric Acid Suppression and the Risk of Nosocomial Clostridium difficile Infection. Arch Intern Med. 2010 May 10;170(9):784-790. http://archinte.ama-assn.org/cgi/content/full/170/9/784
4. Sarwar N, Danesh J, Butterworth AS, et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010 May 8;375:1634-1639. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60545-4/abstract
5. Bardy GH, Smith WM, Hood MA, et al. An Entirely Subcutaneous Implantable Cardioverter-Defibrillator. N Engl J Med. 2010 May 12; [Epub ahead of print] http://content.nejm.org/cgi/content/full/NEJMoa0909545
6. Meier B. Under-Skin Defibrillators Seen Closer to Reality. The New York Times (New York edition). 2010 May 12. Page B3. http://www.nytimes.com/2010/05/13/business/13device.html?ref=health