Anticoagulant Accumulation / Toxicity

Question 1

Balancing Risk of Anticoagulant Use
Thrombosis vs Bleeding

Answer 1

• Implications of thrombosis – dependent on indication
  – Mechanical heart valves (INR 2.0-3.5) → valve thrombosis /
  stroke
  – Atrial fibrillation (INR 2.0-3.0) → stroke
  – Venous thromboembolism (INR 2.0-3.0) → pulmonary
  embolism
  – Different patient populations (contrast VTE vs AF)
• Bleeding – defined
  – Minor - trivial
  – Major bleeding – bleeding into a critical organ or a decline in
  Hgb 20g/L (clinical trials – transfusions [1 pack blood ~ 10g/L])
• CBCs annually in those on anticoagulants
• Error of omission vs commission
  – Educated patients prefer to be therapeutically anticoagulated

Minor resolves within 20 mins - expected
Major bleeding less common- definition of Major bleeding and clinical trials was a 20 gram per liter drop in hemoglobin.
When we transfuse patients. If you give them a unit of red cells, it’ll raise it by 10

Question 2

Major Bleeding: Intracranial vs Extracranial

Answer 2

Most feared complication, fortunately is uncommon
* Different types:
– Epidural or subdural hematoma – trauma, elderly - generally do well
– Subarachnoid or intracerebral hemorrhage –more likely to do less well
* Fixed space (within skull), concern with initial volume & expansion of bleeding
* Once hemorrhage occurs on anticoagulants, the initial volume, risk of expansion, severity and probability of death is higher
– Overall mortality rate of 40-67% with probability of functional recovery 17-24%
* Warfarin – 0.2-0.4% although older studies as high as 3%
* DOACs reduce the risk of ICH by 30-70% (compared to warfarin), with intracranial hemorrhage reported:
– smaller volumes of blood
– less severe strokes (more having functional recovery)
– fewer deaths

Question 3

Major Bleeding: Intracranial vs Extracranial

Answer 3

• Most common site is gastrointestinal but could be anywhere
• Majority result in full recovery with appropriate medical attention
• Requires reversal or interruption of therapy
  – Predisposes to risk of thrombosis, depending on duration of held anticoagulant
  – Identification of reason / source of bleeding –
  treated vs not

Question 4

Major Bleeding with OACs

Answer 4

• Crude estimates for warfarin in real world:
  – 2-5% for major bleeding; 0.5-1% for fatal bleeding; 0.2-0.4% for
  intracranial bleeding
• Clinical Trials vs Real World
  – Notable that only 12.6% of the 28,787 patients screened were
  enrolled in 6 AF clinical trials of warfarin vs placebo

Meta-analysis pooling results of DOAC (N=42,411) & warfarin N=29,272):
– Major bleeding overall: HR 0.86 (95% CI 0.73-1.00; P=0.06)
– Intracranial hemorrhage: HR 0.49 (95% CI 0.39-0.59; P<0.0001)
– Gastrointestinal bleeding: HR 1.25 (95% CI 1.01-1.55; P=0.043)

1. Major bleeding overall less than warfarin
2. Intracranial hem signif less with DOACs there was an increase in gi bleeding with the DOACs compared to warfarin

Question 5

Bleeding Risk Scales

Answer 5

• Indication dependent, reflecting different patient populations
• High bleeding risk score is not a reason to avoid anticoagulation
  – In AF, thrombotic and bleeding risk often rise in parallel
  – In VTE, implications with extended (secondary prevention) therapy –
  prophylactic dose vs cessation of therapy
• Benefit: awareness of bleeding risk for the front line clinician

Question 6

Assessment of Bleeding

Answer 6

• Bleeding - location
  – Major bleeding
• Extracranial
• Intracranial
  – Minor bleeding
• Timing of blood loss
  – When did it start? Stop?
  – Frequency?
  – Had this in the past?
• Qualify & quantify blood loss:
  – Color
  – Amount
  – Explanation (e.g., hemorrhoids)?
  – Hemoglobin drop?
  – Symptoms of anemia?
• Immediate Management
  – Monitor (CBC, S/Sx)
  – Refer to physician vs emergency department
• Future Management
  – Treatment of source vs not?
  – Mitigate other risk factors?
• Impact of major bleed vs clotting event
  – the error of commission vsomission
  – Most patients would prefer to
  be over-anticoagulated

Question 7

Anticoagulant Re-initiation Post-Bleeding

Answer 7

• Varies based on:
  – Bleeding characteristics: severity (significance), source (known
  vs unknown) & source treated vs not
  – Thrombotic risk (indication based)
  – Other factors: overall prognosis, adherence / stability of INRs, etc.
• Generalities of timing to restart:
  – < 2 weeks – increased risk of bleeding (unless cause of bleeding
  identified and rectified – then within a week)
  – 2-8 weeks – conservative approach to restart
• Observational data shows:
  – Post GIB: restarting decreases risk of thrombosis & mortality
  and does not increase risk of recurrence*
  – Post ICH – restarting reduces risk of ischemic events & mortality
  & had no difference in major bleeding**

If had intracranial hem - off anticoag for at least 1 week
GI bleed that’s managed - restart right awy
The more the the higher the thrombotic risk. Obviously the more urgency there is to restart anti coagulants.

general rule of thumb. We we usually wait a couple of weeks after Major bleed to restart - varies depending on person

Question 8

Exaggerated Impact of Warfarin:
Critical INRs

Answer 8

• Defined as an INR > 5.0
  – Different labs, different
  cut-offs
• Laboratory pages
  ordering clinician
• WHO requires labs to
  perform QA testing
  between an INR of 1.5-
  4.5 only
  – What does an INR of
  15.6 really mean????
  – Lab reports INR > 9 or
  >10

Question 9

Risk of Intracranial Hemorrhage
in Outpatients

Answer 9

Hemorrhage risk highest during initial phase of treatment
Rate varies with age and likely other risk factors
Rate of life-threatening hemorrhage is low

aaICH most concerning,
have a fixed area (within
the skull) – can have larger
hematoma volumes /
expansion vs spontaneous ICH

we do know that intracranial hemorrhage does increase as the in our gets higher and pictured here, you can see that certainly is the in our exceeds 4 and arguably as it exceeds 5, the risk of of ICH increases

Question 10

Warfarin Mechanism of Action
Warfarin 5 mg daily
- Typical Response

Answer 10

Warf only impacts clotting factors that are being produced by the liver - reason why its so delayed
Have to wait for liver to produce clot facotrs

it prevents the reduction of vitamin K.

So what we what we have is more oxidized versus reduced vitamin K. We need reduced vitamin K to transfer a carboxyl group to all of the vitamin K Dependent clotting factors.

This extra carboxyl group is needed to have the clotting factors that are vitamin K dependent be activated.

based on the mechanism of action. We’re most concerned with the half-life of the clotting factors.

focus on the most is factor 2 0r thrombin factor.
as long as the patient has enough a factor 2 on board. They’re able to form clots. Okay, Factor 2 has the longest half life at 60 h.
so that again contributes to the delay of warfarin and onset, and also offset.

Question 11

Maintenance Dosing Chart
(Target INR 2.5; range 2.0 – 3.0)

Answer 11

INR Action
< 1.5 Reload 0 – 2,  weekly dose by 5 – 15%
1.5 – 1.9 Reload 0 – 1,  weekly dose by 0 – 10%
2.0 – 3.0 No change
3.1 – 3.5 Hold 0 – 1,  weekly dose by 0 – 10%
3.6 – 4.9 Hold 0 – 2,  weekly dose by 5 – 15%
5.0 – 9.0 Hold warfarin, Vitamin K 1-2.5 mg PO x 0-1
> 9 Hold warfarin, Vitamin K 2-5 mg PO
Guidelines are to be used as a general framework for dosage
adjustment – to be modified as individual needs dictate

we’re dose adjusting warfare for people that are on regular maintenance, dosing
we’re doing an adjustment of a small percentage of their regular dosing anywhere from 0 t0 15% in general
DOSE RESPONSE IS NOT LINEAR
It’s more curvy linear so the the higher we get with dosing) the more profound fx on INR

Question 12

Factors Impacting (Elevating) the INR
Areas to Target for Patient Assessment

Answer 12

1. Deterioration in Health
   – Acute changes (flu/COVID, fever, diarrhea,
   etc.)
   – Chronic Medical Condition Changes:
   * Exacerbation of heart failure
   * Change in thyroid status
2. Changes to Medications*
   – Prescription, non-prescription, herbals
3. Changes to Lifestyle
   – Vitamin K intake
   – Alcohol Consumption
   – Level of Activity
4. Administration of too much warfarin
   – Inadvertent dose doubling
   – Tablet strength mix up

*Drug Interactions:
1. Induction /Inhibition of Cytochrome P450
* Major 2C9
* Minor 3A4, 1A2
2. Displacement of binding plasma proteins
3. Alterations in Vitamin K Status
4. Contributing to bleeding/ clotting risk
Assess:
-timing of impact
-chronicity of change

Question 13

Warfarin Reversal:
Vitamin K Routes of Administration

Answer 13

• Intravenous
  – Life threatening situations, impact in 6-12 hours, a
  little goes a long way
• Intramuscular
  – Contraindicated, risk of hematoma, prolonged
  leaching from muscle – problematic post reversal
• Subcutaneous
  – Ineffective, inappropriate route
• Oral
  – Effective in non-emergent situations, impact in ~16-24
  hours, dosing ranges from 1-5mg

There’s 4 ways to give it. It should only be given 2 ways.
intravenous and oral are the only 2 ways that it should ever be given.

Intramuscular injections are contraindicated, and somebody that’s got a critical in our risk of hematoma is the biggest concern, and it also is really messy with vitamin. K.
Because vitamin K is a fat, soluble vitamin. So this has happened. Patients, when they get
10 milligrams. I am what happens is that slowly leaches out of their muscle, and they’re sub therapeutic for weeks

Question 14

Warfarin Reversal: IV Vitamin K

Answer 14

• Take home –
  – A little goes a long way
  – Typical dose in ER: Vit K 10mg IV –
  reasonable if bleeding; poses likelihood of
  refractoriness to warfarin reinstitution

On the left we see only half a milligram of IV Vitamin k. Being given, and then on the right is one milligram of vitamin K.

Readily reduces INRs
0.5mg goes a long way

50% of pt who got 1mg vit K overreduced (they lowered it too much)

Target INR was 2 - the 1mg group landed on less than 2

When patients present to emerge in their bleeding, they usually get a full ampoule, which is 10 mg, and that’s fair. If they’ve got Major bleeding going on

Question 15

Randomized trial of PO vs SQ Vitamin K 1mg

Answer 15

• Oral Vitamin K is more effective than SQ
  Vitamin K in re-establishing a therapeutic
  INR for those having an INR of 4.5-10.
  – SQ response is similar to simple holding
  warfarin

This was a randomized trial of oral versus subcutaneous vitamin K. Given at one milligram. The orange bars are oral blue, is subcutaneous.

you can see that Oral had a bigger impact.

. I would suggest to you that subcue Vitamin K is very much like placebo
just doesn’t work.

Question 16

Warfarin Reversal based on Criticality of
INR: Vitamin K 2.5mg Orally

Answer 16

• Conclusion: efficacy / safety of
  holding warfarin for 1-2 days and
  giving Vitamin K 2.5 mg PO x1 if
  INR is 5.0-10.0
  – If INR > 10, may need more Vitamin K

2.5mg oral vit J and reassess in 24 h
4/6 of INRs > than 10 still had INR > than 5 at 24 h.

So this study implied that if we’re going to use vitamin k. For INRs greater than 10. We may need to give more than 2.5mg Okay. So the more critical the in our
potentially the more vitamin. K: you want to get.

Question 17

Vitamin K (low dose): impact on bleeding

Answer 17

Randomized, blinded, placebo-controlled trial assessing if PO Vit K
1.25mg reduces bleeding in non-bleeding patients (INR 4.5-10.0)

• Limitations: not powered to detect differences in major bleeding,
  followed out to 90 days & left warfarin management at clinician’s
  discretion
• Of the 13 major bleeding events; 10 (77%) occurred in patients > 70 years
• No differences in stroke / TE between groups suggesting low dose Vit K is
  safe & lowers the INR more rapidly than placebo
• Practical Use: Even though no difference in outcomes, assess patients
  based on risk of bleeding

placebo-controlled trial of oral vitamin. K. 1.25 mg in non bleeding patients that had INRs between 4.5 and 10.
What we can see is that for those folks that got vitamin K, there was a statistically significant reduction in their inr. although clinical outcomes were unchanged. so no difference in bleeding or any outcomes.

unfortunately, this study wasn’t power to detect differences that were meaningful, like major bleeding

Question 18

Vitamin K in Critical INR Management:
Ambulatory, Non-Bleeding Patient

Answer 18

4.5 - 10.0 “… suggest against the
routine use of Vitamin K.” (2B)
Omit 1-2 warfarin doses, consider
Vitamin K PO 1-2.5 mg & reassess INR
> 10.0 “… suggest Vitamin K be
administered.” (2C)
Hold warfarin, Vitamin K PO 2-5mg & reassess INR

Antidote for Warfarin = Vitamin K
Oral – works within 16-24 hours
IV – begins to works in 6-12 hours
SC – Not recommended
IM – Not recommended
Prothrombin Complex
Concentrate (factors II, VII, IX, X)
Temporary reversal of INR (within minutes)

it’s all oral on an ambulatory basis. Pt swallow the liquid from comm pharm

Can still consider b/w 4.5-10
- we would hold warfare for one or 2 days, and we would consider a lower dose of vitamin K if worried
If they’re greater than 10. It is suggested that vitamin k be administered, i’d say, greater than 9 0r 10, and then,
IV works a little quicker, 6 t0 8 h. Oral takes about 16 t0 24 h to work, a

Question 19

Ambulatory Critical INR Management:
A Simplified Overview

Answer 19

Signs or Symptoms of Bleeding / Unusual Bruising or
Something more Concerning Ongoing
– Medical Attention vs. Ambulatory Management
* Clot vs Bleed Risk
– Immediate Critical INR Management: hold warfarin +/-
administer Vitamin K
* Factor(s) Contributing to Critical INR
– Maintenance Dosing Post-Critical INR Management

Question 20

Patient Counselling with Critical INR

Answer 20

• Specific to warfarin dosing / holding timing instructions
  (ensure understanding)
• Specific to Vitamin K administration, if applicable
• Specific to increased risk of bleeding
• General precautions to mitigate bleeding:
  – Restful evening / day (no contact sports, etc.)
  – General avoidance of exposure to high risk situations that may
  result in cutting oneself (shaving with razors, use of knives, exposure to dangerous equipment) or injuring oneself (falling and hitting head [avoid ladders, stools that may expose you to falling as well as slipping on the ice or in the bath tub / shower]
  – Avoid alcohol, if applicable
• Ongoing monitoring for signs / symptoms of bleeding
  – Overview of what to look for
  – Head to ER if concerning bleeding occurs

Question 21

Post-Critical INR Management
INR is now (near) Therapeutic, Then What?

Answer 21

• Acute, reversible cause identified – simply document an INR < 4.0 (depending on bleed & clot risk, whether vitamin K was given) and
  implement warfarin dosing similar to that prior to the inciting occurring [e.g., ethanol binge]
• Acute event that is now not reversible and going to continue (drug interaction) – document an INR < 4.0 (as above) and empirically decrease warfarin dosing based on experience / literature [e.g., amiodarone initiation]
• No identifiable reason – document an INR < 4.0 (as above) then depending on clot vs bleed risk reduce maintenance dosing accordingly (typically ~10% decrease although based on clot vs bleed risk)
  – Generally speaking, frequency of assessment would differ amongst 3 strategies

Question 22

read case for VQ

Answer 22

we’re restarting warfare in the setting where we know what their maintenance though, should should be, we restarted at 1.5 x reg dose for 3 days

We found that if we restart regular maintenance dosing, it can take as long as 20 days to get a therapeutic INR

Question 23

Urgent Warfarin Reversal:
Prothrombin Complex Concentrate (PCC

Answer 23

• Derived from human plasma, administered by IV infusion
• Contains Factors II, VII, IX, X, protein C & S
• Reduces INR within minutes, effect is not sustained (6-12
  hours)
  – Must also administer Vitamin K to sustain reversal in INR
  – Vitamin K route is IV; doses are typically 10mg (entire vial)
• Indications:
  – Serious or life-threatening bleeding
  – Require urgent (< 6 hours) interventions with risk of bleeding
• aPCC (activated PCC) – contains activated FVIIa

when we give patients pccs, we all feel better because the inr is reversed. But do they do Well, so this is stroke registry data from Canada, and what it shows is even with INR reversal, these patients do poorly.

dropped pretty good less than 1.5 within an hour of the Pccs
Still high mortality rate? Bad to bleed in brain while on warf

Question 24

DOACs: Mechanism of Action

Answer 24

• Exert effect
  directly on
  clotting factor,
  hence “direct”
  OAC
• Warfarin
  indirect via Vit K
• LMWH requires
  a cofactor
  (antithrombin)
  to exert effect
  on clotting
  factors

Question 25

DOACs – General Overview

Answer 25

• DOACs peak @ 2-4 hours & have shorter half-lives (7-14
  hours) – timing of last dose & adherence important
• Renal elimination – dabigatran (80%) > edoxaban (50%) >
  rivaroxaban (33%) > apixaban (25%)
  – Dabigatran is removed by dialysis (drug blood concentration
  decrease by 62% @ 2 hours)
• Accumulation if:
  – Overdose
  – Acute renal failure
  – DDI (strong P-gp inhibition for dabigatran & edoxaban; strong Pgp + 3A4 inhibition for rivaroxaban & apixaban)
• Need for “reversal” (as opposed to watch & wait):
  – Major bleeding or urgent need for procedure
  – Acute ischemic stroke (and desire for thrombolysis – off label)
• Assessment of DOAC concentration (quantifiable – not
  typically readily available) vs presence (qualitative)
  – Correlate these with timing of dosing

Question 26

DOAC impact on Coagulation Tests
NO Routine Coagulation Testing is Done

Answer 26

see slide 36

Question 27

“Reversing” (Warfarin &) DOACS

Answer 27

slide 37

Question 28

Anti-fibrinolytics:
Tranexamic Acid, Aminocaproic Acid

Answer 28

Mechanism: Inihibit fibrinolysis by preventing
conversion of plasminogen to plasmin

– Not antidotes, rather blocks the breakdown of blood clots
– Arrest / mitigate bleeding if other components of hemostasis
system are intact
– Practical Uses: topical if dental/nasal bleeding, oral if heavy
menstruation or intravenous in an operating room

Question 29

Idarucizumab (Praxbind™)
Antidote specific for only Dabigatran

Answer 29

Engineered antibody fragment (fab) that binds non-competitively
to dabigatran with ~350 stronger affinity than thrombin; half-life
4.5-9 hours

• Indicated for adult patients treated with dabigatran when rapid
  reversal of anticoagulant effect is required for:
  – Emergency surgery / urgent procedures
  – Life-threatening or uncontrolled bleeding
• IV bolus / infusion of two vials (each idarucizumab 2.5mg = 5g
  dose)
• Use in Emergency Departments / Operating Rooms
  It’s a really good antidote specific to dabig. It binds to dabig very, very strongly, and sucks it out of the circulation.

There was a bleeding at a cohort and a cohort that needed procedures, and they both d

it’s indicated for surgery and urgent procedures, if it’s emergent within 4 t0 6 h. Or if there’s life-threatening or uncontrolled bleeding.
it’s an Iv product it can be given by bolus, and it’s 5 grams given

Question 30

Andexanet Alfa
Antidote for Factor Xa Inhibitors

Answer 30

• Modified recombinant factor Xa (FXa) molecule that
  acts as a decoy to target and sequester with high
  specificity both oral and injectable FXa inhibitors –
  competitive binding
  – catalytically inactive, and retains a high binding affinity to
  FXa inhibitors
• Bolus (400 or 800mg) followed by intravenous
  administration (4 or 8mg/min for 2 hours) – “short”
  half life (2.7-3.3 hours)
• Not approved but soon coming to Canada, conditional
  approval in USA (labeled only for apixaban &
  rivaroxaban reversal)
• Requires refrigeration, expensive in the USA

Question 31

“Real World” Use of Antidotes …

Answer 31

Warfarin:
– Dedicated stroke centres took 380 minutes for time to
treatment (PCCs)
– RE-LY – of 421 with major bleeds on warfarin only 5
received PCCs
* Idarucizumab
– Approved for:
* Life-threatening or uncontrolled bleeding
* Emergency surgery / urgent procedures
– Product available in stroke centres (N=23)
– Only a handful of uses over the past year
* Prevention is key
– Right drug, right dose, right patient

Question 32

Prevention of Future Bleeding

Answer 32

• Control / management of modifiable risk factors:
  – Blood pressure
  – Alcohol consumption
  – Fall risk / stability
  – Age, renal dysfunction, hepatic dysfunction
• Medication Management
  – Antiplatelet agents / NSAIDs
  – Appropriate anticoagulant
• If warfarin, INR target / control
  – Drug-drug interactions that enhance anticoagulant