Algorithms for monitoring warfarin use: Results from Delphi Method

Kano, Eunice Kazue; Borges, Jessica Bassani; Scomparini, Erika Burim; Curi, Ana Paula; Ribeiro, Eliane

doi:10.1590/1806-9282.63.10.842

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ORIGINAL ARTICLES • Rev. Assoc. Med. Bras. 63 (10) • Oct 2017 • https://doi.org/10.1590/1806-9282.63.10.842 copy

Algorithms for monitoring warfarin use: Results from Delphi Method

Algoritmos para monitorar o uso de varfarina: resultados do método Delphi

Authorship SCIMAGO INSTITUTIONS RANKINGS

Summary

Warfarin stands as the most prescribed oral anticoagulant. New oral anticoagulants have been approved recently; however, their use is limited and the reversibility techniques of the anticoagulation effect are little known. Thus, our study’s purpose was to develop algorithms for therapeutic monitoring of patients taking warfarin based on the opinion of physicians who prescribe this medicine in their clinical practice. The development of the algorithm was performed in two stages, namely: (i) literature review and (ii) algorithm evaluation by physicians using a Delphi Method. Based on the articles analyzed, two algorithms were developed: “Recommendations for the use of warfarin in anticoagulation therapy” and “Recommendations for the use of warfarin in anticoagulation therapy: dose adjustment and bleeding control.” Later, these algorithms were analyzed by 19 medical doctors that responded to the invitation and agreed to participate in the study. Of these, 16 responded to the first round, 11 to the second and eight to the third round. A 70% consensus or higher was reached for most issues and at least 50% for six questions. We were able to develop algorithms to monitor the use of warfarin by physicians using a Delphi Method. The proposed method is inexpensive and involves the participation of specialists, and it has proved adequate for the intended purpose. Further studies are needed to validate these algorithms, enabling them to be used in clinical practice.

Keywords:
Delphi technique; warfarin; decision-making; medication therapy management

Questions	First Round
Questions	Response	Amount (%) (responses/doctors)	Consensus (> 70%)
1. What is the initial dose of warfarin for an adult outpatient who has never taken warfarin and whose desirable INR range for therapy is between 2 and 3?	5 mg/day	94% (15/16)	Yes
	2.5 mg/day	06% (16/01)	Yes
2. And for those patients in poor nutritional status, the elderly, patients with liver disease or those at high risk of bleeding?	2.5 mg/day	75% (12/16)	Yes
	2.0 mg/day	13% (02/16)
	5 mg/day	06% (16/01)
	I would not use	06% (16/01)
3. Is there any difference in the initial dose of warfarin between inpatients and outpatients?	No	75% (12/16)	Yes
	Yes	25% (04/16)	Yes
^* * Questions contained in the questionnaire of the second round. 4. After how many days from taking the initial dose should the first INR testing be done to assess the patient?	5 days	50% (08/16)	No
	3 days	25% (04/16)
	7 days	25% (04/16)
^* * Questions contained in the questionnaire of the second round. 5. What should be the frequency of INR monitoring until the desired range is reached?	weekly	63% (10/16)	No
	every 2-3 days	31% (05/16)
	Daily	06% (16/01)
^* * Questions contained in the questionnaire of the second round. 6. Is there a preferable period in a day to collect blood for INR testing?	Yes, morning.	56% (09/16)	No
	No	44% (07/16)	No
7. What should be the frequency for monitoring of INR after reaching the therapeutic range?	monthly	81% (13/16)	Yes
	every 6 weeks	13% (02/16)
	weekly	06% (16/01)
8. When should dose adjustment be done?	If INR is out of the therapeutic range, after 4-6 days from the beginning of therapy.	75% (12/16)	Yes
	If INR is out of the therapeutic range, in two consecutive measurements;	44% (07/16)
	If after 3 days using warfarin, the patient has not yet reached the expected INR range	06% (16/01)
^ Questions contained in the questionnaire of the third round. 9. Which INR ranges would determine an action for changing the dose?	INR ≤ 1.5/1.5 < INR ≤ 1.8/ 1.9 ≤ INR < 3.2/ 3.2 ≤ INR < 5.0/INR ≥ 5.0	25% (04/16)	Yes
	1.0 ≤ INR <2.0/ 3.0 < INR < 6.0/ 6.0 ≤ INR < 10.0/ 10.0 ≤ INR ≤ 18.0/ INR > 18.0	69% (11/16)
	INR ≤ 1.5/1.51 ≤ INR ≤1.99/ 2.0 ≤ INR ≤ 3.0/ 3.01 ≤ INR < 3.99/ 4.0 ≤ INR ≤ 4.99/5.0 ≤ INR ≤ 8.99/ INR ≥ 9.0	13% (02/16)
	other	25% (04/16)
	No answer	13% (02/16)
Questions 10 to 16 refer to an outpatient whose therapeutic INR range is between 2 and 3, and in none of the cases the patient has shown evidence of hemorrhage.
^* * Questions contained in the questionnaire of the second round. 10. If a patient shows an INR lower than or equal to 1.5; what would the dose adjustment be?	Increase 20%	38% (06/16)	No
	Increase 33%	31% (05/16)
	Double the dose	06% (16/01)
	other	25% (04/16)
10a. After how many days would you reassess patient status?	5-7 days	100% (16/16)	Yes
^* * Questions contained in the questionnaire of the second round. 11. What if 1.5 ≤ INR ≤ 1.8?	Increase 15%	38% (06/16)	No
	Increase 10%	31% (05/16)
	Recollect after a week	06% (16/01)
	Other	25% (04/16)
11a. After how many days would you reassess patient status?	5 to 7 days	88% (14/16)	Yes
11a. After how many days would you reassess patient status?	14 days	13% (02/16)	Yes
12. What if 1.8 ≤ INR ≤ 3.2?	Do not change the dose	81% (13/16)	Yes
12. What if 1.8 ≤ INR ≤ 3.2?	Reduce the dose by 25%	13% (02/16)	Yes
^* * Questions contained in the questionnaire of the second round. 12a. After how many days would you reassess patient status?	7-10 days	44% (07/16)	No
	30 days	44% (07/16)
	other	13% (02/16)
^* * Questions contained in the questionnaire of the second round. 13. What if 3.2 ≤ INR <4.9?	Discontinue the next dose and reintroduce warfarin at a weekly dose reduced by 10 -20%.	50% (08/16)	No
	Discontinue the next dose and reintroduce warfarin at a weekly dose reduced by 33%.	44% (07/16)
	Discontinue for three days and reintroduce warfarin at a dose reduced by 25-50%.	06% (16/01)
13a. After how many days would you reassess patient status?	5-7 Days	88% (14/16)	Yes
	2-5 days	06% (16/01)
	14 days	06% (16/01)
^* * Questions contained in the questionnaire of the second round. 14. What if 5.0 ≤ INR <9.0, with no evidence of bleeding	Discontinue warfarin and assess the need to give vitamin K orally (2-4 mg). After 24 hours, if there is no more risk of bleeding, reintroduce warfarin with reduction of 15% in the weekly dose.	38% (6/16)	No
	Discontinue the next three doses and then restart the treatment at a dose 33% lower	38% (6/16)
	Discontinue the next dose and then restart the treatment at lower doses until reach the therapeutic INR	06% (16/01)
	Discontinue until desirable INR and reintroduce at reduced dose	06% (16/01)
	Discontinue until desirable INR, reassess in 2-3 days, and reintroduce at reduced dose	06% (16/01)
	Discontinue warfarin and assess the need to give vitamin K orally (2-4 mg). After 24 hours, if there is no more risk of bleeding, reintroduce warfarin with reduction of 50% in the weekly dose.	06% (16/01)
^* * Questions contained in the questionnaire of the second round. 14a. After how many days would you reassess patient status?	3-7 days	56% (9/16)	No
	2 days	25% (04/16)
	24 hours	13% (02/16)
	No answer	06% (16/01)
15. And if INR > 10.0, with no evidence of bleeding?	Discontinue warfarin until INR reduction and give 5 to 10 mg of vitamin K orally.	75% (12/16)	Yes
15. And if INR > 10.0, with no evidence of bleeding?	Other	31% (05/16)	Yes
^* * Questions contained in the questionnaire of the second round. 15a. After how long would you reassess patient status?	24 hours	69% (11/16)	No
	Every 2 Days	31% (05/16)	No
16. In case there is evidence of minor bleeding, what is the dose of vitamin K?	Discontinue warfarin, give vitamin K 10mg and, if necessary, supplement with fresh plasma or prothrombin concentrate.	94% (15/16)	Yes
	Discontinue warfarin, give vitamin K, and restart later	06% (16/01)	Yes
16a. After how many days would you reassess patient status?	12 hours	75% (12/16)	Yes
16a. After how many days would you reassess patient status?	24 hours	25% (04/16)	Yes
The question below refers to the case of a patient showing evidences of major bleeding:
17. Sugiro: How would you manage warfarin therapy?	Discontinue warfarin, give prothrombin complex and vitamin K 10mg 75% (12/16)		Yes
17. Sugiro: How would you manage warfarin therapy?	other	25% (04/16)	Yes
17a. After how long should the patient be reassessed?	12 hours	81% (13/16)	Yes
17a. After how long should the patient be reassessed?	1 day	19% (3/16)	Yes
The question below refers to the case of a patient experiencing life-threatening bleeding: 18. Sugiro: How would you manage warfarin therapy?	Discontinue warfarin, give prothrombin complex and vitamin K 10mg	75% (12/16)	Yes
	Other	25% (04/16)	Yes
18a. After how many days would you reassess patient status?	12 hours	81% (13/16)	Yes
18a. After how many days would you reassess patient status?	1 day	19% (3/16)	Yes
Questions	Second Round
Questions	Response	Amount (%) (responses/doctors)	Consensus (> 70%)
^ Questions contained in the questionnaire of the third round. 1. How many days after taking the initial dose should the first INR testing be done to assess the patient?	3 days	27% (3/11)	No
	5 days	55% (6/11)
	1 week	18% (2/11)
^ Questions contained in the questionnaire of the third round. 2. What should be the frequency of INR monitoring until the desired range is reached?	Every 2-3 days	36% (4/11)	No
	Weekly	64% (7/11)	No
^ Questions contained in the questionnaire of the third round. 3. Is there a preferable period within the day to collect blood for INR testing?	Yes, morning	36% (4/11)	No
	No	64% (7/11)	No
4. When should dose adjustment be done (tick all possible alternatives)?	If the INR is out of therapeutic range after 4-6 days from the beginning of the therapy.	100% (11/11)	Yes
The following questions refer to an outpatient whose therapeutic INR range is between 2 and 3, and in none of the cases the patient shows evidence of hemorrhage.
^ Questions contained in the questionnaire of the third round. 5. If a patient shows INR lower than 1.5, which would be the dose adjustment?	Increase by 20%	27% (3/11)	No
	Double the daily dose	9% (1/11)
	Increase by 33%	55% (6/11)
	Other	9% (1/11)
^ Questions contained in the questionnaire of the third round. 6. What if 1.5 ≤ INR ≤1,8	Increase by 15%	64% (7/11)	No
	Increase by 25%	36% (4/11)	No
7. After how many days would you reassess the status of a patient showing 1.9 ≤ INR ≤ 3.4?	7-14 days	73% (8/11)	Yes
	30 days	27% (3/11)	Yes
^ Questions contained in the questionnaire of the third round. 8. What if 3.4 ≤ INR ≤ 5.0	Suspend the next dose and reintroduce warfarin with a weekly dose reduced by 10-20%	55% (6/11)	No
	Suspend the next dose and reintroduce warfarin with a weekly dose reduced by 33%	45% (5/11)	No
^ Questions contained in the questionnaire of the third round. 9. What if 5.0 ≤ INR ≤ 9.0 with patient under risk to develop hemorrhage in the next 30 days?	Discontinue treatment for the 3 next doses and then restart therapy at a dose 33% lower	45% (5/11)	No
	Discontinue warfarin treatment and assess the need for oral administration of vitamin K (2-4 mg). After 24 hours, if there is no more risk of bleeding, reintroduce warfarin with 15% reduction	45% (5/11)
	Other	9% (1/11)
^ Questions contained in the questionnaire of the third round. 9a. After how many days would you reassess patient status?	24h	55% (6/11)	No
	2 days	9% (1/11)
	3-7 days	36% (4/11)
10. What if 9.0 ≤ INR ≤ 20.0?	Discontinue warfarin therapy until reduction of INR. Reintroduce therapy at low-dose of warfarin and restart dose titration. If required, give vitamin K (5-10mg)	73% (8/11)	Yes
10. What if 9.0 ≤ INR ≤ 20.0?	Other	27% (3/11)	Yes
^ Questions contained in the questionnaire of the third round. 10a. After how many days would you reassess patient status?	Daily	64% (7/11)	No
	Every 2 Days	36% (4/11)	No
Questions	Third Round
Questions	Response	Amount (%) (responses/doctors)	Consensus (> 70%)
1. Is there a preferable period during the day to collect blood for INR testing?	Yes, morning	50% (4/8)	No
	No, but always in the same period	50% (4/8)	No
Questions 2 to 5 refer to an outpatient whose therapeutic INR range is between 2 and 3, and in none of the cases the patient shows evidence of hemorrhage.
2. If a patient shows INR lower than 1.5, which would be the dose adjustment?	Increase by 20%	38% (3/8)	No
	Increase by 33%	62% (5/8)	No
3. What if 1.5 ≤ INR ≤1.8	Increase by 15%	38% (3/8)	No
	Increase by 25%	50% (4/8)
	Other	12% (1/8)
4. What if 3.2 ≤ INR ≤ 4.9	Suspend the next dose and reintroduce warfarin with a weekly dose reduced by 10-20%	62% (5/8)	No
	Suspend the next dose and reintroduce warfarin with a weekly dose reduced by 33%	25% (2/8)
	Other	12% (1/8)
5. What if 5.0 ≤ INR ≤ 9.0 with no evidences of bleeding?	Discontinue the next 3 doses and then restart the therapy at a dose 33% lower	50% (4/8)	No
	Discontinue warfarin treatment and assess the need for oral administration of vitamin K (1-2 mg). After 24 hours, if there is no more risk of bleeding, reintroduce warfarin with 15% reduction	38% (3/8)
	Other	12% (1/8)
6. In case there is evidence of bleeding, classified as minor, what should the management be?	Suspend the next dose, give vitamin K according to INR (1-2 mg for INR> 4.5; p 1-2,5mg/5.0 <INR <9.0; 2,5-5,0mg for INR> = 9.0), monitor, and repeat if necessary, the dose of vitamin K, and restart warfarin therapy	50% (4/8)	No
	Discontinue and give vitamin K 1-2 mg, monitor, and repeat if necessary vitamin K, and restart therapy	38% (3/8)
	Other	12% (1/8)
7. In case there is evidence of bleeding, classified as minor, what should the management be?	Discontinue, give 5-10mg of vitamin K by slow intravenous infusion plus 25-50U/kg of prothrombin complex concentrate or 15ml/kg of fresh plasma, and reassess	100% (8/8)	Yes
8. In case there is evidence of a life-threatening bleeding, what should the management be?	Discontinue, give 10mg of vitamin K by slow intravenous infusion and 25-50U/kg of prothrombin complex concentrate OR 150 to 300 ml of fresh plasma, and reassess	75% (6/8)	Yes
	Discontinue, give 10mg of vitamin K by slow intravenous infusion, 25-50U/kg of prothrombin complex concentrate and 15ml/kg of fresh plasma, and reassess	25% (2/8)	Yes

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