IHGM Presentation

22 Feb 2013

Speaker: Dr Grace Chan, TWEH HKEC

Chairman: Dr KH Wong

2 patients with warfarin

overdose

Case 1

F/65

Lives with husband. ADL I

PMH:

◦ HT

◦ Chronic rheumatic heart disease with severe MR and TR

Echocardiogram showed posterior MVL prolapse with severe MR and TR with moderate pulmonary HT, preserved LV systolic function

Complicated with atrial flutter and congesive heart failure

MVR done 6/2011

Put on warfarin since after MVR

Latest OPD FU in 10/2012

◦ On warfarin 3.5mg

◦ Good drug compliance

◦ INR 3.1 ( 4/9/12 ), 3.5 ( 8/10/12 ), 3.2 ( 30/10/12 )

Admission on 15/12/12

Fever, cough with yellowish sputum, chest

pain on coughing

Physical exam:

◦ Febrile 38 degrees

◦ BP / P stable

◦ Chest: transmitted sound

◦ CVS: mechanical heart sound

CXR: no gross consolidation, mild RLZ

hazziness

Blood test:

◦ CBP WBC raised 10.4, RFT normal, LFT slightly raised ALT 63, INR 3.5

Treated as pneumonia

Started on augmentin + clarithromycin(15/12/12 )

INR repeated 2 days later – 4.2 (17/12/12)

LFT ALT 71, ALP Bil normal

Clinically no bleeding

Warfarin withold

INR repeated 4.5 (18/12/12), 4.4 (19/12/12)

Prolonged INR while taking usual dose

warfarin

◦ ? Diet

◦ ? Drug compliance

◦ ? Drug interaction with antibiotics

◦ ? Liver derangement

Transferred to TWEH for convalscence

Antibiotics continued and completed course

Warfarin withold

LFT improved and normalised

INR down to 2.2, usual dose warfarinresumed

Serial INR 2.6, 3.3

FU 2 weeks later, INR 3.0

15/12 16/12 21/12 22/1219/12 20/1217/12 18/12 23/12 24/122

weeks later

INR 3.5 4.2 4.5 4.4 2.2 2.6 3.3 3.0

Augmentin

klacid

Warfarin

off

Antibiotics completed

Warfarin resumed

Case 2

F/89

Lives with family. ADL partially dependent,

walks with frame with assistance

Allergic to penicillin

PMH:

◦ HT / AF on warfarin

◦ Gastric erosions on OGD ( episode of tarry stool ); colonscopy normal

Last OPD FU 11/2012

◦ On warfarin 2mg

◦ INR 2.1 (9/12), 3.1 (10/12), 3.0 (11/12)

◦ Good drug compliance – supervision by son

◦ Dose of warfarin reduced to 1mg

Admission on 23/12/12

Poor appetite

Nausea and vomiting

No diarrhoea

No fever

No abdominal pain

No chest / urinary symptoms

Physical exam on admission

◦ BP / P stable. Low grade fever 37.5 degrees

◦ Mildly dehydrated

◦ Chest clear

◦ Abdomen soft non tender, bowel sound normal

CXR: no consolidation

AXR: no dilated bowels

ECG: AF 70/min, no new ischemic

changes

Blood test : CBP WBC normal, Hb normal,

RFT Ur / Cr normal Na 130 K 3.0, LFT

normal, CK normal, INR 2.6, TSH normal

Treated as sepsis ? UTI

IVF rehydration

Started on empirical levofloxacin since

24/12/12

Transferred to TWEH for convalscence

Fever down

Oral intake improved

MSU grew enterococcus

Completed course of levofloxacin

Continued warfarin at usual dose 1mg

Repeated INR > 8.0

No clinical bleeding

Warfarin taken off

Serial monitoring INR downtrend

Warfarin resumed at lower dose 1 mg

FU 2 weeks later – INR 2.0

23/12 24/12 4/1 5/12/1 3/129/12 30/12 6/1 8/1

INR 2.6 3.1>

8.07.6 5.5 4.2 3.2 1.7

Cravit

Cravit

completed

Warfarin

off

Warfarin

resumed at

lower dose

ANTICOAGULATION WITH WARFARIN

Warfarin has been the standard oral anticoagulant used in a variety of clinical settings.

The drug is metabolized primarily by the CYP2C9 hepatic microsomal enzyme system.

This enzyme system is inducible by many drugs and has a number of genetic variants, both of which may profoundly alter warfarin's in vivo activity.

The drug is strongly protein-bound, primarily to albumin; only the non-protein-bound fraction is biologically active.

Accordingly, any agent that is also bound to albumin may displace warfarin from its albumin binding sites and increase its biological activity.

Excretion is via the urine, primarily as drug metabolites

Mechanism of action

Warfarin inhibits the vitamin K-dependent gamma-carboxylation of coagulation factors II, VII, IX, and X

On the other hand, warfarin also inhibits the vitamin K-dependent gamma-carboxylation of proteins C and S, which have anticoagulant properties through their inhibition of activated factors VIII and V

This results in the creation of a

biochemical paradox by producing an

anticoagulant effect due to the inhibition

of procoagulants (factors II, VII, IX, and X)

and a potentially thrombogenic effect by

impairing the synthesis of naturally

occurring inhibitors of coagulation

(proteins C and S).

The ultimate anticoagulant effect is delayed until the normal clotting factors are cleared from the circulation.

The peak effect does not occur until 36 to 72 hours after drug administration ( ~ half life of factor II ).

Equilibrium levels of factors II (prothrombin), IX, and X, approximately 10 to 35 percent of normal at therapeutic INR levels, are reached about one week after the initiation of therapy.

For this reason, parenteral anticoagulants and warfarin should overlap by 4 to 5 days when warfarinis initiated in patients with acute thrombotic disease.

Laboratory monitoring

Use of the INR ( International

Normalized Ratio ) —The INR is the PT

ratio obtained by testing a given sample

using the WHO reference thromboplastin.

Serial monitoring of the INR will detect

many patients who are over-

anticoagulated before they have had a

bleeding episode.

However, monitoring is not completely

protective.

A study cohort consisted of 2391 patients on long term warfarin. ◦ Warfarin-related hemorrhage occurred 1.3% of

patients .

◦ The mean INR at the time of the bleeding event is 5.9◦ The mean last INR before the bleeding event is 3.0◦ The last INR before the bleeding event were obtained

an average of 11.6 days before the event.

◦ Serial INRs are poor predictors of hemorrhagic events.

There appears to be only a brief warning period during which a slightly elevated INR predicts an imminent bleeding event.

International normalized ratio increase before warfarin-

associated hemorrhage: brief and subtle. Arch Intern Med.

2004;164(19):2176

Guidelines on oral anticoagulation with warfarin – fourth edition, BRITISH COMMITTEE FOR STANDARDS IN HAEMATOLOGY

Venous thromboembolism (VTE)

◦ First episodes of VTE should be treated with an INR target of 2.5

◦ Warfarin used for treatment of VTE should be introduced along with parenteral anticoagulation (1A) which should continue for at least 5 days and until the INR is >2 for at least 24 h

Atrial fibrillation

◦ Patients with AF who require warfarin for the prevention of cardio-embolic should have an

INR target of 2.5

Valvular heart disease

◦ Patients with mitral stenosis or regurgitation who have atrial fibrillation or a history of

systemic embolism or left atrial thrombus or

an enlarged left atrium should receive

warfarin with an INR target of 2.5

Mechanical heart valves

Bioprosthetic heart valves◦ Patients with a bioprosthesis in the mitral position should

receive 3 months of anticoagulation with warfarin with an INR target of 2.5

◦ Patients with a bioprosthetic valve and a history of systemic embolism should have at least 3 months of anticoagulation with warfarin with an INR target of 2.5

◦ Patients with a bioprosthetic valve and left atrial thrombus at surgery should receive warfarin until the clot has resolved with an INR target of 2.5

◦ Patients with bioprosthetic valves and other prothrombotic risk factors, such as atrial fibrillation and low ventricular ejection fraction, should receive warfarinwith an INR target of 2.5

Myocardial infarction and cardiomyopathy

◦ The use of warfarin following myocardial infarction has become less common as a

result of the emergence of new management

strategies

◦ Patients with dilated cardiomyopathy who are anticoagulated to prevent systemic embolism

should have an INR target of 2.5

Warfarin interactions

◦ Genetic interactions — Polymorphisms in the genes for the following two enzymes have

been associated with altered sensitivity to

warfarin

◦ Drug interactions

Warfarin interactions

◦ Genetic interactions — Polymorphisms in the genes for the following two enzymes have

been associated with altered sensitivity to

warfarin

◦ Drug interactions

A wide range of drugs has been linked to an

increased risk of major bleeding in warfarin users

Concurrent Use of Warfarin and Antibiotics and the Risk of Bleeding in Older Adults, American Journal of Medicine vol 125 Feb 2012

A wide range of drugs has been linked to an increased risk of major bleeding in warfarinusers.

Concomitant use of antibiotics is particularly common and is associated with a high risk of overanticoagulation.

The primary mechanisms by which

antibiotic medications interact with

warfarin to increase the risk of major

bleeding is through disruption of intestinal

flora that synthesize vitamin K, and

inhibition of cytochrome p450 isozymes,

which metabolize warfarin.

Methods

◦ A case-control study nested within a cohort of 38,762 Medicare beneficiaries enrolled in

Medicare of 2007 who were continuous users

of warfarin.

◦ Continuous warfarin users were followed from January 1, 2008 until hospitalization for a

bleeding event or the end of study period

(December 31, 2008), whichever occurred

first.

Cases

◦ Patients who experienced a bleeding event requiring hospitalization at any time in 2008 based on ICD-9-CM codes, in the primary diagnosis position.

◦ Identified bleedings: gastrointestinal, non-gastrointestinal, intracranial and general warfarintoxicity.

Controls

◦ Controls were assigned an index month corresponding to the event date of matched cases.

Definition of Exposure

◦ Antibiotic exposure was determined by assessing the number of days in a given prescription period.

◦ Patients whose most recent prescription period for any antibiotic agent with the 15-day period before the event/index date were defined as exposed.

◦ Antibiotic agents included: azole antifungals, macrolides, quinolones, cotrimoxazole, penicillins, and cephalosporins

Potential Confounders

Use of potentially confounding

medications.

◦ Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors

(SNRIs), antiplatelets , corticosteroids and

cytochrome and P450 isozyme 2C9 inhibitors

(amiodarone, gemfibrozil, nicardipine,

clofibrate, fluvastatin sodium, fenofibrate,

lovastatin, zafirlukast, and fenofibric acid).

Results

◦ 38,762 patients who were defined as continuous warfarin users

◦ 1136 patients (2.9%) were hospitalized with a primary diagnosis of bleeding

◦ 798 patients met the definition for a case

◦ Exposure to any antibiotic agent within the 15 days of the event/index date was associated

with an increased risk of bleeding

All 6 specific antibiotic drug classes

examined (azole antifungals, macrolides,

quinolones, cotrimoxazole, penicillins, and

cephalosporins) were associated with an

increased risk of bleeding.

Azole antifungals and cotrimoxazole had

the highest risks.

Frequent monitoring of INR has been

recommended for patients who are

concurrently taking warfarin and

antibiotic agents.

To monitor INR 1 week after initiating

antibiotic therapy.

More frequent monitoring should be

considered for patients at higher risk for

bleeding

TREATMENT FOR WARFARIN OVERDOSE

There are very few randomized studies

comparing the various treatment options

for patients with an elevated INR and /or

bleeding following the use of warfarin.

2012 American College of Chest Physicians (ACCP) clinical practice guidelines ◦ INR between 4.5 and 10 without bleeding —

The 2012 ACCP guidelines suggest against the routine use of vitamin K in this setting (moderate quality evidence) whereas the 2008 guidelines suggested its use, particularly if the patient is at an increased risk of bleeding (high quality evidence).

◦ Major bleeding —The 2012 ACCP guidelines suggest rapid reversal of anticoagulation with four-factor prothrombin complex concentrate (PCC) rather than with plasma (low quality evidence) plus the use of 5 to 10 mg of intravenous vitamin K (low quality evidence).

ANTICOAGULANTS OTHER THAN WARFARIN

A number of anticoagulants other than the

heparins and vitamin K antagonists are either

currently available or in clinical trials.

The mechanisms of action of the

anticoagulants discussed here include:

◦ Direct inhibition of thrombin (eg, dabigatran)

◦ Inhibition of Factor

◦ Inhibition of other coagulation factors (eg, tissue factor, factor VIIa, factor V, factor VIII, factor IXa)

Dabigatran

◦ An orally active direct thrombin inhibitor

◦ Used in the prevention and treatment of venous and arterial thromboembolic

disorders (eg, prevention of venous

thromboembolism after total knee or total

hip arthroplasty, treatment of acute VTE,

prevention of stroke in atrial fibrillation)

◦ A half-life of approximately 12 to 14 hours in adult with normal renal function, which requires twice daily dosing.

◦ Drug clearance is longer in older adults and those with reduced renal function.

◦ Does not interact with the cytochrome P450 system.

◦ However, it is a substrate for the efflux transporter P-glycoprotein. Certain P-glycoprotein inducers or inhibitors may alter dabigatran bioavailability (eg, rifampin, quinidine, ketoconazole, verapaml, amiodraone, clarithymycin).

◦ Routine monitoring of coagulation is not recommended.

◦ No antidote available

Summary

Drug interaction between warfarin and

antibiotics are common, and may course

increased bleeding risk.

May consider closer monitoring on INR

while patient is on course of antibiotics.

Patient education is important.

Newer agents are becoming available.

THE END

Thank you