Commentary by Judith Brenner MD, Associate Program Director, NYU Internal Medicine Residency Program
This week’s ShortCuts begins with a follow up of a story first presented in March, 2008, when the recall of potentially contaminated heparin was reported.
Typical case: 73 year old woman with a complex medical history including end-stage renal disease treated with the use of hemodialysis for 7 years routinely receives heparin intravenously during hemodialysis. In January 2008, during a dialysis session, she develops hypotension with associated nausea and dyspnea and requiring resuscitation with IV fluids. During a subsequent dialysis session, an anaphylactoid reaction is reported, with a sudden drop in blood pressure, dyspnea, nausea, vomiting and constitutional symptoms.
The uniting features of this case include hypotension, facial swelling, tachycardia, urticaria and nausea. Initially, the culprit was thought to be dialysis equipment, but it soon became evident that the culprit was likely to be heparin since cases in patients receiving heparin for reasons other than dialysis began to be reported. This prompted Baxter Pharmaceuticals to recall all heparin in single and multi-dose vials and heplocks. A German manufacturer announced a second recall because of additional reports of reactions to heparin. As reported on April 23rd on the NEJM website, Kishimoto et al published Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System, which identifies the culprit to be an oversulfated chondroitin sulfate, aka OSCS. In this study, suspected contaminated heparin, as well as control lots containing synthetically manufactured OSCS, were found to activate the complement system, specifically the kinin–kallikrein pathway which leads to the generation of bradykinin, a know vasodilator. Further activation of the complement system was evidenced by the generation of breakdown products of complement, C3a and C5a, representing activation of two separate pathways, both capable of producing the type of reaction typical of the case reported above. As of April 13, 2008, there were 81 reports of death involving at least one sign or symptom of an allergic reaction or hypotension in patients receiving heparin. Whether all of these were due to the potentially contaminated heparin is unknown. For now, all contaminated heparins appear to have been recalled and the FDA announced that the frequency of death due to heparin has returned to baseline levels. However, it would seem to me that remaining vigilant to unusual reactions would be prudent.
From the same issue of NEJM, Seung et al published Stents versus Coronary-Artery Bypass Grafting for Left Main Coronary Artery Disease, the so called ‘MAIN-COMPARE’ trial. The study examined outcomes in patients with left main CAD treated with stents (either bare metal or drug eluting–approximately 1100 patients) vs those treated with CABG (approximately 1100 patients). The outcomes measured were threefold: 1) death 2) a composite outcome of death, Q-wave myocardial infarction, or stroke 3) target vessel revascularization. After a mean follow up of 3 years, there was no observed outcome difference in either of the first two areas, namely death (hazard ration 1.18) or the composite outcome (hazard ratio 1.10) There was, however, a significant difference found in terms of revascularization, where a hazard ratio of 4.76 was found in the group stented vs the group that underwent CABG. So what should we conclude? Is this enough that we should advise our patients to have their left main disease stented rather than undergo CABG. This obviously has huge potential implications in the world of interventional cardiology as well as cardiothoracic surgery. The accompanying editorial written by Robert Jones, a prominent cardiothoracic surgeon from Duke, , concludes with an adamant ‘NO’. He reminds us that what is needed is a true RCT of stent vs CABG for left main disease (5 remain ongoing at this time). We must remain cautious because this trial followed patients for only 3 years. The longevity of the therapy with stents is still debatable. For now, it seems as though we need to be patient and wait, all the while remaining cautiously optimistic about the potential for invasive cardiologists to have another lesion to intervene on.
To stay true to the theme of cardiology for a moment longer, Stone et al published Comparison of an Everolimus-Eluting Stent and a Paclitaxel-Eluting Stent in Patients With Coronary Artery Disease A Randomized Trial (SPIRIT III) in the April issue of JAMA. In this study, 1002 patients were randomized to everolimus-eluting (669 pts) vs. paclitaxel-eluting stent (436 pts) and followed for one year. Everolimus is a cell cycle inhibitor and as well as an inhibitor of smooth muscle proliferation. The primary end point was assessment of noninferiority or superiority of in-segment late loss, which is measured by angiography and assesses neointimal hyperplasia The secondary end point was noninferiority of target vessel ischemic events, namely cardiac death, MC or revascularization at 9 months. Patients took aspirin (>80 mg/day) indefinitely and clopidogrel (75 mg a day for at least 6 months). Results are simple and hopeful: late loss was less in the everolimus group and it was noninferior in terms of target vessel failure. We must investigate further and, if we learn from history, we’ll remember that vigilance must remain the operative word after larger populations of people are treated, outside of the controlled world of trials.
Short-shortcut: I’ll comment briefly on a study from the April 19th issue of Lancet, which reported on a new diagnostic strategy for PE. In it, Righini et al reported a strategy of combining a clinical risk assessment with D-dimers with multislice CT and concluded that it is as safe and effective method a method of excluding PE as a similar strategy that includes lower extremity ultrasound. The clinical assessment was made using the revised Geneva score, a clinical scoring system that uses clinical variables: advanced age, previous venous thromboembolism, recent surgery or trauma, cancer, unilateral leg pain, hemoptysis, heart rate, pain on palpation of leg and unilateral edema.
And last but not least, we shift gears and search for the key to eternal youth. A Harvard researcher and founder of Sirtris Pharmaceuticals, David Sinclair thinks he has found the secret of eternal youth in the form of resveratrol, an ingredient in wine that made yeast live longer. GlaxoSmithKline is willing to pay $720 million dollars to buy Sirtris. Whether or not this will work and how it works, time will tell. But before leaving this week’s ShortCuts, think back to Greek mythology and the lives of Tithonus and Ganymede, two beautiful youths kidnapped by Eos to be her lovers. Zeus, being more powerful, stole Ganymede and gave him the gift of eternal youth. This angered Eos and they made a deal: Tithonus would remain immortal. What Eos forgot to ask for was eternal youth and thus, a conundrum; Tithonus continued to age, shrivel away with pain and progressive dementia–all the while remaining immortal. Makes me wonder what drugs like resveratrol will lead to…..