Incidence of Thrombo-Embolic Events in Relation to Activated Prothrombin Complex Concentrate Exposure: A Literature Meta-Analysis

Introduction

The development of factor VIII (FVIII) inhibitory antibodies is one of the major challenges of the treatment of hemophilia, because it hinders FVIII replacement for the treatment and prevention of bleeding events (Leissinger 2015). Two products are currently available to control bleeding in patients with inhibitors: the activated prothrombin complex concentrate (aPCC; FVIII inhibitor bypassing activity, FEIBA VH; Shire plc, USA) and recombinant activated factor VII (rFVIIa; NovoSeven, Bagsvaerd, Denmark). Both agents have shown similar efficacy, with some patients responding better to one over the other (Astermark 2007). Both agents have been associated with the development of thromboembolic events (TEEs) (Aledort 2004). Aim of this study was to estimate TEE incidence in patients with congenital hemophilia with inhibitors and acquired hemophilia exposed to aPCC, by using a meta-analytic approach based on published scientific literature.

Methods

A systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The incidence rate of TEEs was estimated via a meta-analytic approach by using a Generalized Linear Mixed Model based on a Poisson distribution.

Stratified analyses according to study design (prospective vs. retrospective), hemophilia type (congenital vs. acquired) and treatment modality (on-demand, prophylaxis and surgery) have been conducted.

Results

We identified a total of 144 papers through the electronic literature search and out of the 61 fully evaluated articles, 39 studies with TEE data related to the use of aPCC in patients with congenital hemophilia with inhibitor or acquired hemophilia were included in the meta-analysis. The studies included were published from 1980 to 2016, providing information on safety related to 678,447 aPCC infusions (7,291 infusions as on-demand treatment, 77,203 in prophylaxis, 3,296 in surgery and 590,657 in unspecified treatment modalities).

In the 39 studies included overall, 46 TEEs were reported: 13 disseminated intravascular coagulation (DIC), 11 ischemic coronary syndrome (ICS), 4 pulmonary embolism (PE), 3 thrombotic cerebrovascular accidents (CVA), 3 deep vein thrombosis (DVT), 3 superficial vein thrombosis (SVT), 6 unspecified thrombosis (unreported location) and 3 fibrinogen reduction. No thrombotic microangiopathic events have ever been reported. Out of the 39 studies included, 31 (79%) reported no TEEs.

The estimated pooled TEE incidence rate was 2.87 (95% CI 0.32-25.40) per 100,000 aPCC infusions. When stratifying for retrospective and prospective studies, 35 TEEs in 649,343 aPCC infusions (pooled incidence rate, 5.42 per 100,000 infusions), and 11 TEEs in 29,104 infusions (pooled incidence rate, 1.09 per 100,000 infusions) were respectively reported. TEE incidence rate in patients treated with aPCC on-demand was 5.09 per 100,000 infusions, while in patients treated with prophylaxis, no TEEs were reported. Five TEEs were reported in 11 studies in hemophilia patients with inhibitors undergoing surgery, being the pooled TEE incidence rate 112.03 per 100,000 aPCC infusions. Finally, pooled TEEs incidence rate in acquired hemophilia patients was 287.79 per 100,000 infusions, but less than 0.01 per 100,000 infusions in congenital hemophilia patients.

Conclusions

The pooled incidence rate was lower than 3 TEEs per 100,000 aPCC infusions, demonstrating a relatively low risk and confirming previous figures reported (Erlich 2002, Aledort 2004). Stratified analysis showed that the incidence is even lower in patients with congenital hemophilia and no TEE in prophylaxis. These findings provide robust evidence of safety of aPCC over almost 40 years of published studies.