ihgm presentationhkgs.org/ihgm/ihgm_grace chan_22feb2013.pdf · 2015. 4. 17. · 22 feb 2013...
TRANSCRIPT
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IHGM Presentation
22 Feb 2013
Speaker: Dr Grace Chan, TWEH HKEC
Chairman: Dr KH Wong
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2 patients with warfarin
overdose
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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
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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 )
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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
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CXR: no gross consolidation, mild RLZ
hazziness
Blood test:
◦ CBP WBC raised 10.4, RFT normal, LFT slightly raised ALT 63, INR 3.5
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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)
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Prolonged INR while taking usual dose
warfarin
◦ ? Diet
◦ ? Drug compliance
◦ ? Drug interaction with antibiotics
◦ ? Liver derangement
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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
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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
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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
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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
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Admission on 23/12/12
Poor appetite
Nausea and vomiting
No diarrhoea
No fever
No abdominal pain
No chest / urinary symptoms
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Physical exam on admission
◦ BP / P stable. Low grade fever 37.5 degrees
◦ Mildly dehydrated
◦ Chest clear
◦ Abdomen soft non tender, bowel sound normal
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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
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Treated as sepsis ? UTI
IVF rehydration
Started on empirical levofloxacin since
24/12/12
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Transferred to TWEH for convalscence
Fever down
Oral intake improved
MSU grew enterococcus
Completed course of levofloxacin
Continued warfarin at usual dose 1mg
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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
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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
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ANTICOAGULATION WITH WARFARIN
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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.
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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
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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
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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).
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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.
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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.
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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.
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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
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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
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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
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Mechanical heart valves
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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
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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
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Warfarin interactions
◦ Genetic interactions — Polymorphisms in the genes for the following two enzymes have
been associated with altered sensitivity to
warfarin
◦ Drug interactions
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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
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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.
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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.
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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.
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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.
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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
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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).
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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
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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.
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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
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TREATMENT FOR WARFARIN OVERDOSE
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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.
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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).
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ANTICOAGULANTS OTHER THAN WARFARIN
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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)
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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)
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◦ 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).
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◦ Routine monitoring of coagulation is not recommended.
◦ No antidote available
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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.
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THE END
Thank you