When Clopidogrel Fails…

March 10, 2010

imagesMarisa Mizus

Faculty peer reviewed

Clopidogrel (Plavix) has been the standard of care for patients with coronary artery disease following percutaneous coronary intervention (PCI) for the past decade.  Although it is a successful antiplatelet treatment in many patients, like any hero, it has a weakness: formation of its active metabolite depends on two hepatic cytochrome P450 (CYP450)-dependent steps.  Clopidogrel resistance, or non-response, is correlated with an increased risk of major adverse cardiovascular events, including reinfarction and stent thrombosis.(1)  It is often unclear why a patient does not respond to clopidogrel, although there is speculation that clopidogrel resistance results from the attenuating effects of proton pump inhibitors (PPIs) and CYP450 reduced function polymorphisms.(2)

Patients showing inadequate platelet response to clopidogrel have been treated with varying success with either a larger dose of clopidogrel or the addition of a glycoprotein IIb/IIIa inhibitor. Prasugrel (Effient), another thienopyridine, has been shown to be a more potent inhibitor of platelet aggregation than clopidogrel. (3) In fact, some studies have shown prasugrel’s superior efficacy even in combination with PPIs or in patients with CYP450 reduced function alleles, thus making it a second-line therapy in patients exhibiting clopidogrel resistance, with the potential of replacing clopidogrel as the drug of choice in certain types of patients.

PPIs are typically prescribed prophylactically with anti-platelet therapy in order to reduce the risk of gastrointestinal bleeding.  PPIs have been shown to inhibit CYP450 enzymes, thereby reducing the efficacy of drugs like thienopyridines.  Clopidogrel activation specifically depends on CYP2C19 activity.  The extent to which PPIs, especially omeprazole, actually affect clinical outcomes in patients taking thienopyridines is controversial. (4)  However, it has been shown that administration of certain PPIs significantly decreases clopidogrel’s inhibitory effect on platelet reactivity (5) and that current use of PPIs in patients also on clopidogrel status-post MI is associated with an increased risk of reinfarction and readmission for MI. (6)  Similarly, patients with reduced function polymorphisms in CYP450 alleles show decreased anti-platelet activity and are at greater risk for re-infarction and stent thrombosis.  This effect is thought to be even more pronounced in patients taking clopidogrel with a PPI. (7) In contrast, it has been shown that prasugrel, which depends on the enzyme CYP3A, retains anti-platelet activity even with PPI co-administration.(8)  Prasugrel also maintains anti-platelet efficacy in the face of reduced function polymorphisms of hepatic CYP450 alleles.(9)  However, prasugrel has been shown to increase the risk of major bleeding compared with clopidogrel and, at this point, its use is suggested for patients who are at low risk for bleeding and for patients who do not respond to clopidogrel therapy.

The FDA approved prasugrel to prevent thrombotic events in patients undergoing angioplasty in July of 2009.  It is suggested that clinicians weigh the risks of major bleeds against the benefits of superior anti-platelet activity, keeping in mind the limitations of applying data from a study population to individual patients in the community. 

Marisa Mizus is a 3rd year medical student at NYU School of Medicine.

Faculty peer reviewed by Dr. Robert Donnino, NYU Division of Cardiology.

1)  Simon DI, Jozic J.  Drug-eluting stents and antiplatelet resistance.  Am J Cardiol. 2008;102 (9 Suppl):29J-37J. Accessed October 12, 2009.

 2) Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.  JAMA. 2009;301(9):937-944.  Accessed October 21, 2009.

 3) Wiviott SD, Braunwald E, McCabe CH, et al.  Prasugrel versus clopidogrel in patients with acute coronary syndromes.  N  Engl J Med. 2007:357(20):2001-2015.  Accessed on October 19, 2009.

 4) Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? Lancet. 2009;374(9694):952-954.  Accessed October 19, 2009.

 5) Roden D, Stein C.  Clopidogrel and the concept of high-risk pharmacokinetics.   Circulation. 2009;119(16):2127-2130.  Accessed on October 21, 2009.

 6) Li XQ, Andersson TB, Ahlstrom M, Weidolf L.  Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole, on human cytochrome P450 activities.  Drug Metab Dispos. 2004;32(8):821-827.  Accessed October 12, 2009.

 7) Mega  JL, Close SL, Wiviott S, et al. Cytochrome p-450 polymorphisms and response to clopidogrel.  N Eng J Med. 2009;360(4):354-362.  Accessed October 12, 2009.

 8) Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel.  J Clin Pharmacol. 2008; 48(4):475-484.  Accessed October 21, 2009.

 9) O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomized trials.  Lancet. 2009;374(9694):989-997.  Accessed October 21, 2009.



Zolpidem and Uncontrollable Nocturnal Eating Binges

February 24, 2010


John Cruz

Faculty peer reviewed

A number of studies have shown that zolpidem (Ambien), the most commonly prescribed sleep-inducing medication on the market, can produce uncontrollable nocturnal eating behavior among users.  Sleep related eating disorder (SRED) is characterized by partial arousals from sleep to ingest food, usually within the first three hours after sleep onset, occurring one to six times per night.1  Patients describe an “automatic” inclination to eat and an inability to return to sleep unless they eat.  The foods are often high in calories and ingested in massive quantities.2

The occurrence of zolpidem-induced nocturnal eating is probably more common than currently reported.  In a New York Times article3 entitled “Study links Ambien use to unconscious food forays,” Stephanie Saul interviewed Judie Evans, a 59-year-old woman who lived alone and suffered from zolpidem-induced SRED.  At the time of her diagnosis, Ms. Evans was recuperating from spinal surgery, wore a full body cast, and always required help to get out of bed.  Shortly after her physician prescribed zolpidem for her sleeping difficulties, she noticed that food started to disappear from her home.  She initially accused the two nursing aides who were caring for her, but it was not until her son stayed with her for several days that she realized what was really occurring.  “During the day, I couldn’t even make it to the bathroom by myself,” Ms. Evans said.  However, on the first night he stayed over, her son found her, body cast and all, frying eggs and bacon in the kitchen.  The next night, he caught her eating a sandwich and promptly sent her back to bed, but later found her back in the kitchen with the oven turned to 500 degrees, causing the pots stored in the oven to melt.3

Another woman who suffered from SRED was Helen Cary, a labor and delivery nurse in Dickson, Tennessee.  Ms. Cary started taking zolpidem to help her sleep through the day so that she could work 12-hour night shifts at the hospital.  Although she said that zolpidem helped her survive “five years of night shift,” she felt “very ambivalent” about the medication because while on zolpidem her behavior became very strange.  “One day,” she said, “I got up-my husband describes this in great detail-I got a package of hamburger buns and I just tore it open like a grizzly bear and just stood there and ate the whole package. He said a couple things to me until he realized I was asleep.”  Ms. Cary no longer takes zolpidem, and has switched to working days.3

Zolpidem is a benzodiazepine agonist that binds to the benzo 1 receptors found in the cortex and cerebellum and creates a hypnotic effect.  However, unlike the anxiolytic drugs alprazolam (Xanax) and clonazepam (Klonopin), zolpidem does not bind to the benzo 2 receptors in the striatum, hippocampus, and spinal cord, and is less likely to cause ataxia, dependence, paradoxical disinhibition, withdrawal symptoms and, most importantly, respiratory depression.4  Consequently, many doctors prescribe zolpidem to treat insomnia.

A number of sleep experiments have confirmed the relationship between zolpidem and nocturnal eating.  Dr. Michael Silber was one of the first to describe SRED with amnesia in zolpidem users.  In a 2002 article,5 he described three cases where nocturnal eating began as a result of starting zolpidem and two cases where pre-existing nocturnal eating increased in frequency. 

Melissa Feltmann, a spokesperson for Sanofi-Aventis, the French company that makes zolpidem, defends the safety of the drug.  She states that “Sanofi-Aventis has received reports of people eating while sleepwalking and those reports, like all reports of adverse events, have been provided to the U.S. Food and Drug Administration.”  Ms. Feltmann says that the package insert for zolpidem warns that the drug may cause a sleep-related eating disorder, but she cautions that every case of SRED in patients taking zolpidem might not necessarily be caused by the drug itself.3

A definitive etiology has not been elucidated, but a number of hypotheses are currently being explored.  Dr. Carlos Schenck, a sleep disorders expert at the University of Minneapolis, believes that under the influence of zolpidem, sleeping and eating become confused by the brain.3  Morgenthaler5 and Mahowald6 further elucidate Schenck’s hypothesis.  They found that the concurrence of a sleep disorder that increases arousals during slow-wave sleep (e.g. restless leg syndrome; periodic limb movement disorder; obstructive sleep apnea; and withdrawal from nicotine, alcohol, opiates and cocaine) can often lead to SRED in the setting of zolpidem use. 

Until researchers discover the exact mechanism by which zolpidem causes SRED, treatment options include targeting the underlying sleep disorder (pramipexole for restless leg syndrome, CPAP for sleep apnea), discontinuing zolpidem, and replacing zolpidem with another benzodiazepine agonist such as eszopiclone (Lunesta) or pyrazolopyrimidine (Sonata).5  Najjar et al. found that despite being in the same medication class as zolpidem, eszopiclone and pyrazolopyrimidine were associated with resolution of SRED.7

Until further studies elucidate the exact mechanisms by which zolpidem induces SRED, physicians should exercise caution when prescribing it, especially in obese or diabetic patients.

John Cruz is a fourth year medical student at NYU Medical Center.

Peer reviewed by Andrea Kondracke MD


1) Winkelman JW.  Clinical and polysomnographic features of sleep-related eating disorder. J Clin Psychiatry. 1998;59:14-19.

 2) Schenck CH, Hurwitz TD, Bundlie SR, Mahowald MW. Sleep-related eating disorders: polysomnographic correlates of a heterogeneous syndrome distinct from daytime eating disorders. Sleep. 1991;14(5):419-431.

 3) Saul S. Study links Ambien use to unconscious food forays. NY Times. March 24, 2006.  Accessed on October 21, 2009.

 4) Albers LJ, Hahn RK, Reist C. Handbook of Psychiatric Drugs 2008. Hightown, Lancaster, UK: Current Clinical Strategies:72.

 5) Morgenthaler TI, Silber MH. Amnestic sleep-related eating disorder associated with zolpidem. Sleep Med. 2002:3(4)323-327.

 6) Mahowald MW, Schenck CH. NREM sleep parasomnias. Neurol Clin. 1996;14(4):675-696.

 7) Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med. 2007;3(6):637-638.

Breaking News: FDA issues new warning for Exenatide (Byetta®)

November 5, 2009

byettaKanika Ballani, Pharm.D.
Diana Hubulasvili, Pharm.D.

 Developed by Amylin Pharmaceuticals, Exenatide (Byetta®) is an incretin mimetic that is used as an adjunctive therapy with metformin, a sulfonylurea or a thiazolidinedione to improve glycemic control in type 2 diabetic patients. Mechanistically, Exenatide mimics the actions of endogenous incretin hormone, glucagon-like peptide (GLP-1), causing an increase in insulin secretion which slows gastric emptying and leads to a decrease in food intake. On November 3rd 2009, the FDA issued a safety warning on Exenatide associating it with the incidence of renal failure. This FDA warning was based on 78 postmarketing cases reported between April 2005 and October 2008. The average patient age in the case reports was 60 years. The FDA approved revisions to the drug label for exenatide due to the temporal-causal relationship that was observed with the initiation of exenatide and the occurrence of serious potential consequences of altered kidney function.1

Sixty-two of the cases reported were classified as acute renal failure and the remaining 16 cases were categorized as renal insufficiency. The postmarketing surveillance data of these cases reported that after the initiation of exenatide, hospitalization was required in 91% (71/78) of the patients. Two patients needed kidney transplantation and there were 4 fatalities. Dialysis had to be initiated in eighteen patients, of which, 2 patients had a known prior history of altered kidney function. Upon discontinuation, 39 patients reported improved signs and symptoms after the discontinuation of the drug. Recurrence in kidney dysfunction was reported in one patient who was reinitiated on exenatide.1

Forty-two patients (54%) reported symptoms associated with volume depletion, such as diarrhea, vomiting, and dehydration. These common gastrointestinal manifestations of exenatide are believed to be the risk factors for the development of altered kidney function. Weiss et al. reported the incidence of exenatide induced ischemic renal failure in 4 patients and established a temporal causal relationship between exenatide and the incidence of renal dysfunction. The induction of nausea and vomiting associated with exenatide use contributes to extracellular volume contraction, which when combined with concomitant therapy with diuretics and ACEIs, leads to an exaggerated decline in glomerular filtration rate. GLP-1 has also been proposed to cause natriuresis decreasing renal perfusion; an effect believed to be shared by exenatide as well.2,3

It must be noted that the time frame for the development of acute renal insufficiency was wide, ranging from 3 days to up to 2 years after the initiation of exenatide. Moreover, pre-existing kidney disease or risk factors for developing renal dysfunction such as- cardiac insufficiency, hypertension, pancreatitis, rhabdomyolysis, urinary tract infections and concomitant use of NSAIDs, antiretrovirals, and diuretics, were evident in 95% (74/78) of patient cases reported. It is plausible that the incidence of renal dysfunction noted in these patients could also have precipitated secondary to the independent risk factors initially present in these patients. In addition, 14 of the cases had a prior medical history of chronic kidney disease, and 4 cases with chronic renal failure, despite recommendations against the use of Byetta in these patients in the current prescribing information.1

Interestingly, Exenatide was approved as a first line agent, in conjunction with diet and exercise to improve glycemic control in type 2 diabetes mellitus on the same day this warning regarding the incidence of renal insufficiency was issued. Based on this warning, practitioners must weigh out risks and benefits before prescribing exenatide as monotherapy for the management of diabetes and exert precaution in administering it concomitantly with other nephrotoxic agents.


2. Weiss et al. Exenatide-Associated Ischemic Renal Failure. Diabetes Care. 2009;32(2):e22-23
3. Gutzwiller JP et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89:3055-3061

Clinical Questions: How do you dose argatroban?

April 16, 2009


Frederick Gandolfo, MD

Case: An 85 year-old woman admitted to the hospital with pneumonia and after a prolonged hospital course developed heparin-induced thrombocytopenia (HIT). She is currently being treated with argatroban and her platelet counts are recovering. You are the covering physician and are called by the lab for an INR of 12 on her routine labs. The patient shows no signs of bleeding and she is not on warfarin. The PTT at the time is 160 seconds. What is the appropriate course of action?

A few questions immediately come to mind:
• How are the INR and PTT interpreted while on direct thrombin inhibitors?
• Is there a co-existing coagulopathy and can that be determined from the numbers provided?
• How can this patient be safely transitioned to warfarin for long term therapy?

The direct thrombin inhibitor argatroban is widely used in the treatment of HIT to prevent thrombotic complications of the disease. The usual course of therapy conshists of discontinuing all sources of heparin, starting an alternative injectable anticoagulant, and then initiating warfarin when the platelet count recovers to above 150, 000/mL. Warfarin and the non-heparin anticoagulant should then overlap for 5 days. The INR on warfarin should be therapeutic (between 2-3) for at least 48 hours before discontinuing the injectable anticoagulant.

Converting patients from agratroban to warfarin is problematic, since argatroban elevates the PT/INR making the actual PT/INR difficult to interpret while the patient is still receiving argatroban. GlaxoSmithKline, the manufacturer provides a curve to estimate the actual INR from the measured INR while receiving ( Using the curve, to obtain an actual INR of 2-3 with warfarin alone, the measured INR while on argatroban and warfarin can be between 3-6 depending on the specific reagent used by the lab. Thus, one way of successfully transitioning patients from argatroban to warfarin is to aim for an INR goal of approximately 4 measured at a time when the PTT is in the therapeutic range. It can then be predicted that the INR once off argatroban will be approximately 2-3, which solely reflects the influence of warfarin. However, the manufacturer warns that this linear relationship becomes unpredictable at argatroban doses exceeding 2 mcg/kg/min.

Is there a way to predict the actual INR from the measured INR at higher argatroban doses? In the case above, was the elevation in INR solely due to the supratherapeutic dose of argatroban or was it too high to be explained by argatroban alone and may instead be a result of a concomitant coagulopathy? A brief review of the literature revealed a study by Warkentin et al.that measured the PTT and INR elevations obtained y spiking plasma samples with several direct thrombin inhibitors including argatroban. The therapeutic concentration of argatroban in humans (defined as increasing the PTT twofold) is approximately 1 micromole/L. The highest concentration of argatroban tested in this study, 8 micromoles/L (eight times the therapeutic concentration), resulted in a PTT of approximately 150 seconds and an INR range of approximately 8-14, depending on the reagent used by the lab. Thus, the INR prolongation obtained by extreme supratherapeutic concentrations of argatroban does indeed appear unpredictable, resulting in a wide range of the measured INR. It also appears that the INR increase observed at supratherapeutic concentrations of argatroban rises out of proportion to the 1-2 INR units expected when argatroban is used at therapeutic concentrations. Thus, caution should be used when dosing argatroban, as the effect on INR prolongation is variable at supratherapeutic doses.

To monitor coumadin anitcoagulation in these patients, it is recommended to hold argatroban until the PTT is elevated to approximately two times the upper limit of normal and to recheck the INR at that time, using the adjustment curve provided by the manufacturer. An alternative to the INR would be to measure factor X activity by chromogenic assay.

Thus, in the case above, the proper course of action in the non-bleeding patient it to hold the argatroban and recheck the INR and PTT in approximately 2 hours. If the PTT decreases to normal but the INR remains elevated then there is evidence for a concomitant coagulopathy that cannot be explained by argatroban or alternatively the patient is highly sensitive to Coumadin AC.

Bottom line:
• The goal PTT for argatroban therapy is two-times the upper limit of normal for the lab.
• In HIT, warfarin should be started after both the platelet count recovers above 150,000 and the patient has been therapeutic on argatroban.
• After a minimum of five days of argatroban therapy and warfarin overlap, it is safe to stop the argatroban when BOTH the PTT is in the therapeutic range AND the INR has been approximately 4 for a minimum of 48 hours.
• The INR should be rechecked 2-4 hours after discontinuing argatroban. This should be the “true” INR reflective of warfarin alone, and should now be between 2-3.
• In patients on argatroban, the INR should not be monitored until the patient is ready to be transitioned to warfarin therapy.
• In patients on argatroban, the INR should not be interpreted when the PTT is greater that twice the upper limit of normal.

Faculty Peer Reviewed and Commentary by David Green PhD, MD NYU Division of Hematology and Oncology

HIT is said to be the most hypercoagulable state known. There is now widespread recognition of this rare but potentially devastating complication. HIT is much less common with low-molecular-weight heparin and to my knowledge there is only a single published case report of HIT with fondaparinox.

Fortunately, we have three direct thrombin inhibitors (DTIs) available as alternative anticoagulants for the treatment of HIT. HIT laboratory testing is highly sensitive but suffers from poor specificity and we are consequently over-diagnosing HIT. In the above clinical vignette, the INR on DTI therapy is significantly elevated. But why was it ordered to begin with? After all, the calculation of INR is heavily influenced by the ISI assignment of the thromboplastin, which is calibrated by its sensitivity to the relative depletion of vitamin K dependent factors by warfarin. The use and interpretation of INR in other clinical settings is controversial. The INR alone should not be used to guide clinical decision-making of patients on DTIs unless they are being transitioned to warfarin, since the known interference of the INR by DTIs values makes it difficult to interpret. One must consider the basis and limitations of clinical laboratory testing. Adding to the uncertainty, PTT reagents are not standardized for sensitivity to DTIs, although there is no practical alternative at the moment. Fortunately in practice the transition from DTIs to warfarin anticoagulant is fairly seamless, even if the tools for monitoring anticoagulation intensity in this setting are far from optimal.

Further reading:

N Engl J Med. 2006 Aug 24;355(8):809-17. PMID: 16928996

Walenga JM, Fasanella AR, Iqbal O, Hoppenstaedt D, Sarfraz A, Wallis D, Bakhos M. Coagulation laboratory testing in patients treated with argatroban. Semin Thromb Hemost 1999;25:61-66. PMID: 10357154

Warkentin TE, Greinacher A, Craven S, Dewar L, Sheppard JI, Ofosu FA. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost 2005;94:958-64. PMID: 16363236

Fenyvesi T, Joerg I, Harenberg J. Influence of lepirudin, argatroban, and melagatran on prothrombin time and additional effect of oral anticoagulation. Clin Chem 2002; 48:1791-1794. PMID: 12324500

Siegmund R, Boer K, Poeschel K, Wolf G, Deufel T, Kiehntopf M. Influence of direct thrombin inhibitor argatroban on coagulation assays in healthy individuals, patients under oral anticoagulation therapy and patients with liver dysfunction. Blood Coagul Fibrinolysis 2008;19(4):288-93. PMID: 18469550

Fred Gandolfo is a third year resident in Internal Medicine at NYU Medical Center

Grand Rounds: “Activated Protein C, Translational Research models of Sepsis and Stroke”

January 28, 2009

Grand Rounds Image

Commentary by Adi Diab MD, PGY-3

This past week on January 21th, Medical Grand Rounds was given by guest speaker Dr. John Griffin who shared his knowledge of the role of Activate Protein C in both human and murine models of sepsis and stroke.

Activated protein C (APC) is a FDA approved drug that reduces mortality in adult severe sepsis patients, but also increases the risk of serious bleeding. APC exerts anticoagulant activity by proteolysis of factors Va/VIIIa. However, additional clinical trails using other anticoagulants, antithrombin III and tissue factor pathway inhibitor, failed to show similar benefit in septic patients. These results and other data suggested that APC exerts pleotrophic effects that are independent from the anticoagulant activity. These anti-inflammatory, anti-apoptotic, and vascular endothelial permeability effects of APC are mediated via engagement of the endothelial cell protein C receptor (EPCR) and secondary activation of the G protein-coupled receptor, protease-activated receptor 1(PAR1). As noted above,  the anticoagulant activity of APC is mediated by receptor independent proteolytic inactivation of factors Va/VIIIa.

Using both Human and Murine models, Dr Griffin shows that total deficiency in protein C can result in fatal disease and neonatal purpura fulminans. In clinical observations, the surviving infants are often blind and retarded, and they benefit from  protein C supplement for life. If partial deficiency (heterozygous Protein C deficiency) occurs, there is increased risk for venous thrombosis in adults. In-vitro studies showed that HDL provides anticoagulant cofactor activity for  APC/protein S in certain clotting  assays.  Patients with a history of venous thrombosis or with recurrent venous thrombosis were found to have lower levels of HDL, as well as other anticoagulant cofactors such as protein S. These data along with other studies indicates that HDL deficiency is associated with venous thrombosis. This information raises the question whether lipid lowering drugs will reduce the risk of venous thrombosis.

As mentioned earlier, there are many documented benefits from the pharmacological use of APC.  Not only does it increase survival in septic patients, but it also has neuroprotective activity in ischemic stroke as it reduces tPA-induced neurotoxicity and bleeding. Additionally, murine injury models show that it attenuates inflammatory lung injury and improves islet transplantation. But, because of the failure of different anticoagulants in phase 3 severe sepsis clinical trials, Griffin and others hypothesized that the APC success in sepsis cannot be explained only by anticoagulant activity. To evaluate the relative importance of the APC anticoagulant activity versus  its cytoprotective actions, Dr Griffin’s lab engineered APC mutants deficient in either anticoagulant (5A-APC) or cytoprotective (E149A-APC) activities. Using these selectively altered APC mutants or genetically altered mice for in vivo animal injury studies, they were able to demonstrate that the 5A-APC mutant (that maintains the cytoprotective actions)  caused improved survival in the LPS Endotoxemia challenge whereas the mutant (E149A-APC) with only anticoagulant activity  failed to protect mice  from similar lethal LPS challenge.

Several clinical studies have shown that plasma protein C is an inverse risk factor for ischemic stroke and that cerebral ischemia increases circulating APC. Based on this and other data, colleagues at the Univeristy of Rochester (Prof. B. Zlokovic’s group) studied whether APC plays any protective role in murine ischemic stroke and whether it can be beneficial when given with tPA. Using in vitro hypoxia/apoptosis assays and an in vivo murine stroke model, they were able to conclude that: 1) APC is neuroprotective via PAR1 and EPCR; 2) APC is angiogenic and neurogenic in ischemic brain; 3) APC attenuates tPA-neurotoxicity including tPA-induced bleeding & neuronal apoptosis; and 4) APC is effective in multi-dose bolusing given at 6-72 hr after ischemia onset.

Thus, APC’s mortality reduction in various injury models primarily involves cytoprotective mechanisms.  In the future, developing APC variants with selectively reduced anticoagulant activity may improve therapy allowing increased dosing regimens with reduced bleeding risk.

Breaking News: Revenge of the Gila Monster?

August 20, 2008

gila-monster.jpgCommentary by Rachana Jani MD, PGY-2

As recently reported in ShortCuts, Byetta recently made headlines after the suggestion of a mortality benefit for patients taking the drug in a small subset of the Accord study.  So is this the new golden drug for diabetics? Perhaps not. This week, the FDA updated a previous alert warning providers about the risks of pancreatitis in patients taking Byetta. Last October, the FDA first issued an alert after there had been 30 postmarketing reports of acute pancreatitis in patients who had recently been started on Byetta. Though concerning, a causal relationship was difficult to ascertain and it was believed that patients had more than 1 risk factor for pancreatitis. Many physicians continued to prescribe the drug due to its differentiated clinical profile and the rare incidence of the disease given that hundreds of thousands of patients had been started on the drug without consequence.  However, since October, 6 additional cases of necrotizing pancreatitis have been reported, and 2 of these patients died in the interim. The FDA is now working with Amylin for a more prominent warning label about the risk of necrotizing pancreatitis. Though still argued to be a rare adverse outcome, the number of lawsuits is beginning to pile. This, in addition to more user-friendly options, such as Januvia, which comes in pill form, may lead to the end of the Byetta era.

Image courtesy of Wikimedia Commons, Gila monster

New National Network E-mails Drug Alerts Instantly to U.S. Doctors

July 31, 2008

logo_hcnn.gifCommentary by Marilena S. Antonopoulos Pharm.D, Pharmacology Section Editor

Until recently, drugs safety alerts (aka “Dear Doctor letters”) were sent out to physicians through traditional U.S. mail, a slow and error-prone process. These alerts can be significantly delayed and may not even reach the intended recipient. In an effort to improve the speed and efficacy of the delivery of FDA mandated patient safety alerts to physicians and other healthcare providers, the Health Care Notification Network (HCNN) has announced the launching of its online service that e-mails patient safety alerts instead of sending them via U.S. mail. The HCNN may also be used to notify physicians in the event of national public health emergencies or bio-terror events.

The iHealth Alliance is a not-for-profit organization whose mission is to protect the interests of patients and providers as healthcare increasingly moves online. The iHealth Alliance governs the HCNN and will ensure that the network is used only for patient safety alerts.

This new online network will ensure fast and convenient delivery of vital patient care information, and healthcare providers can have confidence that they will receive recall alerts before their patients learn about them in the press. All physicians are encouraged to register for HCNN because it will help improve patient safety and reduce liability. In 2007, the FDA guidance to manufacturers (pharmaceutical and medical device) indicated that online alert systems such as HCNN are preferred for delivering patient safety alerts to providers and are preferable in most cases to paper-based delivery.

Additional benefits of joining the HCNN network include the ability to get more information regarding specific patient safety alerts, enter into a discussion area with other providers who have received an alert, and have alerts automatically sent to other designated staff. The service is free for all physicians and healthcare providers who wish to receive these alerts electronically. Provider emails will be kept secure and not be sold or disclosed to other 3rd parties. Physicians who decide not to join the HCNN will continue to receive patient safety alerts on paper via U.S. mail. Providers can register now at

Breaking news: FDA issues new Boxed Warning for Fluoroquinolones

July 10, 2008

cipro.jpgCommentary by Marilena S. Antonopoulos, PharmD, Pharmacology Editor

On July 8th, the FDA notified the manufacturers of fluoroquinolone antimicrobial drugs that a Boxed Warning in the product labeling and a Medication Guide for patients concerning the increased risk of tendinitis and tendon rupture is necessary. The FDA conducted a new analysis of the available literature and post-marketing adverse event reports which reconfirms that the use of fluoroquinolones is associated with an increased risk of tendon rupture.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in people older than 60 years, in those taking corticosteroid drugs, and in kidney, heart and lung transplant recipients. Patients experiencing pain, swelling, inflammation of a tendon or tendon rupture should be advised to stop taking their fluoroquinolone medication and to contact their health care professional promptly about changing their antimicrobial therapy. Patients should also avoid exercise and using the affected area at the first sign of tendon pain, swelling, or inflammation.

Tendinitis and tendon rupture most frequently involve the Achilles tendon. Tendinitis and tendon rupture in the rotator cuff, the hand, the biceps and the thumb have also been reported. Tendon rupture can occur during or after completion of fluoroquinolone use, with cases reportedly occurring up to several months after completion of therapy.

These warnings would apply to fluoroquinolones for systemic use (e.g., pills, tablets, capsules and injectable formulations). The warnings would not apply to fluoroquinolones for topical ophthalmic or otic use (e.g., eye and ear drops). Medications involved in this action are: Cipro and generic ciprofloxacin, Cipro XR and Proquin XR (ciprofloxacin extended release), Factive (gemifloxacin), Levaquin (levofloxacin), Avelox (moxifloxacin), Noroxin (norfloxacin) and Floxin and generic ofloxacin.


The Skinny on Hoodia

May 16, 2008

hoodia_weight_loss_pill.jpgCommentary by Melissa Freeman, PGY-2 

As summertime is just around the corner, many begin to evaluate whether their bodies are ready to expose what has been hidden under those bulky winter clothes. Between busy lives and an innate desire for quick results, people sometimes turn to over-the-counter diet pills for a slimmer physique. With recently banned products like Ephedra, consumers are looking for newer, more promising weight loss products. During a recent clinic visit, a patient asked me about my thoughts on diet pills that contained hoodia. Though I had never heard of this ingredient, I soon learned that hoodia has made more than a few headlines and was even featured in a segment on 60 Minutes back in 2004. Reporter Leslie Stahl traveled to Africa just to ingest the native plant. Read more »

Class Act: The Polypill Panacea

May 1, 2008

pills.jpgCommentary by David Hatcher, MSIII (reviewed by Neil Shapiro, MD Editor-In-Chief, Clinical Correlations)

C.M. is a 68 year-old retired Caucasian male with a past medical history significant for coronary artery disease, hyperlipidemia, HTN, and a 30 pack year history of smoking. His drug regimen consists of a beta-blocker, an ace inhibitor, a statin, and aspirin.

Patients like C.M. are now more common than ever before. He has already had one heart attack, and he has multiple risk factors for another, many of them preventable. In the United States alone, heart disease and stroke are the first and third leading causes of death. For those like C.M., this means a lifetime on multiple medications; unfortunately, however, not everyone has access to the same resources or is as compliant. Despite the availability of medications proven to be effective for primary and secondary prevention of cardiovascular disease, they often are not used optimally, even in developed countries. A gap currently exists between our knowledge of prevention and its actual practice. Poor drug adherence to multidrug regimens and costly medications are common barriers to treatment, especially in middle and lower income areas. Read more »

Future Medicine: The Search for a New Anticoagulant

April 16, 2008

coumadin.jpgFuture Medicine is a new section of Clinical Correlations devoted to hot areas of research and development in various fields of medicine. In tihis series, we will highlight treatments in their infancy, from basic research opening up new targets for treatment, to following small molecules throughout their clinical investigation. We will also bring you the latest on technology and devices, as well as perspectives on drug discovery from a business point of view. Watch out – the future is just around the corner!

Commentary by Aaron Lord MD, PGY-1

We have all been there before: a patient sitting in front of you, be it in clinic, the ER, or as an inpatient, with newly diagnosed atrial fibrillation (AF), and it’s up to you and the patient to decide on a plan for anticoagulation. With an aging population, AF has not only become more prevalent, but the decision of whether to anticoagulate has become more difficult – Can my patient reliably take Coumadin everyday? Can they understand the complex and changing dosing? Will they follow-up in Coumadin clinic? All of the pitfalls of Coumadin therapy have driven a number of pharmaceutical companies to develop new forms of anticoagulation that have far less drug-drug and drug-food interactions and do not require frequent INR checks. We will quickly review the necessity of anticoagulation in atrial fibrillation and then take a look to see if any of the new drugs compare favorably to the efficacy and safety profile of that old workhorse Coumadin. Read more »

Class Act: Do Statins Always Have to Be Taken in the Evening?

January 10, 2008

lipitor.jpgClass act is a feature of Clinical Correlations written by NYU 3rd and 4th year medical students. These posts focus on evidenced based answers to clinical questions related to patients seen by our students in the clinics or on the wards. Prior to publication, each commentary is thoroughly reviewed for content by a faculty member. Enjoy…

Commentary by David Leaf, MSIV

HMG-CoA reductase inhibitors (statins) are the most powerful drugs used for lowering LDL cholesterol, with median reductions in the range of 30 to 63 percent.(1,2,3) Consequently, these drugs have emerged as a first line treatment in patients with coronary artery disease or coronary risk equivalents, and have been shown to cause substantial reductions in mortality.(4)

Patients have traditionally been instructed by their physicians to take statins in the evening for maximal effect.(5) The rationale for this recommendation comes from evidence that hepatic HMG-CoA reductase activity6 and cholesterol biosynthesis(7) are greatest at night, while the half-lives of many statins are relatively short. For example, Lovastatin, (8) Fluvastatin, (9) and Simvastatin (10) all have half-lives less than six hours. Thus, in order to achieve maximal LDL lowering, it has been advised to administer statins in the evening in order to inhibit the enzyme while it is most active. Indeed, early studies with simvastatin found that evening administration resulted in significantly greater reductions in LDL cholesterol when compared to daytime administration (21% versus 15% reduction, respectively).(11)

While the evening administration of statins has become commonplace, several studies have evaluated the applicability of the above “conventional wisdom” to the newer, more potent, HMG-CoA reductase inhibitors such as Atorvastatin and Rosuvastatin. These statins have significantly longer half-lives (14 and 19 hours, respectively)(12,13) than their older counterparts, therefore calling into question the importance of morning versus evening administration. As might be expected based on their slower metabolism, studies have in fact demonstrated that the LDL-lowering efficacy of Atorvastatin (14,15) and Rosuvastatin(16) is independent of the time of day of drug administration. Similarly, the efficacy of extended-release Fluvastatin was also recently shown to be uninfluenced by the time of intake.(17)

Because treatment with statins is usually chronic, or even lifelong, compliance to therapy is essential.(18) Given that once-daily dosage regimens have been shown to facilitate patient compliance,(19)one may extrapolate that complicating a previously once-daily (morning) regimen by adding an evening medication might decrease compliance. Clinicians should therefore be aware that not all statins have similar pharmacodynamic and pharmacokinetic properties, and many statins can achieve equal LDL-lowering efficacy (and arguably improved compliance) when administered in the morning as compared with the evening.

1. Levy, RI. A quarter century of drug treatment of dyslipoproteinemia, with a focus on the new HMG-CoA reductase inhibitor fluvastatin. Circulation 1993; 87(4 Suppl):III45.
2. Jones, P, Kafonek, S, Laurora, I, et al for the CURVES Investigators. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81:582.
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