Therapeutics
4F-PCC was noninferior to plasma in patients with acute major bleeding who needed urgent VKA reversal
Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasmacontrolled, phase IIIb study. Circulation. 2013;128:1234-43.
Clinical impact ratings: E ★★★★★★✩ C ★★★★★★✩ H ★★★★★★★★ Question
Main results
In patients with acute major bleeding who need urgent vitamin K antagonist (VKA) reversal, what is the relative efficacy of 4-factor prothrombin complex concentrate (4F-PCC) and plasma?
4F-PCC was noninferior to plasma for effective hemostasis and rapid INR reduction and was superior to plasma for rapid INR reduction (Table).
Methods
Conclusion
Design: Randomized controlled trial. ClinicalTrials.gov NCT00708435.
In patients with acute major bleeding who needed urgent vitamin K antagonist reversal, 4-factor prothrombin complex concentrate was noninferior to plasma for achieving hemostasis and rapid reduction of the international normalized ratio.
Allocation: Unclear allocation concealment.* Blinding: Blinded* (assessors of hemostatic outcomes and serious adverse events of interest to the Data Safety Monitoring Board).
*See Glossary.
Follow-up period: 24 hours from start of treatment.
Source of funding: CSL Behring.
Setting: 36 clinical centers in the USA and Europe.
For correspondence: Dr. R. Sarode, University of Texas Southwestern Medical Center, Dallas, Texas, USA. E-mail ravi.sarode@ utsouthwestern.edu. ■
Patients: 216 adults ≥ 18 years of age (mean age 70 y, 50% women) who had an acute major bleeding event, were receiving VKA treatment, and had an international normalized ratio (INR) ≥ 2.0 within 3 hours before study treatment. Exclusion criteria included expected surgery in < 1 day; intracranial hemorrhage; acute trauma for which VKA reversal would not be sufficient to control bleeding; use of heparin within 24 hours; history of thrombotic events, cardiovascular disease, or other prothrombotic condition; sepsis; receipt of plasma product or platelets within 2 weeks; large blood vessel rupture; or inhibitors to factors II, VII, IX, or X. Intervention: 4F-PCC, 25 IU/kg to 50 IU/kg of factor IX based on baseline INR, infused intravenously in 1 dose with a maximum rate of 3 IU/kg/min to a maximum of 5000 IU (n = 107); or plasma, 10 mL/kg to 15 mL/kg based on baseline INR, infused intravenously at a rate of 1 U/30 min to a maximum of 1500 mL (n = 109). Outcomes: Hemostatic efficacy within 24 hours of starting treatment and rapid INR reduction at 30 minutes after the end of infusion. Hemostatic efficacy was rated as excellent, good, or poor/none. Both excellent and good ratings were considered effective hemostasis. Noninferiority of 4F-PCC for both efficacy outcomes was demonstrated if the lower limit of the 95% CI for the between-group differences was > −10%. Patient follow-up: 81% (intention-to-treat analysis). 4-factor prothrombin complex concentrate (4F-PCC) vs plasma in patients with acute major bleeding who needed urgent vitamin K antagonist reversal† Outcomes
Event rates 4F-PCC Plasma
Effective hemostasis within 24 h of starting treatment
72%
Rapid INR reduction within 30 min of ending treatment
62%
65% 9.6%
RBI (95% CI)
NNT (CI)
11% (−8 to 34)‡
Not significant
547% (262 to 1094)‡
Commentary Acute care physicians now have 3 alternatives to plasma for patients with VKA-associated bleeding: nonactivated PCC, which is available as 3-factor (2, 9, 10) or 4-factor (2, 7, 9, 10) formulations, and activated PCC or factor VIII inhibitor bypassing activity, which has been used for hemophilia management. These agents all have theoretical benefits and distinguish themselves over plasma by virtue of smaller infusion volumes, reduced risk for infection and lung injury, and more rapid administration; however, they are more expensive. The trial by Sarode and colleagues is welcome, as evidence to support the use of 4F-PCC in VKA-associated bleeding was sparse. The trial was limited, however, by its risk for bias due to lack of blinding of study staff and suboptimal follow-up. Although it was underpowered to detect differences in such adverse events as death and thromboembolism, issues related to the complications of volume overload were common in the plasma group (13% vs 5% in the 4F-PCC group). The high rate of adverse events in both groups suggests a need for caution with both treatments. With shelf-based storage and no need for refrigeration, PCC products offer practical advantages for timely administration for the most unstable patients with bleeding. The finding of noninferiority suggests that a selective approach is best. As a result, plasma is appropriate for managing bleeding in patients who are not at risk for heart failure or shock lung (i.e., massive transfusion patients) or who have liver insufficiency, whereas PCCs are more appropriate when rapid administration and smaller volumes are preferred. Validated risk stratification tools for gastrointestinal bleeding should define the need for rapid reversal in that population (1).
2 (2 to 3)
†INR = international normalized ratio; other abbreviations defined in Glossary. RBI, NNT, and CI calculated from event rates in article.
Eddy Lang, MD University of Calgary Calgary, Alberta, Canada Reference 1. de Groot NL, Bosman JH, Siersema PD, van Oijen MG. Prediction scores in gastrointestinal bleeding: a systematic review and quantitative appraisal. Endoscopy. 2012;44:731-9.
‡Difference met the criterion for noninferiority (lower limit of the 95% CI for between-group difference > −10%).
© 2014 American College of Physicians JC6 Downloaded From: http://annals.org/ by a University of South Dakota User on 11/19/2014
15 April 2014 | ACP Journal Club | Volume 160 • Number 8
4F-PCC was noninferior to plasma in patients with acute major bleeding who needed urgent VKA reversal
Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasmacontrolled, phase IIIb study. Circulation. 2013;128:1234-43.
Clinical impact ratings: E ★★★★★★✩ C ★★★★★★✩ H ★★★★★★★★ Question
Main results
In patients with acute major bleeding who need urgent vitamin K antagonist (VKA) reversal, what is the relative efficacy of 4-factor prothrombin complex concentrate (4F-PCC) and plasma?
4F-PCC was noninferior to plasma for effective hemostasis and rapid INR reduction and was superior to plasma for rapid INR reduction (Table).
Methods
Conclusion
Design: Randomized controlled trial. ClinicalTrials.gov NCT00708435.
In patients with acute major bleeding who needed urgent vitamin K antagonist reversal, 4-factor prothrombin complex concentrate was noninferior to plasma for achieving hemostasis and rapid reduction of the international normalized ratio.
Allocation: Unclear allocation concealment.* Blinding: Blinded* (assessors of hemostatic outcomes and serious adverse events of interest to the Data Safety Monitoring Board).
*See Glossary.
Follow-up period: 24 hours from start of treatment.
Source of funding: CSL Behring.
Setting: 36 clinical centers in the USA and Europe.
For correspondence: Dr. R. Sarode, University of Texas Southwestern Medical Center, Dallas, Texas, USA. E-mail ravi.sarode@ utsouthwestern.edu. ■
Patients: 216 adults ≥ 18 years of age (mean age 70 y, 50% women) who had an acute major bleeding event, were receiving VKA treatment, and had an international normalized ratio (INR) ≥ 2.0 within 3 hours before study treatment. Exclusion criteria included expected surgery in < 1 day; intracranial hemorrhage; acute trauma for which VKA reversal would not be sufficient to control bleeding; use of heparin within 24 hours; history of thrombotic events, cardiovascular disease, or other prothrombotic condition; sepsis; receipt of plasma product or platelets within 2 weeks; large blood vessel rupture; or inhibitors to factors II, VII, IX, or X. Intervention: 4F-PCC, 25 IU/kg to 50 IU/kg of factor IX based on baseline INR, infused intravenously in 1 dose with a maximum rate of 3 IU/kg/min to a maximum of 5000 IU (n = 107); or plasma, 10 mL/kg to 15 mL/kg based on baseline INR, infused intravenously at a rate of 1 U/30 min to a maximum of 1500 mL (n = 109). Outcomes: Hemostatic efficacy within 24 hours of starting treatment and rapid INR reduction at 30 minutes after the end of infusion. Hemostatic efficacy was rated as excellent, good, or poor/none. Both excellent and good ratings were considered effective hemostasis. Noninferiority of 4F-PCC for both efficacy outcomes was demonstrated if the lower limit of the 95% CI for the between-group differences was > −10%. Patient follow-up: 81% (intention-to-treat analysis). 4-factor prothrombin complex concentrate (4F-PCC) vs plasma in patients with acute major bleeding who needed urgent vitamin K antagonist reversal† Outcomes
Event rates 4F-PCC Plasma
Effective hemostasis within 24 h of starting treatment
72%
Rapid INR reduction within 30 min of ending treatment
62%
65% 9.6%
RBI (95% CI)
NNT (CI)
11% (−8 to 34)‡
Not significant
547% (262 to 1094)‡
Commentary Acute care physicians now have 3 alternatives to plasma for patients with VKA-associated bleeding: nonactivated PCC, which is available as 3-factor (2, 9, 10) or 4-factor (2, 7, 9, 10) formulations, and activated PCC or factor VIII inhibitor bypassing activity, which has been used for hemophilia management. These agents all have theoretical benefits and distinguish themselves over plasma by virtue of smaller infusion volumes, reduced risk for infection and lung injury, and more rapid administration; however, they are more expensive. The trial by Sarode and colleagues is welcome, as evidence to support the use of 4F-PCC in VKA-associated bleeding was sparse. The trial was limited, however, by its risk for bias due to lack of blinding of study staff and suboptimal follow-up. Although it was underpowered to detect differences in such adverse events as death and thromboembolism, issues related to the complications of volume overload were common in the plasma group (13% vs 5% in the 4F-PCC group). The high rate of adverse events in both groups suggests a need for caution with both treatments. With shelf-based storage and no need for refrigeration, PCC products offer practical advantages for timely administration for the most unstable patients with bleeding. The finding of noninferiority suggests that a selective approach is best. As a result, plasma is appropriate for managing bleeding in patients who are not at risk for heart failure or shock lung (i.e., massive transfusion patients) or who have liver insufficiency, whereas PCCs are more appropriate when rapid administration and smaller volumes are preferred. Validated risk stratification tools for gastrointestinal bleeding should define the need for rapid reversal in that population (1).
2 (2 to 3)
†INR = international normalized ratio; other abbreviations defined in Glossary. RBI, NNT, and CI calculated from event rates in article.
Eddy Lang, MD University of Calgary Calgary, Alberta, Canada Reference 1. de Groot NL, Bosman JH, Siersema PD, van Oijen MG. Prediction scores in gastrointestinal bleeding: a systematic review and quantitative appraisal. Endoscopy. 2012;44:731-9.
‡Difference met the criterion for noninferiority (lower limit of the 95% CI for between-group difference > −10%).
© 2014 American College of Physicians JC6 Downloaded From: http://annals.org/ by a University of South Dakota User on 11/19/2014
15 April 2014 | ACP Journal Club | Volume 160 • Number 8
