Letters to the Editor
621
Risk factors for suboptimal efficacy of 3-factor prothrombin complex concentrates in emergency VKA anticoagulation reversal Francesco Dentali1; Davide Imberti2; Eleonora Tamburini Permunian1; Ezio Croci3; Walter Ageno1 1Department
of Clinical Medicine Insubria University, Varese, Italy; 2Haemostasis and Thrombosis Center, Department of Internal Medicine, Piacenza Hospital, Piacenza, Italy; 3Clinical Pathology, Piacenza Hospital, Piacenza, Italy
Dear Sirs, Vitamin K antagonists (VKAs) are an effective and commonly used treatment for the long-term primary and secondary prevention of arterial and venous thromboembolism. (1). Patients on VKAs are at increased risk of bleeding, with the incidence of major bleeding events ranging from 1 to 3 %. Major bleeding, which is commonly gastrointestinal (30–60 %), but also intracranial (17–30 %) can be life-threatening (2, 3). It is estimated that 3% to 7% per year of VKA-treated patients require rapid reversal of the anticoagulant effect because of major bleeding or because they need urgent surgery or other invasive procedures (4). Due to its more rapid effect in reversing warfarin-related coagulopathy compared to fresh frozen plasma, and to its smallvolume of preparation, recent systematic reviews and international guidelines support the use of prothrombin complex concentrates (PCCs) as the treatment of choice for the reversal of the anticoagulant effect of VKAs (1, 5). All PCCs contain vitamin K-dependent coagulation factors II, IX, X in a concentrated form and in a well standardised amount, and a variable content of factor VII (6). Although the administration of PCCs with significant factor VII content does not seem to be essential or any more
Correspondence to: Francesco Dentali U.O. Medicina I, Ospedale di Circolo Viale Borri 57, 21100 Varese, Italy Fax: +39 0332 393640 E-mail: [email protected] Received: October 15, 2013 Accepted after major revision: April 23, 2014 Epub ahead of print: June 26, 2014 http://dx.doi.org/10.1160/TH13-10-0851 Thromb Haemost 2014; 112: 621–623
© Schattauer 2014
effective than PCCs with low (or no) factor VII activity to reverse warfarin-induced bleeding complications (7), a few studies have suggested that 3-factor PCCs may have a suboptimal efficacy in correcting the INR in some patients (8, 9). However, there is little information regarding potential factors influencing the efficacy of 3-factor PCCs in achieving adequate INR reversal in anticoagulated patients. Therefore, we performed a retrospective cohort study to investigate potential risk factors for suboptimal efficacy of 3-factor PCCs in the emergency reversal of anticoagulation with vitamin K antagonists in patients with major bleeding. Adult patients treated with VKAs with an index INR > 2 who required an immediate reversal of anticoagulation for a major bleeding complication between 2007 and 2012 treated at two university hospitals in Italy (Piacenza, Varese) were potentially eligible for the study. Patients were included in this study only if an international normalised ratio (INR) value measured within 30 minutes (min) from the infusion of PCCs was available. Exclusion criteria were concomitant acute ischaemic cardiovascular disorder, disseminated intravascular coagulation, sepsis, pregnancy, breast feeding and mental retardation. Patients were consecutively recruited from the cohort of patients treated with VKAs presenting at participating centres with a major bleeding event. A sample of patients included in this study have been already published in two previous prospective studies (10, 11). All included patients received 35–50 IU kg –1 body weight of 3-factor PCCs (Uman complex, Protromplex ®) . PCCs were administered within 6 hours from major bleeding diagnosis at different doses depending on baseline INR levels: 35–39 IU
kg –1 , 40– 45 IU kg –1 or 46–50 IU kg –1 body weight doses were infused to patients with baseline INRs of 2.0–3.9, 4.0–6.0 or > 6.0, respectively. Local treatment protocols required that prior to PCCs infusion patients should have also received intravenous infusion of 10 mg of vitamin K. The following data were collected for each patient: age, gender, indication for anticoagulation, type of VKA used (warfarin or acenocumarol), INR at the admission and after PCCs infusion, use of intravenous vitamin K, major bleeding site (intracranial, gastrointestinal, other), cause of bleeding (traumatic or non traumatic bleedings including mild, moderate and severe injuries ) and death rate. Continuous variables were expressed as mean ± the standard deviation (SD); categorical data are given as counts and percentages. Characteristics of patients who had an adequate INR reversal (INR ≤1.5) and inadequate reversal were compared using Student's t-test (for continuous variables) and the Chi2- or Fischer's exact test (for dichotomous variables). Only variables found significant in the univariate analysis were used as covariates in the multivariate analysis. The present study was approved by local Institutional Review Boards and patient information was codified to ensure anonymity. Of the 190 potentially includible patients, 17 did not have an INR tested within 30 min from the infusion of PCCs (4 died soon after the infusion) and were excluded from the study. Thus, 173 patients (mean age 77.4 years, range 34-97 years, 100 males) were included in the study. Baseline characteristics of included and excluded patients were not statistically different (data not shown). Main indication for anticoagulation and other baseline characteristics are summarised in ▶ Table 1. Mean INR at the time of inclusion was 3.74 (range 2.01-12.80). After PCCs administration, the mean INR was reduced to 1.51 (range 0.94-3.96) and this reduction was highly significant (p< 0.001). One hundred sixty three patients (94.2%) had a post-infusion INR < 2.00 and 109 patients (63.0%) had a post-infusion INR < 1.5, and all the 95 patients (100%) with a pre-infusion INR 1.5). Our results confirm the efficacy of 3-factor PCCs in rapidly correcting INR values in patients treated with VKAs with a major bleeding complication. However, this study suggests that currently used regimens for 3-factor PCCs may result in a suboptimal efficacy in patients with elevated INR values at baseline. In these patients, either more aggressive dosing regimens or the use of 4-factor PCCs with higher factor VII content may be more effective. However, no study has thus far compared different dosing regimens of 3-factor PCCs nor has demonstrated a superior efficacy of 4-factor PCCs, which in turn may be associated with a higher risk
of thromboembolic complications (7). Our results also stress the importance of using intravenous vitamin K in addition to PCCs to obtain a complete reversal of VKAs effect. The rationale for the use of vitamin K is robust also because the half-life of VKAs far exceeds the half-life of PCCs and, thus, a rebound INR increase should be expected 12 to 24 h after PCCs administration in the absence of vitamin K. Vitamin K acts through the synthesis of vitamin K dependent coagulation factors which takes time to be replaced. In our study we measured INR after PCC infusion and Vitamin K was generally infused several minutes or more than 1 h before PCC infusion. Although in patients on VKA therapy, extracranial bleedings are more common, most of the patients included in our study had an intracranial bleeding. This is probably due to a more frequent PCC use in this population and results of multivariate analysis suggest a similar efficacy in different bleeding sites. Our study has some potential limitations. First, the retrospective design of the study limits inferences that can be drawn and increases the risk of bias. However, to minimise this risk, we paid meticulous attention in collecting data on patient characteristics and potential prognostic
factors and we have no missing values in our data collection. Second, the clinical significance of our findings remains questionable since the results of our study are solely based on a surrogate marker of efficacy, that is the reduction of INR levels. However, the association between INR levels and the risk of bleeding complications is well established and some studies suggest a correlation with mortality rate especially in patients with intracranial bleeding (12). Third, although frequently used as a marker of PCC efficacy a post-infusion INR target
621
Risk factors for suboptimal efficacy of 3-factor prothrombin complex concentrates in emergency VKA anticoagulation reversal Francesco Dentali1; Davide Imberti2; Eleonora Tamburini Permunian1; Ezio Croci3; Walter Ageno1 1Department
of Clinical Medicine Insubria University, Varese, Italy; 2Haemostasis and Thrombosis Center, Department of Internal Medicine, Piacenza Hospital, Piacenza, Italy; 3Clinical Pathology, Piacenza Hospital, Piacenza, Italy
Dear Sirs, Vitamin K antagonists (VKAs) are an effective and commonly used treatment for the long-term primary and secondary prevention of arterial and venous thromboembolism. (1). Patients on VKAs are at increased risk of bleeding, with the incidence of major bleeding events ranging from 1 to 3 %. Major bleeding, which is commonly gastrointestinal (30–60 %), but also intracranial (17–30 %) can be life-threatening (2, 3). It is estimated that 3% to 7% per year of VKA-treated patients require rapid reversal of the anticoagulant effect because of major bleeding or because they need urgent surgery or other invasive procedures (4). Due to its more rapid effect in reversing warfarin-related coagulopathy compared to fresh frozen plasma, and to its smallvolume of preparation, recent systematic reviews and international guidelines support the use of prothrombin complex concentrates (PCCs) as the treatment of choice for the reversal of the anticoagulant effect of VKAs (1, 5). All PCCs contain vitamin K-dependent coagulation factors II, IX, X in a concentrated form and in a well standardised amount, and a variable content of factor VII (6). Although the administration of PCCs with significant factor VII content does not seem to be essential or any more
Correspondence to: Francesco Dentali U.O. Medicina I, Ospedale di Circolo Viale Borri 57, 21100 Varese, Italy Fax: +39 0332 393640 E-mail: [email protected] Received: October 15, 2013 Accepted after major revision: April 23, 2014 Epub ahead of print: June 26, 2014 http://dx.doi.org/10.1160/TH13-10-0851 Thromb Haemost 2014; 112: 621–623
© Schattauer 2014
effective than PCCs with low (or no) factor VII activity to reverse warfarin-induced bleeding complications (7), a few studies have suggested that 3-factor PCCs may have a suboptimal efficacy in correcting the INR in some patients (8, 9). However, there is little information regarding potential factors influencing the efficacy of 3-factor PCCs in achieving adequate INR reversal in anticoagulated patients. Therefore, we performed a retrospective cohort study to investigate potential risk factors for suboptimal efficacy of 3-factor PCCs in the emergency reversal of anticoagulation with vitamin K antagonists in patients with major bleeding. Adult patients treated with VKAs with an index INR > 2 who required an immediate reversal of anticoagulation for a major bleeding complication between 2007 and 2012 treated at two university hospitals in Italy (Piacenza, Varese) were potentially eligible for the study. Patients were included in this study only if an international normalised ratio (INR) value measured within 30 minutes (min) from the infusion of PCCs was available. Exclusion criteria were concomitant acute ischaemic cardiovascular disorder, disseminated intravascular coagulation, sepsis, pregnancy, breast feeding and mental retardation. Patients were consecutively recruited from the cohort of patients treated with VKAs presenting at participating centres with a major bleeding event. A sample of patients included in this study have been already published in two previous prospective studies (10, 11). All included patients received 35–50 IU kg –1 body weight of 3-factor PCCs (Uman complex, Protromplex ®) . PCCs were administered within 6 hours from major bleeding diagnosis at different doses depending on baseline INR levels: 35–39 IU
kg –1 , 40– 45 IU kg –1 or 46–50 IU kg –1 body weight doses were infused to patients with baseline INRs of 2.0–3.9, 4.0–6.0 or > 6.0, respectively. Local treatment protocols required that prior to PCCs infusion patients should have also received intravenous infusion of 10 mg of vitamin K. The following data were collected for each patient: age, gender, indication for anticoagulation, type of VKA used (warfarin or acenocumarol), INR at the admission and after PCCs infusion, use of intravenous vitamin K, major bleeding site (intracranial, gastrointestinal, other), cause of bleeding (traumatic or non traumatic bleedings including mild, moderate and severe injuries ) and death rate. Continuous variables were expressed as mean ± the standard deviation (SD); categorical data are given as counts and percentages. Characteristics of patients who had an adequate INR reversal (INR ≤1.5) and inadequate reversal were compared using Student's t-test (for continuous variables) and the Chi2- or Fischer's exact test (for dichotomous variables). Only variables found significant in the univariate analysis were used as covariates in the multivariate analysis. The present study was approved by local Institutional Review Boards and patient information was codified to ensure anonymity. Of the 190 potentially includible patients, 17 did not have an INR tested within 30 min from the infusion of PCCs (4 died soon after the infusion) and were excluded from the study. Thus, 173 patients (mean age 77.4 years, range 34-97 years, 100 males) were included in the study. Baseline characteristics of included and excluded patients were not statistically different (data not shown). Main indication for anticoagulation and other baseline characteristics are summarised in ▶ Table 1. Mean INR at the time of inclusion was 3.74 (range 2.01-12.80). After PCCs administration, the mean INR was reduced to 1.51 (range 0.94-3.96) and this reduction was highly significant (p< 0.001). One hundred sixty three patients (94.2%) had a post-infusion INR < 2.00 and 109 patients (63.0%) had a post-infusion INR < 1.5, and all the 95 patients (100%) with a pre-infusion INR 1.5). Our results confirm the efficacy of 3-factor PCCs in rapidly correcting INR values in patients treated with VKAs with a major bleeding complication. However, this study suggests that currently used regimens for 3-factor PCCs may result in a suboptimal efficacy in patients with elevated INR values at baseline. In these patients, either more aggressive dosing regimens or the use of 4-factor PCCs with higher factor VII content may be more effective. However, no study has thus far compared different dosing regimens of 3-factor PCCs nor has demonstrated a superior efficacy of 4-factor PCCs, which in turn may be associated with a higher risk
of thromboembolic complications (7). Our results also stress the importance of using intravenous vitamin K in addition to PCCs to obtain a complete reversal of VKAs effect. The rationale for the use of vitamin K is robust also because the half-life of VKAs far exceeds the half-life of PCCs and, thus, a rebound INR increase should be expected 12 to 24 h after PCCs administration in the absence of vitamin K. Vitamin K acts through the synthesis of vitamin K dependent coagulation factors which takes time to be replaced. In our study we measured INR after PCC infusion and Vitamin K was generally infused several minutes or more than 1 h before PCC infusion. Although in patients on VKA therapy, extracranial bleedings are more common, most of the patients included in our study had an intracranial bleeding. This is probably due to a more frequent PCC use in this population and results of multivariate analysis suggest a similar efficacy in different bleeding sites. Our study has some potential limitations. First, the retrospective design of the study limits inferences that can be drawn and increases the risk of bias. However, to minimise this risk, we paid meticulous attention in collecting data on patient characteristics and potential prognostic
factors and we have no missing values in our data collection. Second, the clinical significance of our findings remains questionable since the results of our study are solely based on a surrogate marker of efficacy, that is the reduction of INR levels. However, the association between INR levels and the risk of bleeding complications is well established and some studies suggest a correlation with mortality rate especially in patients with intracranial bleeding (12). Third, although frequently used as a marker of PCC efficacy a post-infusion INR target
