Anticoagulant Toxicity- extra questions

Question 1

What factors determine the potential risks and benefits of using anticoagulants?

Answer 1

The potential risks + benefits of using anticoagulants depend on:
- the patient’s PMHx, and
- specific indication for which they’re prescribed for

For eg.,
In a pt w/ a high stroke risk:
- benefits of anticoagulants: preventing thromboembolic events
- risks of anticoagulants: serious bleeds

Question 2

The potential implications of thrombosis vary depending on the indication for the anticoagulant therapy.

Recall the potential implications of thrombosis for VTE.

Answer 2

The use of anticoagulants in VTE is intended to prevent the formation of new clots and decrease the risk of pulmonary embolism.

Thus, the implication of thrombosis in VTE is pulmonary embolism.

Question 3

The potential implications of thrombosis vary depending on the indication for the anticoagulant therapy.

Recall the potential implications of thrombosis for atrial fibrillation.

Answer 3

The use of anticoagulants in atrial fibrillation is intended to decrease the risk of stroke, thus the implication of thrombosis in AF is stroke.

Question 4

The potential implications of thrombosis vary depending on the indication for the anticoagulant therapy.

Recall the potential implications of thrombosis for mechanical heart valves.

Answer 4

valve thrombosis / stroke

Question 5

What is the recommended INR range for patients with VTE, atrial fibrillation and mechanical heart valves, respectively, to prevent pulmonary embolism, stroke and valve thrombosis?

A) VTE: INR: 2-3; AF: INR 2-3; mechanical heart valves: INR 2-3.5

B) VTE: INR 2-3; A-fib: INR 2.5-3.5; mechanical heart valves: INR 2.5-3.5

C) VTE: INR 2.5-3.5; A-fib: INR 2-3; mechanical heart valves: INR 2.5-3.5

D) VTE: INR 2.5-3.5; A-fib: INR 2.5-3.5; mechanical heart valves: INR 2-3.5

Answer 5

A) VTE: INR: 2-3; AF: INR 2-3; mechanical heart valves: INR 2-3.5

Question 6

Which of the following statements is true regarding the occurrence of VTE and atrial fibrillation?

A) Both tend to occur in older patients who have other cardiac issues.

B) Both tend to occur in younger, healthier patients.

C) VTE tends to occur in older patients who have other cardiac issues, while atrial fibrillation tends to occur in younger, healthier patients.

D) VTE tends to occur in younger, healthier patients, while atrial fibrillation tends to occur in older patients who have other cardiac issues.

E) none of the above

Answer 6

D) VTE tends to occur in younger, healthier patients while atrial fibrillation tends to occur in older patients who have other cardiac issues.

Question 7

What are the potential implications of bleeding due to anticoagulant toxicity?

Answer 7

Recall: The potential implications of bleeding due to anticoagulant toxicity are more clearly defined than those of thrombosis.

Minor bleeding events = trivial (eg nosebleed)

Major bleeding events = well-established complications of anticoag tx + can be life-threatening. (eg bleeding into a critical organ).

extra notes: critical organ - brain, <3, lungs

Question 8

indicator that suggests pt is experiencing a severe bleed

Answer 8

Hgb ↓ by 20g/L

Question 9

The ER MD would like to administer a blood transfusion to a patient who has experienced a severe bleed. GOT: increase Hgb levels by 15g/L. How many blood packs would you recommend be adminisered?

Answer 9

1.5 packs

In clinical trials, transfusion of 1 blood pack was typically expected to increase Hgb lvls by ~10g/L.

Question 10

A regular patient with atrial fibrillation visits your pharmacy to pick up a refill of their Xarelto (rivaroxaban) that they’re taking to prevent stroke. During the conversation, the patient reports that they have not experienced any minor bleeding or noticed any blood in their stool or urine. Reviewing the patient’s medical history on Netcare, you discover that their CBC (complete blood count) was last checked 5 months ago.

Based on this information, when would you recommend that the patient undergo another CBC test?

Answer 10

Patients taking anticoagulants should have annual CBCs done to monitor any changes that may indicate bleeding or other complications.

Thus, this pt should get another CBC test in 7 months.

Question 11

What is the clinician’s dilemma in managing anticoag therapy, and how can it lead to errors of omission and commission in treatment decisions?

Answer 11

The clinician’s dilemma in anticoag therapy is balancing the potential risks and benefits of anticoagulants.

Anticoagulants are associated with a risk of bleeding, which is a serious and potentially life-threatening complication. At the same time, they are effective in preventing blood clots that can cause other serious conditions like stroke.

Therefore, clinicians are at irks of making errors of omission and commission.

An error of omission occurs when clinicians fail to prevent a thrombotic event by withholding anticoagulant therapy, while an error of commission occurs when they cause a bleeding complication by administering anticoagulants.

Question 12

How does a pt’s preferences influence anticoagulant treatment decisions?

Answer 12

Patients educated about the risks and benefits of anticoags and who understand the potential consequences of not taking them may prefer to accept the risk of bleeding to prevent thrombotic events depending on their own values.

It’s impt to note that the risk of clotting tends to be higher than the risk of bleeding.

Question 13

What should be done in response to a major bleed event experienced by a patient who’s currently on anticoag therapy?

Answer 13

1 - Stop or reverse the anticoagulation to prevent further bleeding. Note, different methods of reversal or interruption may be required depending on the severity of the bleed.

2 - Determine the cause of the bleeding. Is it anticoagulant-related?

3 - Be aware: stopping anticoagulation can increase the clot risk, esp in pts at high risk for thrombosis. Thus, the duration of interruption should be assessed when weighing the risks + benefits of continuing or interrupting anticoagulants in these pts.

Question 14

What is an example of a type of major bleed that may occur due to anticoagulant toxicity?

Answer 14

intracranial hemorrhage
- epidural or subdural hematoma
- subarachnoid or intracerebral hemorrhage

extracranial hemorrhage

Question 15

Describe the severity of the different types of major bleeds that may occur in a pt taking anticoagulants.

Answer 15

A patient who may be experiencing an accumulation of anticoagulant in the body may experience different types of major bleeds of varying severities.

extracranial hemorrhage (majority will have full recovery)
↓
intracranial hemorrhage: epidural or subdural hematoma (generally less severe)
↓
intracranial hemorrhage: subarachnoid or intracerebral hemorrhage (more severe)

Question 16

Describe the risk and prognosis of epidural hematomas in older adults.

Answer 16

Older adults are at HIGHER risk of experiencing an epidural OR subdural hematoma (intracranial hemorrhage), and generally do WELL and have GOOD outcomes.

Question 17

Which type of intracranial hemorrhage is often associated with situations like a fall or car accident?

Answer 17

Epidural or subdural hematomas are often associated with trauma or injury.

Question 18

Describe the location for each of the types of major bleeds that may occur in a pt experiencing anticoagulant toxicity.
1. intracranial hemorrhage
2. epidural hematoma
3. subarachnoid hemorrhage
4. intracerebral hemorrhage
5. subdural hematoma
6. extracranial hemorrhage

Answer 18

1. intracranial hemorrhage - inside skull
2. epidural hematoma - b/w skull + epidural (outermost brain layer)
3. subarachnoid hemorrhage - space b/w arachnoid membrane + pia mater which surround brain
4. intracerebral hemorrhage - within brain tissue
5. subdural hematoma - b/w subdural and brain
6. extracranial hemorrhage - most commonly in GI, but can be anywhere outside of skull

Question 19

Which of the following are considered a type of extracranial hemorrhage?
A) subarachnoid hemorrhage
B) epidural hematoma
C) subdural hematoma
D) intracerebral hemorrhage
E) none of the above

Answer 19

E) none of the above

Options A) - D) are all considered a type of intracranial hemorrhage.

Question 20

Select all that apply. Which of the following statements is/are correct about intracranial hemorrhages?

A) They refer to bleeding that occurs outside of the skull.

B) Intracerebral hemorrhages occur in the space between the arachnoid membrane and pia mater.

C) Subarachnoid hemorrhages are generally less severe and often associated with trauma or injury.

D) Bleeding within the skull can quickly increase pressure and compress brain tissue, which can lead to permanent brain damage or death.

Answer 20

Incorrect:
A) They refer to bleeding that occurs INSIDE of the skull.

B) SUBARACHNOID hemorrhages occur in the space between the arachnoid membrane and pia mater.

C) Subarachnoid hemorrhages are generally MORE severe.
EPIDURAL OR SUBDURAL HEMATOMAS are generally less severe and often associated with trauma or injury.

Correct:
D) Bleeding within the skull can quickly increase pressure and compress brain tissue, which can lead to permanent brain damage or death.

Question 21

Explain why the following statement is true or false.
“Extracranial hemorrhages may result in significant morbidity and mortality.”

Answer 21

FALSE.

INTRACRANIAL hemorrhages are the most feared major bleed complication of anticoagulant therapy because they can result in significant morbidity and mortality.

Whereas, the majority of patients who experience an extracranial hemorrhage will fully recover (ie leave the hospital w/ same QOL).

Question 22

Describe one reason why subarachnoid and intracerebral hemorrhages are considered more severe than epidural or subdural hematomas.

Answer 22

Epidural and subdural hematomas occur outside the brain, between the skull and the outermost brain layer (dura mater), whereas subarachnoid and intracerebral hemorrhages occur inside the brain. Any bleed within the skull can quickly increase pressure and compress the brain, which is especially problematic in subarachnoid or intracerebral hemorrhages where brain tissues can become damaged.

Since the subarachnoid and intracerebral hemorrhages involve more internal areas of the brain where brain tissue can become damaged, permanent brain damage or death can occur unlike in epidural and subdural hematomas, hence they’re considered more severe.

Question 23

Describe the estimated risk of major bleeds with oral warfarin in the studies we discussed in class. What was the limitation of this study?

Answer 23

Study 1:
- major bleed 2.5% –> intracranial bleed 0.2-0.4%
- fatal bleed 0.5-1%

Study 2: meta-analysis
- major bleed 3.09-3.43% / year

limitation: Only 12.6% of screened individuals were enrolled in 6 anticoag-treated atrial fibrillation clinical trials. AF pts may have diff bleed risk profiles than non-AF pts, thus excluding them from estimate calculations could lead to an incomplete understanding of the bleed risk associated with PO warfarin in this specific population. Especially since anticoags are commonly used in AF pts. It is possible that researchers selected pts w/ lower bleed risk to participate in the trials to create favourable results.

Study:
- Incidence, clinical impact and risk of bleeding during oral anticoagulation therapy in the real world, based on a review of avail literature
- Evaluation of bleeding in patients receiving DOACs

Question 24

Describe the estimated risks of major bleeding with direct oral anticoagulants (DOACs) from the meta-analysis we talked about in class.

• dabigatran 150mg, 110mg
• rivaroxaban
• apixaban
• edoxaban 60mg, 30mg

Answer 24

edoxaban 30mg: 1.61%/yr

apixaban: 2.13%/yr

dabigatran 110mg: 2.71%/yr

edoxaban 60mg: 2.75%/yr

dabigatran 150mg: 3.11%/yr

rivaroxaban: 3.6%/yr

TAKEAWAY: DOACs were associated with a lower bleed risk than warfarin = DOACs are safer.

Study: Evaluation of bleeding in patients receiving DOACs

Question 25

Describe the prognosis for a pt that experiences an intracranial hemorrhage while using an PO anticoag.

Answer 25

Once an ICH occurs in a pt taking anticoag, the initial volume, risk of expansion, severity and probability of death ↑.

Overall mortality rate = 40-67%

Probability of functional recovery 17-24%

TAKEAWAY: prognosis is not good :(, hence ICH is considered a severe major bleed complication of anticoag toxicity

Study: Epidemiology of ICH associated with oral anticoagulants in Spain

Question 26

Compare the risk of intracranial hemorrhage between warfarin and DOACs. Provide specific details.

Answer 26

DOACs have a lower risk of ICH compared to warfarin (↓ risk by 30-70% vs warfarin).

&

In DOAC-rltd ICHs, there were reports of:
- ↓ volume of blood
- ↓ stroke severity (↑ fxnal recovery)
- ↓ deaths

Study: Epidemiology of ICH associated with oral anticoagulants in Spain.
Context:
- warfarin: 0.2-0.4% –> 3% incidence

Question 27

Explain why the following statement is true or false.

“A high bleed risk score is considered an absolute contraindication to anticoagulant use.”

Answer 27

FALSE.

A high bleed risk score is not an absolute contraindication to anticoag use. For eg, in AF, the thrombotic + bleed risk often ↑ in parallel. Ie risk of thrombosis ↑ b/c irregular heart rhythm can cause blood to pool and clot within <3. At the same time, anticoag also ↑ risk of bleed b/c it ↓ blood’s ability to clot.

Thus, assessing a pt’s OVERALL risk profile is necessary to guide decision-making around anticoag. B/c while a high bleed risk score may suggest a ↑ risk of bleeding, it does not necessarily mean that anticoag should be avoided altogether.

Question 28

You’re a pharmacist working in a hospital and a pt w/ a recent hx of stroke due to AF has been admitted. The pt is currenty taking an PO anticoag, but has a hx of bleeding. How would you assess the pt’s risk of bleeding?

Answer 28

Bleeding risk scales are indication-dependent and reflect different pt popns. Thus, you must select the appropriate scale validated for your pt.

In AF, bleeding risk scales that can be used include:
- HEMORR
- HAGES
- HAS-BLED
- ATRIA

Question 29

You are a pharmacist in a hospital and a pt w/ a recent VTE is being discharged on extended prophylactic anticoag therapy. How would you use bleeding risk scales to guide your decisions?

Answer 29

Bleeding risk scales are indication-dependent and reflect different pt popns. Thus, you must select the appropriate scale validated for your pt.

In VTE, bleeding risk scales that can be used include:
- RIETE
- CHEST

Based on the score, consider the balance b/w the risk of recurrent VTE if anticoag is stopped vs the risk of bleed w/ ongoing anticoag.
- If the pt is @ high risk of bleeding, consider using prophylactic anticoag doses or even cessation of anticoag altogether.
- If pt is @ low risk of bleeding, consider continuing anticoag at recommended dose for extended prophylaxis.

Question 30

Describe how would you assess a pt who is experiencing bleeding?

Answer 30

S/C: colour? amt?
H: bleed hx?
O: onset? when did it stop? frequency?
L: minor / major? extracranial / intracranial?
Red flags: anemia sx?
E: anticoag-rltd? something else?

labs: Hgb ↓ ?

Question 31

What are the 3 components of managing bleeding in a pt receiving anticoag?

Answer 31

1. immediate mgmt
   
   • monitor signs + sx, CBC
   • refer to MD or ED?
2. future mgmt
   
   • tx of source or no?
   • mitigate other risk factors?
3. re-initiate anticoag post-bleed?
   note: recall error of commission vs omission + fact that most pts would prefer to be over-anticoagulated

Question 32

Recall the characteristics of a bleed in an anticoagulated pt that influence the decision to re-initiate anticoagulant therapy after the bleed.

Answer 32

• bleed severity
• source (known vs unknown; correctable vs uncorrectable)
• thrombotic risk
• overall prognosis
• adherence
• INR stability (for warfarin)

Question 33

Observational data discussed in class highlighted the benefits of re-initiating anticoag post-GI bleeds and post-ICHs. Recall these benefits.

Answer 33

Observational data shows:
post-GIB:
- restarting ↓ clot risk + mortality
- there was no ↑ risk of GIB recurrence

post-ICH:
- restarting ↓ risk of ischemic events + mortality
- there was NO DIFFERENCE in incidence of major bleeds

Question 34

When would you re-initiate a pt’s anticoag tx after a bleed?

Answer 34

If the pt has a significant risk of bleeding again, do not restart
- < 1wk if the cause of the bleed has been identified + rectified
- < 2wks if cause of the bleed is unknown

The common, conservative approach to anticoag re-initiation is to wait 2-8 wks.

Question 35

In class, we discussed the study: “Warfarin Reinitiation After Intracranial Hemorrhage: A Case Series of Heart Valve Patients”.

What was the study about and what was its main objective?

Answer 35

The main purpose of the study was to examine the outcomes of heart valve pts who had experienced ICH while on warfarin, and to assess the safety and efficacy of reinitiating warfarin therapy in these pts.

Question 36

In class, we discussed the study: “Warfarin Reinitiation After Intracranial Hemorrhage: A Case Series of Heart Valve Patients”.

What were the characteristics of the 13 pts who experienced ICH episodes while on warfarin?

Answer 36

13 (0.3% of pts managed by anticoag-specialty clinic) had 16 ICH episodes.

Their median GCS score of 15 indicated that the pts experienced relatively mild hemorrhages that did not cause significant impairment in neurological fxn.

7 of 13 had INR values within range, 3 had subtherapeutic.

Question 37

In class, we discussed the study: “Warfarin Reinitiation After Intracranial Hemorrhage: A Case Series of Heart Valve Patients”.

How does the study challenge the traditional assumption that warfarin is always the primary cause of bleeding in pts on anticoagulation?

Answer 37

7 of 13 pts had INR values within range and 3 had subtherapeutic. Ie, some pts had INRs within or below therapeutic range at the time of their ICH. Thus, the bleed risk assoc w/ warfarin may not be as high as previously thought, esp when the drug is properly managed and kept within the therapeutic range. Other bleeding risk factors should be considered.

Question 38

In class, we discussed the study: “Warfarin Reinitiation After Intracranial Hemorrhage: A Case Series of Heart Valve Patients”.

How did the specialty clinic modify the management of pts who experienced ICH while on warfarin, and what were the outcomes?

Based on this info, what are the implications for the post-bleed management of pts w/ ICH while on warfarin?

Answer 38

The specialty clinic modified the INR targets, either by ↓ the targets, narrowing the range, or both.

Despite the traditional assumption that warfarin is the primary cause of bleeding in pts who experience ICH while on warfarin, post-ICH pts who restarted warfarin after the bleed generally did well.

Implications: Management of pts w/ ICH while on warfarin is complex and variable. However, the use of bleeding risk scales and modifying INR targets can help manage the bleeding risk assoc w/ warfarin. Additionally, the study suggests that post-ICH pts who restart anticoags generally do well, despite the expected high bleeding risk assoc w/ warfarin.

Question 39

How often are anticoagulant antidotes used in practice?

Answer 39

Not often. Could be used more.

In literature:
warfarin-PCCs
- dedicated stroke centres took 380 mins for time-to-tx
- RE-LY study: only 5/421 pts experiencing major bleeds received PCC
idarucizumab
- pdt was avail in 23 stroke centres, but only a handful were used in AB over the past year

Question 40

warfarin moa

Answer 40

inhibits enzyme responsible for converting oxidized vit K back to reduced (active) form = prevents vit K recycling = decrease clot factor production = takes longer for blood to clot

Question 41

Why is warfarin considered an indirect PO anticoag?

Answer 41

Warfarin only impacts hepatically-produced clot factors, not the free-floating ones.

Question 42

How does the half-life of clotting factors impact the monitoring and dose adjustments required during warfarin therapy, and why is it more important than the half-life of warfarin itself?

Answer 42

Considering the t1/2 of clot factors is more impt than warfarin t1/2 when monitoring the balance between anticoagulation and bleeding risk b/c clot factors directly affect the balance, unlike warfarin, which is an indirect anticoagulant. Additionally, ea clot factor has a different t1/2, and warfarin will not affect the lvls of these clot factors equally. Therefore, the t1/2 of clot factors determines the freq of monitoring and dose adjustments required during warfarin tx.

Question 43

A critical INR is defined as…

Answer 43

INR > 5

Question 44

True/False: As INR ↑ past 4, the risk of ICH ↑ significantly.

Answer 44

True.

Although a critical INR is defined as INR > 5, as INR ↑ past 4, ICH risk ↑ significantly.

Question 45

When is a lab required to perform quality assurance testing during the determination of a sample’s INR as mandated by the WHO?

Answer 45

WHO requires labs to perform quality assurance testing b/w INR of 1.5-4.5 only.

Question 46

Which of the following factors can cause an increase in a patient’s INR while taking warfarin?

A. Frequently taking antacids
B. Increasing vitamin K intake
C. Taking an antibiotic that inhibits cytochrome P450 CYP2D6
D. High caffeine intake
E. None of the above

Answer 46

E. None of the above

INCORRECT:
A. Frequently taking antacids –> no effect
B. Increasing vitamin K intake –> An increased intake of vitamin K does not cause an increase in INR because vitamin K is necessary for the production of clotting factors that are inhibited by warfarin. Warfarin works by blocking the action of vitamin K, which leads to a decrease in the production of these clotting factors. Therefore, an increase in vitamin K intake would actually counteract the effects of warfarin and increase the production of these clotting factors, leading to a decrease in the INR value.
C. Taking an antibiotic that inhibits cytochrome P450 CYP2D6 –> inhibition of 2C9, 3A4 or 1A2
D. High caffeine intake –> high EtOH intake

Question 47

LC is a 65-year-old who has been taking warfarin for the past year for the treatment of DVT. They regularly get their INR levels checked, and pick-up their rx for warfarin from your pharmacy.

Today, you notice that LC’s INR was higher than expected. On top of adjusting their warfarin dosing to address this, what nonpharm would you recommend to LC to prevent further INR increases?

Answer 47

Consult PharmD if starting any new meds to prevent drug-drug interactions w/ warfarin incl meds that inhibit cytochrome P450 CYP -2C9, -3A4, -1A2.

Limit EtOH intake to less than is needed to become drunk.

Consult PharmD or MD during acute or chronic changes leading to deterioration in health. Acute: flu, COVID, fever, diarrhea. Chronic: HF exacerbation.

Question 48

How may using warfarin lead to an increase in INR?

Answer 48

INR may increase if too much warfarin is taken. This may happen if a pt inadvertently doubles their doses or if a mix-up in tab strengths occurs (eg. dispense wrong strength tabs).

Question 49

Select all that apply. Which of the following route of administrations may be used to administer vitamin K for the reversal of warfarin effects?
A. PO
B. subcut
C. IM
D. IV
E. A, B, D
F. A and D only
G. A, B, C, D

Answer 49

F. A and D only

PO and IV

Question 50

JH is a 70-year-old patient who has been taking warfarin for a few years for stroke prevention due to atrial fibrillation. They present to the emergency department with extensive bruising and blood in their urine. On examination, the patient appears pale and their BP is 80/50 mmHg. Their INR level is 7.5. What would you recommend?

Answer 50

This is an emergency as patient is experiencing potentially life-threatening bleeding (as suggested by their current presentation).

Rapid reversal of warfarin’s effects and INR correction are needed.

Hold warfarin. Order vitamin K 10 mg IV, and if appropriate, consider adjunct PCC or aPCC.

Note: Upon resolution of bleeding, monitor for refractoriness to warfarin reinstitution. Determine when to re-initiate warfarin, if appropriate, by bleed vs thrombotic risk. Recall that a common, conservative approach is to wait 2-8 weeks post-bleed.

Question 51

What change in INR would you expect to see in a pt who receives vitamin K IV, and when?

Answer 51

Onset: 6-12 hrs
Significant decrease in INR.

Question 52

When would it be more appropriate to use vitamin K 0.5 mg IV over vitamin K 10 mg IV?

Answer 52

Lower-than-typical doses like 0.5-1mg IV are used if pt is at risk of developing warfarin resistance or if there’s a risk of overcorrection.

Vitamin K at very low doses can lead to significant increases in clot factors (which is good).

At 24 hours post-admin:
- 0.5 mg: 0% were overcorrected
- 1 mg: 50% overcorrected

Question 53

In what situation should the risk of warfarin resistance be considered?

Answer 53

The risk of warfarin resistance should be considered in patients who experience life-threatening bleeding while receiving warfarin and require rapid reversal of its effects using vitamin K 10 mg IV.

Warfarin resistance, or the phenomenon of refractoriness to warfarin reinstitution, may occur after this treatment and can result in a longer time to achieve the anticoagulant effect when warfarin is restarted.

Question 54

When reversing the effects of warfarin, when would it be more appropriate to use vitamin K PO over IV?

Answer 54

In non-emergent situations where reversal of warfarin’s effects are desired within 24 hours (b/c vit K PO onset = 16-24hr).

In the ambulatory setting, “non-emergent” means the pt is not bleeding.

Question 55

onset of action for PO vitamin K

Answer 55

onset: 16-24 hrs

Question 56

Describe the efficacy of PO vitamin K in reversing the effects of warfarin.

Answer 56

In a study:
withhold warfarin x 1-2D + vit K 2.5 mg PO x 1 = safe & effective in ↓ INR to < 5 in pts w/ initial INR > 5

for pts w/ initial INRs > 10, there’s a chance that their INRs may still be > 5 (ie critical) 24 hrs after vitamin K administration = may require additional vitamin K

Question 57

Describe the safety profile of using low-dose vitamin K PO to reverse the effects of warfarin. Recall that we used an RCT to discuss this in class.

Answer 57

The RCT intended to determine if vitamin K 1.25 mg PO decreased the bleed risk in NON-BLEEDING pts using warfarin and required a rapid reduction in INR (from initial 4.5-10).

Implications from findings:
- low-dose vit K is SAFE and effective in ↓ INR than placebo W/O ↑ risk of stroke, thromboembolism, overall bleeding and major bleeding
- age > 70 may be at ↑ risk for warfarin-assoc bleed complications

BUT, study limitations:
- study not powered to detect differences in major bleed events
- short F/U = lacking long-term safety and efficacy = longer-term F/U may be necessary
- hard to generalize study findings b/c diff pts were receiving diff warfarin regimens

TAKEAWAY: Low-dose vit K PO is useful when rapid ↓ INR is needed, but must still assess balance b/w bleed + thrombotic risk to determine appropriateness of this tx

Study: Oral Vitamin K Lowers the International Normalized Ratio More Rapidly Than Subcutaneous Vitamin K in the Treatment of Warfarin-Associated Coagulopathy (RCT)

Question 58

doses of PO vitamin K that may be used to reverse the effects of warfarin

Answer 58

1 - 5 mg

Question 59

Describe the efficacy of subcut vitamin K in reversing the effects of warfarin.

Answer 59

subcut vit K = INEFFECTIVE

In an RCT, subcut vit K was as effective as placebo in decreasing INR 24hrs after administration

Question 60

Why is it not recommended to use IM vit K to reverse the effects of warfarin?

Answer 60

vit K IM = CONTRAINDICATED

risk of hematoma (localized swelling filled w/ blood due to blood vessel damage)

vit K may leach out of muscle slowly over time
= makes it difficult to control the extent of warfarin reversal
= problematic if pt experiences bleed post-reversal b/c it’ll be difficult to quickly stop vit K’s effect
= risk of overcorrection

Question 61

Recall the 4 steps of managing warfarin-induced critical INR in the ambulatory setting.

Answer 61

1. Determine situation severity:
   
   • signs or sx of bleeding, unusual bruising or other concerning presentations?
   • if so, pt may require immediate medical attn rather than ambulatory mgmt
2. Assess clot vs bleed risk
   
   • if high bleed risk, immediate critical INR mgmt necessary: HOLD warfarin +/- (vit K OR PCC/aPCC)
3. Consider factors contributing to critical INR (recall assessment of a bleeding patient).
4. Adjust warfarin maintenance dosing post-critical INR mgmt to prevent future critical INRs. Also provide education for future prevention.

Question 62

You are caring for a pt who uses warfarin, and notice that their most recent INR has returned as 8. You consult your ambulatory pharmacist colleague about how to manage this critical INR, and they ask you if the patient is bleeding, and if so, how bad is it.

Explain why this question is relevant to the ambulatory management of critical INRs.

Answer 62

The bleeding status and severity of the pt determines if vitamin K PO or IV should be used as well as if PCC or aPCC should be added onto IV vitamin K if it is administered.

Question 63

True/False: PCC and aPCC can be used as monotherapy to reverse a warfarin-induced critical INR.

Answer 63

FALSE.

PCC and aPCC duration of action = 6-12 hrs, so have to admin vit K 10 mg IV to sustain INR reversal

Question 64

What is PCC?

Answer 64

prothrombin complex concentrate
derived from human plasma

composition:
- Factor ll
- Factor Vll
- Factor lX
- Factor X
- protein C
- protein S

Question 65

What is aPCC?

Answer 65

activated prothrombin complex concentrate
derived from human plasma

composition:
- same as PCC
- additionally contains activated FVlla

Question 66

When is aPCC more appropriate to use over PCC?

Answer 66

In patients experiencing hemophilia.

In 1 study in class:
- poor prognosis in warfarin-assoc ICH despite anticoag reversal
- anticoag-assoc ICH present w/ ↑ hematoma volume, ↑ risk of hematoma expansion + worse outcome than spontaneous ICH
- when PCC was admin: 80% pts achieved INR < 1.5 after 1 hr, but hematoma expansion occurred in 46% still

Question 67

PCC / aPCC duration of action

Answer 67

6-12 hours ∴ must also admin vit K 10mg IV to sustain INR reversal

Question 68

PCC / aPCC onset of action

Answer 68

↓ INR within mins

Question 69

A 64-year-old pt w/ a hx of AF is taking warfarin. They present to the clinic w/ an INR of 6.8 and no signs of bleeding. What would be the appropriate management for this pt?

Answer 69

presentation:
- warfarin-induced critical INR (reversal indicated)
- pt is NOT bleeding (vitamin K PO indicated)
- INR = 6.8 (within 4.5-10)

management:
- hold 1-2 warfarin doses
- consider vit K 1-2.5mg PO
- reassess INR to determine if further intervention is necessary

Question 70

A 78-yr-old pt on warfarin therapy for a hx of DVT presents to the ER w/ GI bleeding. Their INR is 12.3. Hgb has ↓ by 46g/L and is well below therapeutic range. The pt indicates that they have been doubling their usual warfarin dose recently. What is the recommended management for this pt?

Answer 70

warfarin-induced critical INR (reversal indicated)

pt IS BLEEDING (vitamin K IV indicated; HOLD warfarin)

Hgb ↓ > 20g/L (SEVERE bleed = vit K 10 mg IV - not low-dose - indicated)

Hgb is well below the therapeutic range (need to replace blood loss quickly = add PCC to vit K tx)

reassess INR to determine if further intervention is necessary

Question 71

07:00: A 55-year-old pt on warfarin for a hx of mechanical <3 valve presents to the hospital for pre-operative preparations. Their INR is 11.2, and surgery is scheduled for the following day at 20:00. What would be the appropriate mgmt for this pt?

Answer 71

warfarin-induced critical INR (reversal indicated)

pt is NOT bleeding (vit K PO indicated; recall onset is 16-24 hrs)

INR = 11.2 (> 10)

mgmt:
- hold warfarin
- admin vit K PO 2-5 mg
- reassess INR to determine if further intervention is necessary

Question 72

A 65-year-old patient who is taking warfarin due to a history of atrial fibrillation is scheduled for an urgent surgery in 4 hours. The patient’s most recent INR was 6.7, and the surgeon has deemed the procedure to be high risk for bleeding. What is the most appropriate management strategy for this patient?

Answer 72

Given urgency of situation and high risk of bleeding due to the need for urgent surgery, immediate reversal of warfarin required. Vit K alone may not be sufficient to rapidly ↓ INR to safe levels.

∴, PCC or aPCC should be considered in conjunction w/ vitamin K.

These agents contain clotting factors that can quickly restore hemostasis and ↓ the risk of bleeding.

Question 73

When should post-critical INR management be initiated?

Answer 73

when INR nears or is in therapeutic range
INR < 4 = safe zone

note: DOCUMENT an INR < 4

Question 74

2 components of post-critical INR mgmt

Answer 74

1 - establish target INR depending on bleed + clot risk (eg high bleed risk may req ↓ target INR range)

2 - adjust warfarin maintenance dose to reach target INR

Question 75

3 different methods may be used to adjust the maintenance dose of warfarin during post-critical INR mgmt. Describe the differences b/w these methods.

Answer 75

different methods based on the cause of critical INR

1 - acute, reversible cause identified: implement warfarin dosing similar to that prior to the incident occurring –> reassess

2 - acute event that is now not reversible and going to continue: empirically ↓ warfarin dosing based on experience / literature –> reassess

3 - no identifiable reason: depending on clot vs bleed risk, ↓ maintenance dosing accordingly (typically by 10%) –> reassess in 1 WEEK

REMEMBER: if vit K was given (esp vit K 10 mg IV), it can take several days for warfarin to regain its anticoag effect = may be approp to start w/ a lower warfarin dose or delay the next warfarin dose to avoid over-anticoag

Question 76

Describe the effect of holding warfarin on a critical INR.

Answer 76

Expect INR to ↓ to safe zone (ie < 4) 24 hrs after withholding warfarin

Question 77

critical INR pt counselling

Answer 77

recommendation: holding warfarin, vit K admin

E monitoring: expect INR < four 24 hrs after holding warfarin

S monitoring:
- tx ↑ bleed risk, ∴ monitor for signs + sx of bleeding
- bleed prevention strategies
- Ø contact sports
- avoid exposure to high-risk situations that may result in:
- cutting oneself
- shaving w/ razors
- using knives
- exposure to dangerous equipment
- injuring oneself like falling + hitting head, ∴ avoid…
- ladders
- stools
- slipping on ice or in bath / shower
- avoid EtOH (if applicable)
- head to ER if concerning bleeding occurs