© 2008 American Thoracic Society
XPRESS Study: Heparin In ... Not OutTo the Editor:We read with interest the article by Dr. Levi and colleagues, which reported results of the XPRESS study, favoring the superiority of subcutaneous heparin in patients with sepsis (1). In fact, the results shown in Levi and coworkers' Figure 2 are statistically significant at 90% confidence intervals (CI) as the authors have depicted, but do not reach equivalence at 6.2%, and are statistically insignificant at 95% CI. The absolute risk difference of mortality between heparin and drotrecogin alpha is 3.6% (90% confidence intervals [CI], 0.2–7.1) favoring heparin, with a number-needed-to-treat (NNT) to prevent one death with heparin being 28 (90% CI, 15–485). Not only a greater percentage of patients receiving placebo died of non–sepsis-related causes compared with patients receiving heparin (19.4 and 12.2%, respectively), but also the thrombotic events (ischemic stroke and venous thrombotic events) were lower in the heparin arm (61/976 heparin vs. 84/959 placebo; NNT 40 [95% CI, 21–611]). Finally, most important is the fact that patients who were already on baseline heparin had lower mortality compared with patients on placebo, in whom heparin was withdrawn (26.9% heparin vs. 35.6% placebo). This is likely to be the situation in most intensive care units, where patients receive heparin for venous thromboembolism (VTE) prophylaxis as a protocol. There are probably other reasons why heparin did not attain statistical significance. The dose of heparin used was lower than that used in patients with sepsis (5,000 IU sc t.i.d.) (2, 3). Moreover, 85% of the patients had hypotension, in which case the subcutaneous route is less desirable due to poor absorption (4). This might have decreased the efficacy of heparin because of poor bioavailability. Also, t.i.d. is superior to b.i.d. heparin for preventing VTE in hospitalized medical patients (5). In fact, to overcome all these limitations, an ongoing study is using a dose of heparin at 500 IU per hour intravenously versus placebo to study the effects of heparin in sepsis (6). Low molecular weight heparin (LMWH) is probably more effective than unfractionated heparin (UFH) in reducing the risk of VTE (7). One important reason for this is the better bioavailability of LMWH compared with UFH. A trend toward better outcomes was seen with LMWH in the XPRESS study also (130/477 vs. 145/495; absolute risk reduction [ARR], 2.03% [95% CI, –3.6 to 7.7%]). The XPRESS study has only reconfirmed that "heparin is in ... not out" in patients with sepsis. Further studies with a trial design using intravenous UFH or subcutaneous LMWH at more than usual doses used for VTE prophylaxis should be undertaken. The trials should test heparin against placebo or even activated protein C, and should use 28-day mortality as the primary endpoint.
Postgraduate Institute of Medical Education and Research FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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