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Suboptimal Monitoring and Dosing of Unfractionated Heparin in Comparative Studies with Low-Molecular-Weight Heparin

Robert Raschke, MD, MS; Jack Hirsh, MD, FCCP; and James R. Guidry, PharmD

6 May 2003 | Volume 138 Issue 9 | Pages 720-723

Background: Site-specific validation of the activated partial thromboplastin time (aPTT) therapeutic range is required to ensure administration of the optimal dose of unfractionated heparin. Therapeutic ranges of 1.5 to 2.5 times the control value are subtherapeutic for most modern aPTT reagents.

Purpose: To audit the appropriateness of aPTT monitoring in clinical trials comparing unfractionated heparin and low-molecular-weight heparin in patients with venous thromboembolism.

Data Sources: Search of PubMed database from 1984 to 2001.

Study Selection: Randomized, controlled trials that compared unfractionated and low-molecular-weight heparin for the treatment of venous thromboembolism.

Data Extraction: Use of unvalidated and potentially suboptimal therapeutic ranges for aPTT in patients assigned to receive unfractionated heparin.

Data Synthesis: Fifteen studies met inclusion criteria. Only 3 studies used a validated aPTT therapeutic range, and 11 studies used a range that included aPTT values 1.5 times the control value. Ten studies reported unfractionated heparin doses, and 7 of these documented a reduction to less than 30 000 U/d in response to aPTT results.

Conclusions: Most studies monitored unfractionated heparin inappropriately. This shortcoming could be responsible for the reduced efficacy of unfractionated heparin in clinical trials.

Editors' Notes Context Efficacy and safety of unfractionated heparin in thromboembolic disease depend on accurate measurement of the adjusted partial thromboplastin time (aPTT). Failure to standardize aPTT measurement may have led to wide variation in unfractionated heparin dosing in previous studies that showed superiority of low-molecular-weight heparin (LMWH) to unfractionated heparin. Contribution A survey of published randomized, controlled trials comparing LMWH with unfractionated heparin shows that few of the studies used validated aPTT therapeutic ranges or standardized protocols for adjusting unfractionated heparin dose. Implications While this study does not show that variations in aPTT measurement account for the apparent superiority of LMWH to unfractionated heparin, it highlights some serious methodologic concerns. –The Editors

 

Author and Article Information

From Good Samaritan Regional Medical Center, Phoenix, Arizona; Henderson Civic Hospital Research Center, Hamilton, Ontario, Canada; and Desert Samaritan Medical Center, Mesa, Arizona.

Potential Financial Conflicts of Interest:Honoraria: R. Raschke (Aventis).

Requests for Single Reprints: Robert Raschke, MD, MS, Good Samaritan Regional Medical Center, 1111 East McDowell Road, Phoenix, AZ 85006; e-mail, robertraschke{at}bannerhealth.com.

Current Author Addresses: Dr. Raschke: Good Samaritan Regional Medical Center, 1111 East McDowell Road, Phoenix, AZ 85006.

Dr. Hirsh: Henderson Civic Hospital Research Center, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

Mr. Guidry: Clinical Pharmacy, Desert Samaritan Medical Center, 1400 South Dobson Road, Mesa, AZ 85202.

Author Contributions: Conception and design: R. Raschke, J. Hirsh, J.R. Guidry.

Analysis and interpretation of the data: R. Raschke, J. Hirsh, J.R. Guidry.

Drafting of the article: R. Raschke, J.R. Guidry.

Critical revision of the article for important intellectual content: R. Raschke, J. Hirsh, J.R. Guidry.

Final approval of the article: R. Raschke, J. Hirsh, J.R. Guidry.

Provision of study materials or patients: R. Raschke, J.R. Guidry.

Statistical expertise: R. Raschke.

Administrative, technical, or logistic support: R. Raschke, J.R. Guidry.

Collection and assembly of data: R. Raschke, J.R. Guidry.

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