Prothrombin Complex Concentrates Working Group
Teleconference – July 18, 2013
Attend ed: Susan Nahirniak (SN), Dariush Dowlatshahi (DD), Irene Sadek (IS), Katerina Pavenski (KP), Lakshmi Rajappannair (LR), Lucinda Whitman (LW), Michael Hill (MH), Rosemary Tanzini (RT), Man-Chiu Poon (MP), Gabriella O’Reilly (GO’R)
Declined: Rick Trifinov (RIT), Nalin Ahluwalia (NA), Mark Crowther (MC), Yulia Lin (YL), Antonio Giulivi (AG), Bruce Ritchie (BR), Janis Bormanis (JB), Tammy Bungard (TB), Vincent Laroche (VL), Kathryn Webert (KW), Brian Berry (BB), Dana Devine (DD)
Welcome
Susan explained that the NAC Lead province has changed from NL to NB and she then introduced LR as the new Chair and GO’R as the Policy Analyst. SN explained the teleconference was being recorded for the purpose of minute taking. SN performed roll call.
Meeting minutes – April 2013
Yulia added a comment under Post meeting notes (see italics): This may include maintaining a limited supply of PCC in the Emergency Department with appropriate storage and record-keeping to ensure traceability as per CSA standards. The minutes are approved, with the following remark:
MP would like the spelling of his first name corrected.
Action: GO’R to correct spelling mistake and circulate approved minutes.
Pending April 2013 Action Items reviewed by SN.
Ø Action: All members to complete and return COI form
Status: 10 members have completed the COI form. Members who have not completed the COI /Disclosure form must do so at their earliest convenience.
Action: GO’R to send out individual emails to pertinent members who have not completed COI/Disclosure form.
Ø Action: BR and AG to summarize available literature pertaining to the use of PCC for transient reversal of anticoagulant therapy.
Status: Outstanding (April 2013).
Action: SN to bring to BR and AG‘s attention for follow-up.
Ø Action: KP to Confirm infusion rates with manufacturers prior to finalizing revisions. Infusion rates are still different for Beriflex/Octaplex products.
Status: Partially Completed.
KP did follow up with Octapharma Group and they responded with providing a paper in which they performed a study as an ad hoc analysis for the infusion rates but they did not respond to the specific question as to whether or not they are preparing a submission to Health Canada. Last SN heard was that they were no plans to do so at this time. SN referred members to a paper she forwarded on July 18 - 574PLEXARTL1302E regarding infusion rates/speeds - Go to the last figure on last page.
Action: SN to investigate further.
Ø Action: BR to submit wording on for oral vitamin K recommendation
Status: Outstanding (April 2013).
SN provided a copy of the Australian 2013 warfarin reversal consensus guidelines for dose discussion purposes. There is wording in this document on warfarin reversal in terms of their recommendations around Vitamin K1. They recommend that Vitamin K1 can be given to reverse the anticoagulant effect of warfarin. When oral Vitamin K1 is used for this purpose, the injectable formulation, which can be given orally or intravenously, is preferred.
Action: Members, please comment on whether you agree with the wording above taken from the Australian 2013 warfarin reversal consensus guidelines.
Ø Action: DD to draft wording addressing rapid reversal of coagulopathy.
Status Completed. Draft wording is:
1) Under “Indications”, we can consider simply adding the word “Rapid” to “Reversal of warfarin […]”in point A. Not a big change, but it sets the tone.
2) Under “Administration”, how about:
- The treating clinician team must ensure the timely administration of PCC in patients with major bleeding manifestations.
- Individual institutions should adopt a process to facilitate the availability and delivery of PCC for patients with major bleeding manifestations. This may include maintaining a limited supply of PCC in the Emergency Department with appropriate storage and record-keeping to ensure traceability as per the CSA standards.
SN went over the draft wording submitted by DD and a discussion ensued. DD added some context around why he specifically decided on the wording treating clinician team. He also noted that he has seen first-hand problems, with significant delays from the presentation and from the infusion of drugs, due to a lack of ownership. SN suggested changing wording to the treating physician must take ownership to ensure the timely administration of PCC in patients with major bleeding malfunction.
LW added that her institution has an approval process for giving PCCs and there are times when it can be ordered inappropriately. She noted that having PCCs readily available in circumstances that do not warrant their administration could cause an increase in adverse reactions. DD then explained, that is why it should be at the discretion of the Institution. DD also noted that he, as well as AG, have had similar concerns regarding patients showing and getting reversed that are asymptomatic, which have a high INR, no planned surgery and even worse, not on warfarin.
SN suggested to changing wording to, Individual institutions should adopt a process to facilitate the rapid availability and delivery of PCC for patients with major bleeding manifestations. This may include expedited approval processes, pneumatic tube delivery of product or maintaining a limited supply of PCC in the Emergency Department with appropriate storage and record-keeping to ensure traceability as per the CSA standards. Members present agreed with above suggestions made by SN and agreed to include the above wording in the next reiteration of the PCC framework.
Ø Action: SN to look at INR levels, warfarin and factor correlations
Prior to Dosing SN spoke on the several articles she forwarded on July 18, namely, Factor IX and warfarin, INR vs Plasma Factor Levels, Factor VII Levels and Calgary 3 G PCC protocol.
Calgary 3 G PCC protocol demonstrates yet another variable in terms of dosing where the clinical condition is taken into account which can alter the target INR. Looking next, at the the Australian 2013 warfarin reversal consensus guidelines this does have different criteria depending on the indication as well as outlined in their document. The Australian document is very specific in terms of what the clinical setting is and treating from that standpoint and again very specific about ceasing warfarin therapy. The Australian document also has a perioperative stratification risk. SN reminded the group that in the past we talked about the decision making in terms of when individuals are going to reinstitute anticoagulant therapy and this was a past criticism, in that not all patients should be reversed and maintained reversed as they were on anticoagulants for a reason. SN asked members if there were any thoughts on changing some of the dose targets and recommendations on the basis of the type of bleeding presentation or leave as written: clinical significant/ major bleeding. IS says her institution would like a different INR target for intracranial bleeding. Discussion on INRs and % target factor levels ensued. RT in her literature search on dosing and in doing her calculations in terms of target percentage factors was based on feelings not facts. SN discussed that the additional papers she sent dealing in terms of INR versus plasma levels of coagulation factors this info is not based on facts. Also it was noted, it is not known which of these coagulation factors are the most important. We should be very cautious at this time to be dosing to achieve factor level above 40 % but rather dosing on basis that correction should be based on global testing rather than any individual factor level.
Ø Action: RT to do calculation exercise (one table, both products) using target INR of 1.5 and 1.7
RT sent several articles around dosing on July 17, namely, Dose Banding Comparison Summary, Dose Banding Background Re: Rounded Off’ Weight-based Dosing and Dose Bands based on target INR 1.7.
RT walked the group through the document, Comparison of Dosing Recommendations noting that there are various tables and noting that is variability in these documents. Several tables were described: the Schulman/Columina reference which describes dose bands based on target INR 1.5 (40 % of factors), the McMaster reference which describes dose bands based on weight and target INR 1.5 etc. Then RT highlighted the last table in the Comparison of Dosing Recommendations document which is derived from the McMaster reference.
For target INR = 1.5 (derived from McMaster reference):
Target INR = 1.5Weight (kg) / PCC dose if INR > 6
(40 units/kg) / PCC dose if INR 3-6
(30 units/kg) / PCC dose if INR 2-3
(20 units/kg)
35-37 / 1500 / 1000 / 500
38-41 / 1500 / 1000 / 1000
42-43 / 1500 / 1500 / 1000
44-56 / 2000 / 1500 / 1000
57-58 / 2500 / 1500 / 1000
59-62 / 2500 / 2000 / 1000
63-68 / 2500 / 2000 / 1500
69-75 / 3000 / 2000 / 1500
76-87 / 3000 / 2500 / 1500
88-91 / 3000 / 2500 / 2000
92-112 / 3000 / 3000 / 2000
113-136 / 3000 / 3000 / 2500
137 or greater / 3000 / 3000 / 3000
At the end of RT presentation it was not fully evident as how the group should proceed, SN suggested to guide individuals to follow one’s institutional practices, if not, on the basis of publications, NAC is recommending a target INR of 1.5 (using RT table above).
As a general rule of thumb if a lower Target INR = 1.3 is required i.e., Intracranial Hemorrhage then adding 10 units per kg may be appropriate; if aiming for higher INR as part of your indication i.e., 1.7 then subtracting 10 units per kg may be appropriate. The subtraction of 10 units per kg may not be substantiated as RT noted but it could be a recommendation. All members agreed to this analysis.
SN is removing any statements that assume INR is related to factor levels of 40% as this is not evidence based. DD asked whether we need a statement regarding an INR of 1.7, since at this target the question can be raised as to why one is using PCC in the first place and clearly not an urgent need and one could use Vitamin K. SN says that there would be persons who would argue against this, especially those patients at high risk for thrombosis after surgery.
Next steps and timelines
If in the next month there is no statement from BR and AG pertaining to the use of PCC for transient reversal of anticoagulant therapy then the document - Recommendations for the use of PCC in Canada will be revised without any updates re transient reversal.
Action: SN will revised the wording for oral Vitamin K based on the Australian 2013 warfarin reversal consensus guidelines document allowing time for members to provide feedback.
Action: SN will revise wording addressing rapid reversal of coagulopathy.
Action: SN will include in revisions RT dosing recommendations
Action: SN will revise document in August, circulate to members for approval in early September.
KP questioned the intent around infusion rates and it was decided in the reiteration of the PCC framework it would be best to default to manufacturer’s monographs as if manufacturer’s recommendation changes than document will not require revisions due to this change.
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April 2013