Letters: Is Heparin Therapy Outmoded?

July / August 2009

Letters

Is Heparin Therapy Outmoded?

To the Editor:
Dager et al. offer expert, useful, and pertinent advice regarding safe use of heparin (“Heaparin: Improving Treatment and Reducing Risk of Harm,” Jan/Feb 2009). They miss the salient opportunity to make an even stronger case: heparin is outmoded therapy, and should be replaced by use of low- and ultra-low molecular heparins (LMWHs), except perhaps in certain circumstances. LMWHs have been used for more than 20 years in Europe and have been approved for use in the United States since the early 1990s. Indeed, at the American College of Physicians meeting in 1997 in Philadelphia, I recall hearing Dr. Russell Hull state that heparin, even at that time, was outdated therapy. There may be a role for heparin in patients on dialysis or those needing anticoagulation therapy who are at very high risk of bleeding and in whom the clinician wishes to measure and adjust therapy frequently based on aPTT values (and when anti-activated factor X levels are not available). In all other circumstances, use of LMWH has been shown repeatedly to be safer, much more likely to achieve therapeutic efficacy within 24 hours (which is mandatory for reducing late recurrences), easier to use, available for outpatient use when appropriate, and in the long run less expensive than IV heparin. The best way to reduce risk of harm from heparin is to eliminate its use whenever possible.

In the very near future we hope to see novel, oral, rapidly acting, highly effective anticoagulants that will revolutionize the prevention and treatment of venous thromboembolic disease. I would like to see a PSQH article on these modalities, with an emphasis on changing therapy away from heparin, and toward the use of LMWHs until these new products become available. In the meantime, I agree that ways to reduce harm from heparin therapy have been known for nearly 20 years, but it would be better to eliminate use of an outdated, difficult to use, and unpredictable medication such as heparin. Better ways to treat our patients are available now, and even better treatments are on the horizon.

The Author Responds
Having the safest and most effective anticoagulant available for a patient’s individualized needs is a continuous challenge for clinicians. When the low-molecular weight heparins (LMWH) emerged onto the market, many researchers and experts suggested that unfractionated heparin and warfarin may become agents of the past (Bussey et al., 2004).

Insights from clinical trials and experiences including our own have explored the advantages of newer agents in situations such as treatment of thromboembolism in cancer, initiation of parenteral anticoagulation for venous thormboembolism in the home, and other related bridge therapies (Dager et al., 2005). Consider, however, situations in clinical trials where patients are excluded, yet in practice continue to require systemic anticoagulation. Unfortunately, as Dr, Schreiber recognized, available anticoagulants are not ideal for many situations where short acting, reversible, and adjustable agents such as heparin continue to be a preferable choice. Such situations include hemodialysis (acknowledging that LMWH data exists, but the dose remains unclear), critically ill, extracorporeal membranous oxygenation, concurrent major bleeding with thrombosis, surgical procedures, and so on. Just recently the use of heparin as a adjunctive therapy in septic shock was explored, demonstrating that newer uses for unfractionated heparin may continue to evolve (Jaimes et al., 2009). Because unfractionated heparin is monitored with the aPTT, ACT or anti-Xa activity, situations such as heparin resistance from low antithrombin levels in selected populations may be detected that may go unrecognized with LMWH. One could argue for anti-Xa testing when using a LMWH in special populations, but there exists the potential to miss a low antithrombin level that may occur in critically ill patients that may not be noted if the assay adds AT to reduce variability.  Data on the optimal anti-Xa values and approaches to dosing adjustments based on an anti-Xa activity result are also limited and potentially flawed.

Dr. Schreiber mentions several advantages to LMWH, but when looking at meta-analysis of the clinical trials, we see non-inferiority, and very little proven superiority (Dolovitch et al., 2000). Given this, many clinicians will most likely choose therapies based on the agents available and individualized needs of the patient. In many situations, this may be a newer anticoagulant, but in others, unfractionated heparin. Despite all the years of experience with warfarin and unfractionated heparin as well as newer anticoagulants, our understanding on how to use them continues to expand.

Newer anticoagulants in many situations could replace current used agents, however, when used incorrectly, may not achieve desired outcomes. The dose in atrial fibrillation may be different than in the initial approved indication of VTE prophylaxis following orthopedic surgery. Dosing adjustments in special situations including obesity, renal failure, concurrent drug interactions, and the ability to rapidly reverse, may be limitations to their global use.

Keys to successful anticoagulation will continue to include the best agent that is dosed and monitored correctly. To accomplish this, a multidisciplinary approach with clinicians who understand the clinical situation being managed, and how to optimize related therapies may be necessary. Our aim was to explore issues and provide insights relative to unfractionated heparin as it is a focus of The Joint Commission National Patient Safety Goals, and continues to be an agent frequently used in the inpatient setting. Future articles focusing on other therapies should be encouraged, but need to carefully balance the advantages of the agents while exploring and discussing challenges associated with their use. The greater the understanding of any anticoagulant therapies, the more successful patient care can be.

William Dager, Pharm.D., BCPS, FCSHP, FCCP, FCCM
Pharmacist Specialist,
UC Davis Medical Center

Clinical Professor of Pharmacy,
UC San Francisco School of Pharmacy

Clinical Professor of Medicine,
UC Davis School of Medicine

Professor of Pharmacy Practice,
Touro School of Pharmacy

References
Bussey, H., Francis, J. L., & The Heparin Consensus Group. (2004). Heparin overview and issues. Pharmacotherapy, 24(8 Pt 2), 103S-107S.

Dager, W. E., King, J. H., Chow, S., Ferrer, R., Pak, S., Togioke, P., et al. (2005). Outpatient Tinzaparin in patients with pulmonary embolism or deep vein thrombosis. The Annals of Pharmacotherapy, 39, 1182-87.

Dolovich, L. R., Ginsberg, J. S., Douketis, J. D., Holbrook, A. M., & Cheah, G. (2000). A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: Examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Archives of Internal Medicine, 160, 181-188.

Jaimes, F., De La Rosa, G., Morales, C., Fortich, F., Arango, C., Aguirre, D., Muñoz, A. (2009). Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Critical Care Medicine, 37, 1185-1196.