Tristan GrovesLead Pharmacist Anticoagulation

Cardiff and Vale University Health Board

May 2013

Plan Why we have to be so vigilant with Warfarin.The primary and secondary care interface

Information required for safe monitoring of patients Communication problems

Care pathway When do things go wrong?

Improving the safety of Warfarin prescribing. Knowing the indication. Starting Warfarin. How to deal with Low and High results

The future of oral anticoagulation.

1International normalized ratio (INR)

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2

15

8

10

5

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3 4 5 6 7

Intracranial bleed

Therapeuticrange20

Stroke

The Impact of Warfarin on ICH

Warfarin increases the risk of ICH 2- to 5-fold and nearly doubles the mortality associated with ICH1,2

50% of patients with Warfarin-associated ICH die within 30 days1

OR 4.6; 95% CI, 1.0 to 21.8 for 3-month mortality2

1. Aguilar MI, et al. Mayo Clin Proc. 2007;82(1):82-92; 2. Flibotte JJ, et al. Neurology. 2004;63(6):1059-1064.

6

0 500 1000 1500 2000

Survival to stroke (days)

0.6

0.7

0.8

0.9

1.0

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ival

71–100%

Warfarin group

61–70%51–60%41–50%31–40%<30%Non Warfarin

Morgan CL et al. Thrombosis Research 2009;124:37–41

What is an interface?interfacen.) A boundary across which two independent

systems meet and act on or Communicate with each other

Communication between primary and secondary care

What do we need to know from each other in order to safely monitor a Warfarin patient?

Doses patient has takenRecent INR results ? How manyNew medication started or existing medication

stopped?Changes in patient’s condition-i.e. new

diseasesWorsening of existing diseases i.e.. reduced

cognitive function.Diet changes?- i.e.. on dietetic supplements?

What does the NPSA say Patient safety alert 18

“In many cases, the healthcare professional who issues repeat prescriptions for anticoagulants, for example the general practitioner, is not the same practitioner who monitors and adjusts the dosage of the therapy, for example the anticoagulant clinic practitioner. It is for the prescriber supplying the repeat prescription to ensure that it is safe to do so. Repeat prescriptions of anticoagulants should only be issued if the prescriber has checked that the patient is regularly attending the anticoagulant clinic, that the INR test result is within safe limits”

What does the NPSA say Patient safety alert 18 (2007)

“Many medicines interact with oral anticoagulant therapy. Often, the healthcare professional prescribing other medicines, for example the general practitioner, might not be the same person monitoring and adjusting the dosage of the therapy, who could be the anticoagulant clinic practitioner. If possible, medicines should be selected that do not produce clinically significant interactions. If this is not possible, the prescriber who initiates or discontinues a prescription for an interacting medicine is responsible for ensuring that the patient is informed that an interacting medicine has been commenced or discontinued. They should also tell the patient to arrange an INR test within four to seven days of the start or discontinuation of the interacting medicine. The patient should be instructed to provide details of the change in therapy when the blood sample is taken”.

The Warfarin care pathwayDeveloped to try to ensure the patient is safely

initiated on Warfarin and that a patient’s care is safely transferred from secondary care to primary care

No patient on Warfarin is to be discharged from a Hospital within the Health Board, without having a completed Warfarin care pathway. (section 2 to be completed for all patients and section 1 and 2 for newly started patients).

This combined with the Warfarin treatment chart and the DAL provides the information required for the safe transfer of care.

The Adult IN-patient Warfarin chart and Care PathwayWarfarin chartAll Wales Warfarin

Treatment Chart AWA001.pdf

Care pathwayCV Warfarin Care Pathway.pdf

The Warfarin care pathwayAll patients must have a confirmed

appointment made with a monitoring clinic prior to dischargeGreat variability in primary care as to when

patients are “stable” enough to be seen

What actually happensDischarge Audits at UHW, Cardiff

INR in range on discharge

Appointment made for INR

check

Completed yellow book

Indication specified

Recent INR/dosing information

2001

41%

71%

59%

87%

49%

2002

43%

79%

53%

82%

58%

2008

67%

74%

65%

no info

52%

When things go wrongRaised INR audit 2010

Dual site both UHW and LLandoughAll inpatients with an INR ≥5.0 were identified

by the coagulation labs.Data collection period June09-Jan 2010All patients where possible had a root cause

analysis form completed by the ward Pharmacist normally within 72 hours of elevated result.LLandough 95UHW 96

Coagulation labs across UHW and LLandough complete an average of approximately 4000 inpatient INR tests monthly.

When things go wrong% of total result occuring on day of admission

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Llan UHW

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% of total

An example94 yr old gentleman admitted due to heamaturia.

Patient on Warfarin for AF (range 2.0-3.0) admitted with INR>22 !!!! (vitamin K administered)

Had been started on Trimethoprim 8 days earlier . Gp had done INR one day after starting course (INR was 4.3) but dose not changed (according to relative).

Patients book was available on admission but no doses were recorded in the book and dates not fully completed.

Due to patients age range decreased on discharge (1.5-2.5)

Another example61 yr old woman on Warfarin for VTE. Admitted

to surgical admissions for cholecystitis. Found on admission to have INR>22. (vitamin K administered)

Liver function tests on admission:Alk phos 1147 (30-115)ALT 535 (5-40)Bil 65 (1-22)

Patient normally on co-agucheck system at GP. Has results on print out. Pt un able to confirm doses taken and no way of confirming doses of Warfarin over weekend with GP.

Poor practice happens on both sides

84 yr old patient on Warfarin for AF (range 2.0-3.0).Discharged from rehab ward with INR 3.6. ? Any

follow up appointment made with a monitoring clinic?

Pt having diarrhoea on discharge!Five days later patient admitted to hospital

following an INR of 12.1 at GP clinic.Raise INR though to be due to Diarrhoea and poor

understanding of the treatment by the patient (?poor compliance)- these issues should have been addressed before discharge.

Improving the safety of prescribing

Things to consider when treating a patient:

Are you sure of the indication?How to start Warfarin treatment.Frequency of dose changes. (avoiding

over tinkering).How to deal with low and high results

Knowing the indicationWill affect the Desired INR range

i.e..... “heart valve” Aortic Bioprosthtic valve- may only need Aspirin Medtronic Valve (aortic) INR range 2.0-3.0 Starr Edwards Valve (mitral) INR range 3.5-4.5

Will affect how we start Anticoagulation/ frequency of monitoring

Will affect duration of treatmentWill affect how we deal with Low and high

resultsWill affect how we deal with procedures

(i.e.... dental surgery)

Starting patients on Warfarin

Patient specific and disease specific loading regimen should be utilized.

Concomitant use of Heparin/LMWHNeed for intensive monitoring when first

starting ? Always appropriateAll patients must have baseline INR result

and Full blood count.

Starting patients on WarfarinExamples of Loading Regimens10mg,10mg,5mg –INR Day 310mg,5mg,5mg- INR Day 310mg,3mg,3mg -INR Day 35mg Daily – Monitor INR Day 43mg Daily – Monitor INR Day 72mg Daily – Monitor INR Day 14

Initiating Warfarin for AF In general the short term risk of a stroke is low and as a

result patients with AF can be anticoagulated on an outpatient basis with Warfarin alone (1).

A slow-low dose loading regimen is suitable for patients with AF and achieves therapeutic anticoagulation in the majority of patients within 3 – 4 weeks (2).

A baseline INR should Always be taken. If the INR is <1.4 the patient can be commenced on a low dose of Warfarin e.g. 3mg per day, for 7 days before a repeat INR measurement is required (3)

1. Singer et al. Antithrombotic therapy in atrial fibrillation. Antithrombotic and thrombolytic therapy: ACCP evidence based clinical practice guidelines (8th edition). Chest 2008; 133: 546-592.

2. Baglin et al. British Committee for Standards in Haematology Guidelines on oral anticoagulation (Warfarin). British Journal of Haematology 2005; 132: 277-285.

3. Janes et al. Safe introduction of Warfarin for thrombotic prophylaxis in atrial fibrillation requiring only a weekly INR. Clinical and Laboratory Haematology 2004; 26: 43-47.

Our AF protocol3mg Warfarinisation Protocol.doc

Frequently changing the dose The earliest changes in the International

Normalized Ratio (INR) are typically noted 24 to 36 hours after a dose of Warfarin is administered. These changes are due to the clearance of functional factor VII, which is the vitamin K dependent clotting factor with the shortest half-life (six hours). However, the early changes in the INR are deceptive because they do not actually affect the body's physiologic ability to halt clot expansion or form new thromboses.

How to deal with low and high results

Treatment options depend on:Clinical condition of patientActual INR- How low is low, How High is HighCondition being treatedHow long has patient been on WarfarinIdentifiable cause of abnormal result

Advice given to GPsFrom service level agreement.

Warfarin therapy: maximum recall periods during maintenance therapy**(not initiation)One INR high: recall in 7-14 days (stop treatment for 1-3 days) (maximum 1 week in prostheticvalve patients)One INR low: recall in 7-14 daysOne INR therapeutic: recall in 4 weeksTwo INRs therapeutic: recall in 6 weeks (maximum for prosthetic valve patients)Three INRs therapeutic: recall in 8 weeks, apart from prosthetic valve patientsFour INRs therapeutic: recall in 10 weeks, apart from prosthetic valve patientsFive INRs therapeutic: recall in 12 weeks, apart from prosthetic valve patientsNB Patients seen after discharge from hospital with prosthetic valves may need more frequent INRs in thefirst few weeks.(Based on data from Ryan et al (1989) British Medical Journal 299, 1207-1209)

Guidelines for the management of excessive oral anticoagulation

Treatment depends on the INR, and whether there is major, minor or no bleeding. Also depends on

indication for anticoagulation (e.g. heart valve )The following recommendations are adapted from those of the British Society for Hematology and are on the back of the all Wales Adult In-patient Warfarin Treatment chart

INR in therapeutic range - patient bleeding.

• Investigate source of bleeding. Consider risk/benefit of stopping Warfarin INR < 6.0 but > 0.7 above target INR - no bleeding

• Reduce the dose following the ‘Maintenance Dosing’ table above INR > 6 - no bleeding or minor bleeding from mucosae (nose,

oropharynx, urinary tract, rectum, anus)• Stop Warfarin and restart when INR < 5.0• Assess patient for their risk of bleeding: recent surgery/trauma, extensive bruising, minor mucosal bleeding If at high risk of bleeding give Vitamin K 2mg orally:Use 0.2 ml Konakion® MM paediatric (phytomenadione 2mg in 0.2ml). Draw up using oral dispenser provided, then drop onto the tongue• Recheck INR after 24 hours, repeat dose of Vitamin K if INR is still too high

Major bleeding: Life or limb threatening bleeding, including intracranial haemorrhage

• Stop Warfarin.• Give 10mg vitamin K IV (1ml phytomenadione 10 mg/ml - Konakion MM®.) Give as an IV

bolus over 3-5 minutesundiluted or diluted with 10-20ml with glucose 5% to aid slow administration• Give prothrombin complex concentrate (PCC - Factor II, VII, IX, and X concentrate) -

dose to be advised by haematologist. • Repeat INR within 1 hour of giving of PCC - consider further dose if INR remains >1.5

and patient still bleeding• Consider risk/benefit of recommencing Warfarin

So what is the future?The new oral agentsHow do they workAdvantages and disadvantagesWhere are we in terms of prescribing these

agents?

Characteristic of an ideal anticoagulant

Oral administrationEffective reduction in thromboembolic eventsPredictable dose response / kineticsLow bleeding rateNo routine monitoringWide therapeutic windowNo dose adjustmentsLittle interaction food / drugs

The new agentsOral Direct thrombin inhibitors

Dabigatran (Pradaxa®)

Oral Factor Xa inhibitors Rivaroxaban (Xarelto®)

Apixaban (Eliquis®) Edoxaban Betrixaban

Rivaroxaban, Apixaban

Dabigitran

How a clot forms (simplified!)

Rivaroxaban, Apixaban

Dabigitran

What are they licensed for?Dabigatran (Pradaxa®)110mg dose BDPrimary prevention of venous thromboembolic events in

adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

Nonvalvular AF (see below).

150mg dose BD Prevention of stroke and systemic embolism in adult patients with

nonvalvular atrial fibrillation with one or more of the following risk factors: • Previous stroke, transient ischemic attack, or systemic embolism (SEE) • Left ventricular ejection fraction < 40 % • Symptomatic heart failure, New York Heart Association (NYHA) Class 2 • Age ≥75 years • Age 65 years associated with one of the following: diabetes

mellitus, coronary artery disease, or hypertension

What are they licensed for?Rivaroxaban (Xarelto®)10mg dose OD -Prevention of venous

thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.

20mg dose OD-Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack.

Treatment of deep vein thrombosis (DVT) and PE, and prevention of recurrent DVT and PE following an acute DVT in adults. (following loading of 15mg BD)

What are they licensed for?Apixaban (Eliquis®)2.5mg dose BD-Prevention of venous

thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

5.0mg BD- Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischemic attack (TIA); age≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).

“Blood clot-busting pills that slash the risk of strokes”

“£2.50 a day pill to beat strokes: A million Britons could benefit from drug available for use within weeks”

“Ask your doctor -How can I avoid all these blood tests?”

“Lets change everybody on Warfarin to the new

Drugs!” “Blood-thinning drug 'better than Warfarin‘”

What the patient sees and hears

A note of caution.Patient’s Indication- (current licences for the new

agents are for VTE prevention post hip/knee surgery/ AF/ New DVT, depending on agent). Lack of evidence of efficacy in Heart valve or patients with recurrent thrombosis etc.

Patients with Renal or Liver impairmentCOST ?Recurrent clot on new agent – what do we do?How to reverse the new agents? (Betrixaban-

antidote)Lack of clinical experience ? Bridging therapyHow to assess compliance?- monitoring?Future drug interactions/ post marketing side

effects (Ximelagatran)/ bleeding rates seen in other countries.

Nice guidanceThis tends to be quite non specific:E.g.

“The decision about whether to start treatment with dabigatran etexilate should be made after an informed discussion between the clinician and the person about the risks and benefits of dabigatran etexilate compared with Warfarin. For people who are taking Warfarin, the potential risks and benefits of switching to dabigatran etexilate should be considered in light of their level of international normalised ratio (INR) control”

Scottish guidelinesThe statement advises that:

on balance of risks and benefits, Warfarin remains the anticoagulant of clinical choice for moderate or high risk atrial fibrillation patients(CHA2DS2-VASc ≥ 2) with good INR control, and clinicians should consider prescribing dabigatran or rivaroxaban in patients with: -

poor INR control despite evidence that they are complying, or

-allergy to or intolerable side effects from coumarin anticoagulants.

Any Questions?