BACKGROUND: In the United States, venous leg ulcers (VLUs) are commonly associated with substantial disability, impaired quality of life, and high economic costs. Compression therapy, which has remained the standard care for VLUs over several decades, is often insufficient to heal VLUs in a timely manner. VLU-related treatment costs are directly related to time to achieve complete wound closure. Advanced wound care matrices (AWCMs) developed to stimulate wound healing may reduce VLU-related costs associated with delayed healing. Randomized controlled trials (RCTs) have evaluated the wound-healing efficacy of several AWCMs in patients with VLUs. However, comparisons of products' clinical and cost efficacy, which may guide clinical and formulary determinations, are lacking. OBJECTIVE: To evaluate, in terms of number needed to treat (NNT), the comparative clinical and cost efficacy of targeted AWCMs as adjuncts to compression therapy for the treatment of chronic VLUs from the U.S. health care system (payer) perspective. METHODS: A review of published articles (from the earliest available Medline publication date to June 1, 2011) identified RCTs evaluating complete wound closure rates for up to 24 weeks in patients with VLUs treated with targeted AWCMs (Apligraf, Oasis, or Talymed) plus compression therapy compared with compression therapy alone. The most favorable estimates of product efficacy (i.e., those that were statistically significant compared with compression therapy) were used. These included statistically adjusted results for Apligraf as reported in the product insert and the biweekly application for Talymed. Based on the reported efficacy of targeted AWCMs, we calculated the NNT to achieve 1 additional treatment success (i.e., complete wound closure) over that which was achieved with standard therapy alone; 95% CIs were estimated using the Wilson score method proposed by Newcombe. Cost efficacy, defined as the incremental cost per additional successfully treated patient, was then calculated by multiplying the NNT associated with each treatment by the product acquisition cost per treated VLU episode. RESULTS: One study for each of 3 targeted AWCMs (Apligraf [n=130 treatment, n=110 control]; Oasis Wound Matrix [n=62 treatment, n=58 control]; and Talymed [n=22 treatment, n=20 control]) met inclusion criteria. Study designs and wound characteristics varied. Average VLU sizes were 1 cm2, 10-12 cm2, and 10-13 cm2 in the studies of Apligraf, Oasis, and Talymed, respectively. Ulcer duration exceeded 12 months for 50% of patients in the Apligraf study and was at least 7 months for 47% of patients in the Oasis study; patients with ulcers exceeding 6 months were excluded from the study of Talymed. Length of follow-up was 24 weeks for Apligraf, 12 weeks for Oasis, and 20 weeks for Talymed. NNT point estimates of clinical efficacy were 2 for Talymed, 5 for Oasis, and 6 for Apligraf; 95% CIs ranged from 2 to 8 for Talymed, 3 to 24 for Apligraf, and 3 to 39 for Oasis. Incremental costs (95% CIs) per additional successfully treated patient were $1,600 ($1,600-$6,400) for Talymed, $3,150 ($1,890-$24,570) for Oasis, and $29,952 ($14,976-$119,808) for Apligraf. CONCLUSIONS: The most expensive AWCM for the treatment of VLUs did not appear to provide the greatest comparative clinical or cost efficacy. Conclusions must be tempered by the small number of available studies (n=3), variability in trial duration (from 12 to 24 weeks) and baseline wound characteristics, and limitations in study quality. Given the high prevalence, economic burden, and substantial disability of VLUs, and the wide variation in costs for AWCMs, payers need more high-quality head-to-head comparisons to guide coverage and reimbursement determinations for these products.