Is there evidence that fresh frozen plasma is superior to antithrombin administration to treat heparin resistance in cardiac surgery?

Abstract

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was, ‘in [patients with heparin resistance] is [treatment with FFP] superior [to antithrombin administration] in [achieving adequate anticoagulation to facilitate safe cardiopulmonary bypass]?’ More than 29 papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Antithrombin (AT) binds to heparin and increases the rate at which it binds to thrombin. The levels of antithrombin in the blood are an important aspect of the heparin dose–response curve. When the activated clotting time (ACT) fails to reach a target >480, this is commonly defined as heparin resistance (HR). Heparin resistance is usually treated with a combination of supplementary heparin, fresh frozen plasma (FFP) or antithrombin III concentrate. There is a paucity of evidence on the treatment of heparin resistance with FFP, with only five studies identified, including one retrospective study, one in vitro trial and three case reports. AT has been studied more extensively with multiple studies, including a crossover trial comparing AT to supplemental heparin and a multicentre, randomized, double blind, placebo-controlled trial. Antithrombin (AT) concentrate is a safe and efficient treatment for heparin resistance to elevate the activated clotting time (ACT). It avoids the risk of transfusion-related acute lung injury (TRALI), volume overload, intraoperative time delay and viral or vCJD transmission. Antithrombin concentrates are more expensive than fresh frozen plasma and may put patients at risk of heparin rebound in the early postoperative period. Patients treated with AT have a lower risk of further FFP transfusions during their stay in hospital. We conclude that the treatment of HR with FFP may not restore the ACT to therapeutic levels with adequate heparinization, but AT is efficient with benefits including lower volume administration, less risk of TRALI and lower risk of transfusion-related infections.

INTRODUCTION

A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1].

THREE-PART QUESTION

In [patients with heparin resistance] is [treatment with FFP] superior [to antithrombin administration] in [achieving adequate anticoagulation to facilitate safe cardiopulmonary bypass]?

CLINICAL SCENARIO

A 63-year old man presented with a non-ST elevation myocardial infarction and remained as an inpatient for 24 days for an operation. Prior to cannulation the perfusionist informs you that the activated clotting time (ACT) is only 281. The anaesthetist has already given a second dose of heparin to bring the total dose to 500 IU per kg. Your consultant arrives and demands two units of fresh frozen plasma (FFP). After 40 min awaiting delivery of the FFP, the repeat ACT is 347, so it is again below 480. Antithrombin (AT) concentrate is given and the ACT rises to over 600. Given the length of the waiting period and the ineffectiveness of FFP, you check the literature for the evidence surrounding heparin resistance (HR) and FFP administration.

SEARCH STRATEGY

MEDLINE 1950 to March 2013 using OVID interface MESH Categories.

[*Cardiopulmonary Bypass/AND Heparin Resistance.mp AND exp Antithrombin/] OR [*Cardiopulmonary Bypass/AND Heparin Resistance.mp AND *Plasma/]

SEARCH OUTCOME

Twenty-nine papers were found using the reported search. From these, six papers were identified that provided the best evidence to answer the question. These are presented in Table 1.

Table 1:

Best evidence papers

Author, date, journal and country Study type (level of evidence)	Patient group	Outcomes	Key results	Comments
Spiess et al. (2008), Ann Thorac Surg, USA [2] Systematic review (level 1)	Systematic review of the literature Search was performed using MEDLINE and PubMed databases between 1975 and 2006 Keywords used: HR, AT, recombinant human AT and FFP. Additional studies were identified from references cited in publications found using the search terms and also in published review articles No prospective clinical trials to date have evaluated the use of FFP in treating heparin resistant patients	ACT Mean heparin dose Time to achieve bypass ACT Safety	Paucity of evidence for FFP in managing HR during cardiac surgery, one retrospective study, one in vitro study and three case reports AT administration better studies but patients who are not AT deficient with RH may not benefit from AT administration Risk of viral transmission or vCJD with FFP Volume load: 1 IU of AT = amount of AT in 1 ml of plasma 500 IU AT = 10 ml 500 IU FFP = 500 ml Retrospective review of TRALI deaths by USFDA FFP was implicated in 50% Cost: 500 IU AT $840 500 IU FFP $110	FFP may not resolve all cases of HR Significant time delay for FFP Transfusion related injuries more likely with FFP
Sabbagh et al. (1984), Ann Thorac Surg, USA [3] Non-randomized controlled cohort (level 3)	44 patients for cardiopulmonary bypass 20 patients ACT < 300 after first dose of Heparin 11 patients extra heparin to 600 units/kg 9 patients 2 FFP and supplemental heparin	ACT	FFP restored heparin ACT response curve 2 FFP increased ACT from 417 [±60] to 644 [±71]	Initial cohort report showing rise in ACT following FFP administration
Williams et al. (2000), Ann Thorac Surg, USA [4] Prospective RCT (level 2)	85 patients ACT <480 after 450 U/kg of heparin Randomized to receive either 1000 IU AT or additional heparin Patients crossed over groups if ACT not satisfactory	Failure of therapy ACT Total heparin used Dosing cycles (marker for time to acceptable ACT)	Heparin dose: AT GP 638 ± 173 Heparin GP 869 ± 188 P < 0.00001 Failure of therapy: AT 2/44 (5%) Heparin 13/41 (32%) P = 0.001 Dosing cycles: AT 1.09 ± 0.42 Heparin 1.95 ± 0.83 P < 0.0001	Patient who required one additional dose of heparin, then FFP followed by an ACT minimum extra time is 40 min Acquired AT deficiency likely cause of HR AT concentrate faster, avoids volume overload and transfusion related injury from FFP No postoperative benefit identified
Lemmer et al. (2002), J Thorac Cardiovasc Surg, USA [5] Prospective observational trial (level 2)	53 aprotinin treated patients HR defined as ACT < 600 after 600 IU/kg heparin	ACT Heparin dose response relationship (HDRR) HDRR = [post-heparin ACT − baseline ACT]/whole blood heparin concentration	Mean ACT: Pre-AT 492 Post-AT 789 HDRR: Pre-AT 37 s/IU ml Post-AT 69 s/IU ml P < 0.0001	45 patients received 500 IU AT, 8 patients received 1000 IU AT Only 1 patient did not achieve the target ACT Heparin resistance is associated with subnormal activity of AT in majority of patients Treating with AT results in a significant increase in ACT
Conley et al. (1998), J Extra Corpor Technol, USA [6] Retrospective review (level 3)	311 patients Group 1 (n = 109) HR treated with more heparin Group 2 (n = 100) HR, treated with AT Group 3 (n = 102) control no HR	Intensive care unit stay, 24 h chest tube drainage, blood and blood product usage, postoperative coagulopathy, reoperation for bleeding	No significant differences for postoperative coagulopathy and reoperation Chest drainage Group 2 (419.37, ±72.96) when compared with Group 1 (782.88, ±360.94) and Group 3 (766.67, ±407.56)	Early treatment with AT and aminocaproic acid may decrease blood loss Giving AT did not affect any post outcomes
Avidan et al. (2005), Anaesthesiology, 14 European and US centres [7] Double blind, placebo-controlled, multicentre trial (level 1)	Recombinant human AT (rhAT) 54 patients randomized HR = ACT <480 s after 400 IU/kg heparin Randomization to receive 75 IU/kg of rhAT or placebo 27 rhAT 27 placebo	ACT post-treatment Additional heparin requirement during cardiopulmonary bypass FFP transfusion	ACT 5 min after treatment: rhAT 601 Placebo 442 P < 0.001 Additional heparin rhAT 46%, placebo 78% P = 0.02 FFP transfusion intraoperative rhAT 19%, placebo 81% P < 0.001 FFP transfusion in hospital rhAT 48%, placebo 85% P = 0.009	HR was caused by a relative AT deficiency in the majority of patients Two units of FFP did not restore AT activity to the normal range rhAT patients had a higher chest tube drainage rate than placebo, this may have been due to heparin rebound

RESULTS

Heparin binds to AT III and increases the rate at which it can bind to thrombin by a factor of several thousand, creating its anticoagulant effect [7]. AT III is commonly referred to in the literature as AT and is a circulating plasma protein that inhibits thrombin, factor Xa and other circulating coagulation factors. AT levels and activity are important to define the heparin dose–response curve [5]. HR is usually defined as the failure to achieve an ACT of 480 s after 450 IU of heparin per kg bodyweight. HR can be treated with either further heparin, FFP or AT concentrate.

Spiess [2], in 2008, performed a detailed systematic review and identified only five papers relating to FFP. Only one was a retrospective study, one was an in vitro study and three were case reports. Five prospective clinical trials investigated AT. Two of the trials were placebo controlled [7, 8] and one was a crossover trial [4]. Spiess identified the risks of transmission of viral infections from FFP as 1 in 10 million donations for HIV, 1 in 1.2 million donations for Hepatitis B and 1 in 50 million donations for Hepatitis C. The risk of prion transfer is mentioned for FFP, but there have been no documented cases. No cases of viral transmissions from AT have been reported in patients who were not transfused with other blood products.

AT is a smaller volume to transfuse than FFP. One IU of AT is defined as the activity of endogenous AT in 1 ml of plasma. 500 IU of AT concentrate is made up in 10 ml, but FFP requires 500 ml of volume to equate to 500 IU, and this may not be suitable for patients with congestive heart failure [2]. Transfusion related acute lung injury (TRALI) from FFP is a major concern. In a retrospective review of 58 TRALI-related deaths by the US Food and Drug Administration, FFP was implicated in 50% of the deaths and suspected or possible cases of TRALI increased the mortality rate by 47% [2].

AT costs approximately eight times more than the price of two units of FFP; however, the delay in theatre can be significant and frustrating. The minimum time to defrost FFP is 20 min, followed by at least another 8 min to reach therapeutic ACT, not factoring transport times.

Sabbagh et al. [3] was the first to suggest FFP as a treatment for HR after a retrospective analysis of 44 patients who underwent cardiopulmonary bypass. Twenty patients had an ACT <300 after 600 IU/kg of heparin was given. Eleven patients had supplemental heparin and 9 had two units of FFP followed by heparin. The transfusion of FFP increased the ACT from 417 s [±60] to 644 s [±71].

In a prospective randomized crossover trial Williams et al. [4] identified that AT was quicker and more effective, and patients had a lower total dose of heparin. HR patients were randomized to receive either 100 IU of AT or additional heparin. Any patients not achieving an ACT above 480 crossed into the other group. To analyse the time required to reach target ACT, they used the surrogate of dosing cycles. Each dosing cycle was ∼12 min. The AT group had half the number of dosing cycles of the heparin group 1.09 ± 0.42 vs 1.95 ± 0.83 P < 0.0001. The total heparin dose was 638 IU ± 173 vs 869 IU ± 188 P < 0.00001. The number of patients who failed therapy and crossed groups was 2/44 [5%] vs 13/41 [32%] P = 0.001.

Avidan et al. [7] reports on a multicentre, randomized, double-blind, placebo-controlled trial with 54 patients. Administration of AT increased the ACT from 442 to 601 P < 0.001. The intraoperative transfusion rate for FFP was 19% in the AT group and 81% in the placebo group, P < 0.001. The in hospital FFP transfusion rate was 48% for the AT, and 85% for the placebo group, P = 0.009. Two units of FFP did not restore AT activity to the normal range. There were no differences in outcome measures, but patients receiving AT had a higher chest tube drainage and drainage rate in the early postoperative period. The authors conclude this was most likely due to heparin rebound.

CLINICAL BOTTOM LINE

AT concentrate is a safe and efficient treatment to elevate ACT. It avoids the risk of TRALI, volume overload, intraoperative time delay and viral or vCJD transmission. AT concentrates are more expensive than FFP and may put patients at risk of heparin rebound in the early postoperative period.

We conclude that the treatment of HR with FFP may not restore the ACT to therapeutic levels with adequate heparinization, but AT is efficient, with benefits including lower volume administration, less risk of TRALI and lower risk of transfusion-related infections.

Conflict of interest: none declared.