CRD summary

This review assessed the effects of replacing heparin with new anticoagulants in patients with heparin-induced thrombocytopenia. The authors' conclusions appear to be that lepirudin and argatroban are effective anticoagulants, but the evidence was limited and further research is required. The authors correctly acknowledged the limitations of evidence from the included observational studies.

Authors' objectives

To assess the effects of replacing heparin with new anticoagulants in patients with heparin-induced thrombocytopenia (HIT).

Searching

MEDLINE (via PubMed), OLDMEDLINE, LocatorPlus, MedlinePlus, DIRLINE, AIDS Meetings, Health Service Research Meetings, Space Life Science Meetings and HSRProj, all via the Gateway search engine, and EMBASE were searched for studies published in English; the search terms were stated. Reference lists in reviews published back to 2000 were also checked.

Study selection

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. The extracted data included the proportion of events in the treatment and control groups, relative risk reductions (RRRs) and 95% confidence intervals.

Methods of synthesis

Results of the review

Nine studies were included: five prospective observational studies (4 used historical controls), two retrospective chart reviews, one report pooling two studies already mentioned, and one report pooling data from three prospective observational studies. The number of patients is reported in the 'Results' section below.

Thrombosis in patients with HIT when heparin was discontinued.

The prospective study found high rates of thrombosis in hip-surgery patients with HIT: 89% (8 of 9) patients with HIT had thrombosis versus 18% (117 of 656) without HIT. Three further studies (retrospective chart reviews and prospective cohort with historical controls, n=314) found the risk for thrombosis after days or weeks in patients presenting with isolated HIT after stopping heparin ranged from 19 to 52%.

HIT.

Two prospective studies compared HIT patients treated with argatroban with the same pool of historical controls. One study found that HIT patients treated with argatroban (n=160) had a reduction in the combined outcome of death, amputation and new thromboembolic events compared with the 147 controls (25.6% versus 38.8%; RRR 0.34). The other study found similar results for the combined outcome among 189 patients treated with argatroban versus 139 controls (28.0% versus 38.9%; RRR 0.28).

HITTS.

The same two prospective studies (as above) found that HITTS patients treated with argatroban (n=144 and n=229) had a reduction in the combined outcome of death, amputation and new thromboembolic events compared with the 46 controls (43.8% and 41.5% versus 56.5%; RRR 0.23 and RRR 0.27, respectively).

One report of a subgroup analysis from two prospective observational studies described the effect of lepirudin treatment in patients with clinical HIT or HITTS, with HIT-IgG in their plasma, compared with historical controls. The study found that patients treated with lepiriudin (n=113) had a reduction in the combined outcome of death, amputation and new thromboembolic events compared with the 75 controls (22.1% versus 47.8%; RRR 0.53).

HIT or HITTS.

Argatroban (same two prospective studies as above): the prospective cohorts had a higher proportion of patients with HITTS than the historical control (47% and 55% versus 24/25%). Studies found that HIT or HITTS patients treated with argatroban (n=304 and n=418) had a reduction in the combined outcome of death, amputation and new thromboembolic events compared with the controls (n=193 and n=185) (34.2% and 35.4% versus 43.0%; RRR 0.20 and RRR 0.18, respectively).

Lepirudin (same two prospective studies as above with same controls used for both studies): the studies found that patients treated with lepirudin (n=71 and n=95) had a reduction in the combined outcome compared with 120 controls (25.4% and 30.5% versus 52.5%; RRR 0.52 and RRR 0.42, respectively).

Patients with a history of HIT requiring anticoagulation for coronary revascularisation.

One report combined three prospective studies with 91 patients undergoing 112 procedures. The combined outcome (death, MI, or revascularisation at 24 hours or hospital discharge) was found in 7.7% of cases (no deaths, 4 MI and 4 revascularisations). Major bleeding occurred in 1.1%.

Bleeding.

Two observational studies found major bleeding rates of 6.9% and 5.7% with argatroban versus 6.7% and 7.0%, respectively, with controls (RRR -2.56 and RRR 18.2, respectively).

Two observational studies found major bleeding rates of 13.4% and 17.0% with lepirudin.

Authors' conclusions

The authors' conclusion appears to be that lepirudin and argatroban are effective anticoagulants, but the evidence was based on studies with a weak design. Further research is required.

CRD commentary

The review addressed a clear question in terms of the participants, intervention and study design. The inclusion criteria for the outcomes were not explicitly defined. Several electronic sources were searched and the search terms were stated, but no attempts to minimise language bias were made. Two reviewers independently selected studies, thus reducing the potential for bias and errors, but since the methods used to extract the data were not described, it is not known whether any efforts were made to reduce errors and bias. Validity was not formally assessed, although the authors highlighted some of the limitations of evidence from cohort and observational studies. The studies were appropriately combined in a narrative, but no clear conclusions were drawn. The authors acknowledged that the evidence of efficacy of drug treatment came from observational studies. The recommendation for further research is supported by the review's findings.

Implications of the review for practice and research

Practice: The authors stated that when patients are suspected of having HIT or HITTS, heparin should be stopped and replaced with an effective anticoagulant that did not cross-react with HIT-IgG. They recommended that argatroban be used for patients with renal impairment, while lepirudin be used for patients with hepatic impairment. Personal preferences should determine which agent is used in patients with normal renal and hepatic function.

Research: The authors stated that well-designed RCTs are required to assess the relative safety and efficacy of different thrombin inhibitors in patients with HIT and HITTS.

Funding

Heart and Stroke Foundation of Ontario; GlaxoSmithKline.

Bibliographic details

Hirsh J, Heddle N, Kelton J G. Treatment of heparin-induced thrombocytopenia: a critical review. Archives of Internal Medicine 2004; 164(4): 361-369. [PubMed: 14980986]

Original Paper URL

http://archinte.ama-assn.org

Indexing Status

Subject indexing assigned by NLM

MeSH

Anticoagulants /adverse effects /therapeutic use; Heparin /adverse effects; Hirudins /analogs & derivatives; Humans; Pipecolic Acids /therapeutic use; Recombinant Proteins /therapeutic use; Risk Assessment; Thrombocytopenia /chemically induced /drug therapy; Thrombosis /etiology

AccessionNumber

12004008178

Database entry date

31/10/2005

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.