By John Hwang, MD
Faculty Peer Reviewed
Ongoing review of documents leaked as part of the Snowden affair reveal the National Security Agency’s astonishing capability to defeat encryption technology safeguarding a wide variety of satellite and Internet communications. At the G20 summit, President Obama is attempting to mend international relations in the wake of revelations that this capability was directed against the United States’ European allies, as well as its regional partners in Central and South America. Meanwhile, intercepted Syrian communiqués are cited in a statement published by the White House on August 30th as evidence that chemical attacks in the suburbs of Damascus on August 21st were directed by government forces. These intercepts reportedly involve senior government officials expressing concern with UN inspectors obtaining evidence of a chemical attack, and are cited as one of several corroborating lines of evidence that a government-sanctioned chemical attack had indeed taken place, along with satellite intelligence, analysis of video taken from social media, and reports made by international humanitarian and domestic medical personnel[1].
Of the chemical agents known to be stockpiled by the Syrian Defense Ministry, sarin and VX are organophosphates originally developed as pesticides and now commonly called nerve agents, for their ability to induce spastic paralysis by inhibiting acetylcholinesterase at the neuromuscular junction. Sulfur mustard, also stockpiled by the ministry, acts as blistering agent, disrupting cell division in skin and respiratory mucosa by irreversibly alkylating DNA during replication. This mechanism of action renders mustard gas mutagenic and carcinogenic, but also highly effective at suppressing hematopoiesis. Discovery of this property during its use in World War I led directly to the development of the first cancer chemotherapy drug, the chemical derivative mustine, used to treat lymphoma shortly after World War II.
Little wonder the saying goes that the only differences between poison and medicine are dose and intent.
Compared with mustard gas, vitamin K antagonists (VKAs) may be more medicine than poison, despite their narrow therapeutic index, teratogenicity, unpleasant side effects—and of course their current use as actual poison. Unfortunately, the premature termination of the RE-ALIGN study, formally published in the New England Journal of Medicine this week, suggests the much-maligned VKAs may remain our only option for long-term anticoagulation in patients with mechanical heart valves, at least in the near future. RE-ALIGN was a phase II open-label trial that sought to establish safe and effective doses of dabigatran for thromboprophylaxis in such patients. The study randomized 252 patients aged 18-75 who had undergone mechanical aortic and/or mitral valve replacement, either at the time of randomization or greater than 3 months prior, to receive either a VKA or dabigatran, dosed twice daily and titrated based on trough measurements. The trial was stopped after an interim analysis showed that, of patients taking dabigatran, nine had suffered stroke and three myocardial infarction, while no such events were recorded in the warfarin group. Additionally, patients on dabigatran were more than twice as likely to suffer a bleeding complication, although the associated increase in major bleeding events was not statistically significant. This excess of thromboembolic and bleeding complications occurred despite the titration protocol, by which patients in the dabigatran arm spent 86% of study time at or above presumably therapeutic trough levels extrapolated from the RE-LY trial. Although the novel anticoagulants have seen growing use in the management of atrial fibrillation and venous thromboembolism, these results suggest that dabigatran may not be an appropriate alternative to VKAs for thromboprophylaxis in patients with mechanical valves[2].
Colchicine is another poison-turned-medicinal workhorse, a plant toxin isolated from the tubers of the autumn crocus, recognized centuries ago as an effective treatment for gout and rheumatism. Today, colchicine is frequently used off-label for the treatment of acute pericarditis. Results of the Investigation of Colchicine for Acute Pericarditis, published in NEJM this week, appear to support this practice. The ICAP trial randomized 240 adults presenting with a first-time episode of acute pericarditis to receive either colchicine 0.5-1mg or placebo, in addition to standard treatment with high-dose aspirin, ibuprofen, or glucocorticoids [3]. Patients taking colchicine were less likely to have persistent symptoms at 72 hours (21% of patients compared with 40% taking placebo) and more likely to have entered remission by 1 week (85% compared with 58% taking placebo). No significant difference in adverse events was observed. While the 2005 CORE trial established colchicine’s effectiveness in treating recurrent pericarditis, these results are the first to support its use in the treatment of first-time episodes of acute pericarditis [4]. However, these results apply only to cases in which cardiac injury or a viral or rheumatologic process is suspected, as the study excluded cases of tuberculous, neoplastic, and uremic pericarditis. Like warfarin, colchicine may be a teratogen with a narrow therapeutic window and frequent adverse effects, but its cheap cost and documented efficacy in treating a wide variety of diseases ensures its place in our pharmacopoeia for the time being.
Unlike the agents discussed above, the thienopyridines are not derivatives of historical poisons but rather repurposed compounds originally identified during a failed search for novel anti-inflammatory drugs in the 1960s. Nevertheless, their use carries a significant risk of complications, most notably bleeding. Current AHA guidelines for the management of patients with NSTEMI undergoing angiography recommend pretreatment with a thienopyridine and/or a GPIIb/IIIa inhibitor[5]. However, the results of the ACCOAST study suggest this practice may increase bleeding risk without reducing ischemic events. In this phase III double-blind trial, 4033 patients with NSTEMI were randomized to receive either loading-dose prasugrel or placebo prior to angiography. Patients who subsequently underwent percutaneous coronary intervention received loading-dose prasugrel intra-procedurally if given placebo initially. The study was prematurely terminated after an interim analysis showed pretreatment did not reduce mortality, rate of stent thrombosis, or ischemic events at 7 and 30 days in the overall population or any of the subgroups studied, including the patients who underwent PCI. Meanwhile, pretreatment was associated with a higher risk of major bleeding (hazard ratio 2.95, 1.39-6.28). With these results in mind, it may be preferable to delay administering a thienopyridine until coronary disease is confirmed and a management strategy selected during angiography, unless the clinician anticipates a delay in angiography or a high risk of recurrent ischemia[6].
“Cured yesterday of my disease, I died last night of my physician.”
Matthew Prior (1664-1721)
Other interesting reads this week:
1. Kwong JC, Vasa PP, Campitelli MA, et al. Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. Lancet Infectious Disease. 2013 Sep;13(9):769-76. doi: 10.1016/S1473-3099(13)70104-X. Epub 2013 Jun 28. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(13)70104-X/fulltext
A causal link between the influenza vaccine and Guillain–Barré syndrome was first posited during the mass vaccination campaign for the 1976 H1N1 influenza pandemic, and has persisted in lay perception since. In this study examining 2831 admissions for GBS between 1993 and 2011 in Ontario, Canada, the authors report the risk of developing GBS within 6 weeks of an influenza diagnosis was nearly 16 times higher (relative incidence 15.81; 10.28-24.32) than the risk attributable to vaccination. The attributable risk associated with vaccination was estimated to be 1.03 admissions per 1 million vaccinations. These results add to a growing body of evidence that more cases of GBS are associated with influenza infection than with influenza vaccination, an observation providers may communicate to patients fearful of this complication. The association between influenza vaccination and GBS remains controversial, with a number of recent retrospective studies failing to find a significant relationship.
2. Corey C, Wang B, Johnson SE, Apelberg B, et al. Notes from the Field: Electronic Cigarette Use Among Middle and High School Students — United States, 2011–2012. CDC Morbidity and Mortality Weekly Report (MMWR), 6 September 2013 / 62(35);729-730. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6235a6.htm#fig
Following up on last month’s Clinical Correlations piece on the rise of electronic cigarettes, this report from the CDC documents a substantial increase in e-cigarette usage among middle and high school students from 2011 to 2012. As an example, approximately 10% of high school students reported having tried e-cigarettes before and 2.8% reported currently using them, a twofold increase from the year prior. The growing popularity of electronic cigarettes nationwide is concerning because the FDA lacks full regulatory power over the rapidly growing market for these devices, and because their long-term health effects are largely unknown.
3. Sunkesula VCK, Kundrapu S, Muganda C, Sethi AK, et al. Does Empirical Clostridium difficile Infection (CDI) Therapy Result in False-Negative CDI Diagnostic Test Results? Clinical Infectious Disease. (2013) 57 (4): 494-500. http://cid.oxfordjournals.org/content/57/4/494.full
While the diagnosis of Clostridium difficile has been made easier by the introduction of PCR detection methods to institutions like Tisch Hospital, the results of this study suggest PCR methods rapidly lose negative predictive value following administration of empiric antibiotics. Of 51 patients with PCR-confirmed C difficile infection, 7 (14%), 18 (35%), and 23 (45%) had converted to PCR-negative results by days 1, 2, and 3 of antibiotics, respectively. It would appear that, just as the collection of cultures prior to initiation of antibiotics is a central principle of antimicrobial therapy, the timing of stool collection for PCR diagnosis is clinically significant. While delays in stool collection are frequently encountered by the house staff and may be unavoidable, it is important to remember that such delays will come at the cost of diagnostic accuracy, and to anticipate these shortcomings when making management decisions.
John Hwang, MD is a second-year internal medicine resident at NYU Langone Medical Center
Peer Reviewed by Matthew Vorsanger, MD, Associate Editor, Clinical Correlations
References
1. White House Office of the Press Secretary. Government Assessment of the Syrian Government’s Use of Chemical Weapons on August 21, 2013. http://www.whitehouse.gov/the-press-office/2013/08/30/government-assessment-syrian-government-s-use-chemical-weapons-august-21
2. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. New England Journal of Medicine. 2013 August 31. http://www.nejm.org/doi/full/10.1056/NEJMoa1300615#t=abstract
3. Imazio M, Cecchi E, Ierna S, et al. Investigation on Colchicine for Acute Pericarditis: a multicenter randomized placebo-controlled trial evaluating the clinical benefits of colchicine as adjunct to conventional therapy in the treatment and prevention of pericarditis: study design and rationale. Journal of Cardiovascular Medicine (Hagerstown) 2007;8:613-617. http://www.nejm.org/doi/full/10.1056/NEJMoa1208536#t=article
4. Imazio M, Bobbio M, Cecchi E, et al. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Archives of Internal Medicine. 2005 September 26; 165(17): 1987–1991. doi: 10.1001/archinte.165.17.1987. http://archinte.jamanetwork.com/article.aspx?articleid=486705
5. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction. Circulation 2007;116:803–877. http://circ.ahajournals.org/content/116/7/e148.long
6. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non–ST-segment elevation acute coronary syndromes. N Engl J Med 2013. http://www.nejm.org/doi/full/10.1056/NEJMoa1308075.