July 22, 2008
Lots New in the Anticoagulation Literature
Even as the ACCP published its long awaited update “Antithrombotic and Thrombolytic Therapy, 8th Ed: ACCP Guidelines”, new articles are appearing in the literature that may lead to further changes in recommendations or new recommendations.
In this month’s issue of Archives of Neurology, Hallevi and colleagues at the stroke center at the University of Texas at Houston report their experience with cardioembolic strokes. Though it is a retrospective study and not a randomized controlled trial, the insights gleaned from their experiences is likely to change the way many neurologists and other physicians approach the issue of anticoagulation of cardioembolic stroke. While most agree on the value of long-term anticoagulation with warfarin for many cases of cardioembolic stroke, a key issue remains when and how to start anticoagulation. Though not part of any formal recommendations, a common practice has been “bridging therapy” in which full anticoagulation with either unfractionated heparin on low-molecular weight heparin (LMWH) is used while waiting for the INR to reach the target level as warfarin is initiated. We often do this because we are concerned that a new embolic event might occur while we are waiting for the INR to reach the therapeutic target range. However, recurrent embolic events in this short time frame are fairly infrequent. Another reason sometimes cited is the fear of the transient hypercoaguable state sometimes seen when warfarin is started without heparin that may lead to skin necrosis. The latter may be more common in patients with protein C deficiency.
The Texas group found that all their patients who suffered symptomatic hemorrhagic transformation of their cerebral infarcts were in the enoxaparin (LMWH) group. In fact, an alarming 10% of patients receiving full bridging anticoagulation with enoxaparin had symptomatic hemorrhagic transformation. They also found that cases of systemic bleeding occureed only during bridging therapy with full heparin anticoagulation (though this affected only 2 patients it was statistically significant). Interestingly, they noted that stroke progression was much more frequent in those patients treated with aspirin alone or no treatment, compared to those treated with warfarin alone or warfarin plus bridging anticoagulation. But, overall, the Texas experience would suggest that bridging therapy in this clinical circumstance may be dangerous. Whether it has a role in certain situations (eg. hypercoagulable states) remains to be determined. Their experience shows that starting warfarin at any point during the hospital stay (along with DVT prophylaxis doses of LMWH or unfractionaed heparin) is safe and effective in most cases. Further randomized controlled trials for specific clinical scenarios is desirable.
Another new article challenges current practices on DVT prophylaxis after knee arthroscopy, which do not recommend pharmacoprophylaxis for uncomplicated arthroscopy. Camporese et al in the Annals of Internal Medicine did a randomized controlled trial of graduated compression stocking vs. LMWH prophylaxis in patients undergoing knee arthroscopy. Patients with other preexisting DVT risk factors were excluded. Their primary efficacy endpoint was a cumulative composite of all-cause mortality, asymptomatic DVT, and symptomatic DVT at 3 months and occurred in 3.2% of patients in the stocking group and 0.9% of patients in the LMWH groups (they had a 7-day LMWH group and a 14-day LMWH group, the latter being subsequently stopped early though data was available). Much of the composite endpoint was made up by symptomatic distal DVT. Clinically significant bleeding was not statistically significantly different between the LMWH and stocking groups. Even the just released ACCP guidelines do not recommend pharmacoprophylaxis for routine knee arthroscopy in normal risk patients. It will be interesting to see if this new study significantly alters that practice. The incidence of serious outcomes in this population is relatively low. They did not see any cases of heparin-induced thrombocytopenia but they only had 1761 total patients in their study. But one would expect cases of HIT to occur if LMWH prophylaxis becomes more widespread after knee arthroscopy, which is the most common orthopedic procedure worldwide. So generalizing safety from a relatively small study to a population of potentially millions may be difficult.
Lastly, as followup to our recent articles on the dangers of heparin flushes, there is another update on heparin flushes in the ISMP July 17, 2008 Newsletter. It speculates on some of the possible errors that may have played a role in the recent incidents. And it notes new technology, aside from barcoding, may have a safety role. They describe use of a refractometer that can readily flag specimens which might have higher heparin concentrations. They also talk about the use of commercially-prepared heparin flush products that run batch assays to assure correct heparin concentrations. Perhaps most significantly, they note there was a conference of key stakeholders last week expected to produce wide-ranging recommendations. Stay tuned.
We’ll be commenting in future columns on some of the recommendations in the new ACCP guidelines. In the meantime, the executive summary of the guidelines is available on the ACCP website.
ACCP. Antithrombotic and Thrombolytic Therapy, 8th Ed: ACCP Guidelines
Chest 2008; 133(6) suppl June, 2008 http://www.chestjournal.org/content/vol133/6_suppl/
Hirsh J, Gordon Guyatt G, Albers GW, Harrington R, Schünemann HJ. Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest Jun 2008: 71S–109S. DOI 10.1378/chest.08-0693
Hallevi H, Albright KC, Martin-Schild S, Barreto AD, Savitz SI, Escobar MA, Gonzales NR, Noser EA, Illoh K, Grotta JC. Anticoagulation After Cardioembolic Stroke.To Bridge or Not to Bridge? Arch Neurol. 2008; 65(9):(doi:10.1001/archneur.65.9.noc70105) http://archneur.ama-assn.org/cgi/content/full/65.9.noc70105
Camporese G, Bernardi E, Prandoni P, Noventa F, Verlato F, Simioni P, Ntita K, Salmistraro G, Frangos C, Rossi F, Cordova R, Franz F, Zucchetta P, Kontothanassis D, Andreozzi GM for the KANT (Knee Arthroscopy Nadroparin Thromboprophylaxis) Study Group. Low-Molecular-Weight Heparin versus Compression Stockings for Thromboprophylaxis after Knee Arthroscopy. A Randomized Trial. Annals of Internal Medicine 2008; 149(2): 73-82 http://www.annals.org/cgi/content/abstract/149/2/73
Institute for Safe Medication Practices. Heparin errors continue despite prior, high-profile, fatal events. ISMP Newsletter July 17, 2008