Disease related symptoms session 4 :

Coagulation disorder

Board review in oncology pharmacy 2013 “Managing Disease – or – Treatment Related Complication”

Suthan Chanthawong, B. Pharm, RPh.

Identify risk factors for VTE

Develop a patient-specific plan

Provide counseling to the individual receiving anticoagulant treatment

Describe the management of an individual with cancer who experiences bleeding or INR above goal range

Objectives

Coagulation disorder

Lectures in Clinical Medicine Association recognized since Trousseau’s

observation more than 130 years ago1

Of all cases of VTE, approximately 4-20% occur in cancer patients.2

VTE has been reported in up to 50% on postmortem examination.3-4

Cancer-associated VTE has important clinical and economic consequences5-7

Armand Trousseau

1. Trousseau, Armand. In Clinique Medicale de l'Hôtel-Dieu de Paris, 2nd ed. Paris: J.B. Bailliere et Fils; 1865 2. Lee AY. Br J. Haematol. 2005;128:291-302. 3. Gao S et al: Expert Rev Anticncer Ther 2004; 4: 303-320.

4. Lyman GH et al: J Clin Oncol 2007; 25: 5490-5505. 5. Sorensen HT, et al. N Engl J Med. 2000;343:1846-1850. 6. Prandoni P, et al. Blood. 2002;100:3484-3488. 7. Khorana AA, et al. J Clin Oncol. 2006;24:484-490.

Patients with cancer: 20%

All deep venous thrombosis and

pulmonary embolism

Coagulation disorder

Incidence of VTE in US Patients: 1979-1999

1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999

1

0

2

3

4 National Hospital Discharge Survey

VTE

Inci

denc

e (%

)

Cancer No cancer

Years

Stein PD, et al. Am J Med. 2006;119:60-68.

Coagulation disorder

Incidence of VTE/PE in different tumor

Levitan N, et al. Medicine 1999;78:285

An analysis of 41.2 million US Medicare (age≥65) patients admitted to the hospital with a malignancy

Site Rate of VTE per 104 pts Head/neck, Bladder, Breast 16-22

Oesophagus, Uterus, Cervix 43-49

Prostate, Lung, Rectal, Liver 55-69

Colon, Leukaemia, Renal, Stomach 76-85

Lymphoma, Pancreas 96-110

Brain, Ovary 117-120

Coagulation disorder

Natural History of Cancer

8

7

6

5

4

3

2

1

0

Chemotherapy

Risk of VTE in the cancer population

Remission

Risk of VTE in the general population

Time

Diagnosis

Metastasis

End of life Hospitalization

Ris

k (O

dds

Rat

io)

Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.

Coagulation disorder

Consequences of VTE

Noble S, et al. Br J Cancer. 2010;102:s2-9.

Increased mortality

Increased morbidity

Increased risk of recurrent VTE

Bleeding complications

Pulmonary Hypertension

Cancer treatment delays

Increased healthcare costs

Coagulation disorder

Homeostatic Cascade

Colman RW, et al. J Exp Med 2006;203:493-5.

Vessel injuries

Vasoconstriction

Decrease blood flow

Platelet release reaction Serotonin

Platelet aggregation

TXA2, ADP

Primary haemostatic plug

Stable haemostatic plug

Tissue factor

Coagulation cascade

Thrombin

Fibrin

phospholipid

Coagulation disorder

Response to Vascular Injury

Furie B, et al. N Engl J Med 2008;359:938-49.

Coagulation disorder

Prothrombotic properties of cancer

Falanga and Rickles, New Oncology:Thrombosis, 2005; Hematology, 2007

Coagulation disorder

Virchow’s Triad

Petralia G, et al. Informa Healthcare. 2008.

Coagulation disorder

Case study: Uraka

Coagulation disorder

UK is a 56-year-old woman recently diagnosed with colon cancer. She has had resection of the cancer.

She is scheduled to start adjuvant chemotherapy with oxaliplatin, fluorouracil, and leucovorin (FOLFOX).

Last week, a central venous catheter (CVC) was placed to facilitate the administration of the IV fluorouracil.

She now reports some swelling in her arm on the same side as the CVC.

She concern about the risk of a blood clot.

Case study: Uraka

Coagulation disorder

Questions: What is/are risk factor(s) for VTE UK?

What is appropriate counseling for UK?

Risk Factors for VTE in cancer

Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007.

Coagulation disorder

Case study: Risk Factors

Coagulation disorder

Diagnosis of Colon cancer: It is important to realize that she has received a

curative surgery for the treatment of colon cancer, and does not have active disease at this time.

Surgery also increases risk of thrombosis.

She has a CVC.

While she has not yet started chemotherapy, it will pose a risk once therapy is initiated.

Case study: Counseling

Coagulation disorder

Recommend that UK seek medical advice immediately to have the situation evaluated with appropriate imaging. This is not a diagnosis that should be made based on clinical symptoms alone.

Encourage the patient to contact her oncology team, as most oncology teams have on-call numbers available for this type of issue.

Encourage the patient to seek medical evaluation immediately, and not to wait until her next appointment.

Diagnosis of VTE Overview

Sign and Symptom DVT Leg pain, tenderness, ankle oedema, calf

tenderness, and swelling, dilated veins, and Homan’s sign (a sharp pain on dorsiflexion of the foot)

PE The signs and symptoms are present to varying degrees in patients with DVT

That objective testing must be carried out to confirm the diagnosis of DVT

Haeger K, et al. Angiology 1969;20:219-23.

Coagulation disorder

Well’s Score System: DVT

Clinical finding Point total

Paralysis, paresis, or recent orthopedic casting of LE 1 Recently bedridden (> 3 days) or major surgery within past 4 weeks 1

Localized tenderness in deep vein system 1 Swelling of entire leg 1 Calf swelling 3 cm > than other leg (as measured 10cm below the tibial tuberosity) 1

Pitting edema greater in the symptomatic leg 1 Collateral non-varicose superficial veins 1 Active cancer or cancer treated within 6 mo 1 Alternative dx > DVT (i.e., Baker’s cyst, cellulitis, SVT, myositis, post-phlebitis, inguinal LAD, etc) -2

Point total

Probability of DVT

Point total

Low -2 to 0 Moderate 1 to 2

High 3 to 8

Wells PS, et al. Lancet. 1997;350(9094):1795-8

Coagulation disorder

Diagnosis of DVT

Wells PS, et al. J Thromb Thrombolysis 2006;21:31-40.

Coagulation disorder

Laboratory testing: PE

Abnormalities on ECG: Unexplained tachycardia

Chest radiographs

Arterial PO2 and the alveolar-arterial oxygen

Elevation of D-dimer level

Limitation: false positive

Infection, cancer, trauma, and other inflammatory states

Tapson VF, et al. Am J Respir Crit Care Med 1999;160:1043-66. Tapson VF. N Engl J Med 2008;358:1037-52.

Coagulation disorder

Well’s Score System: PE

Clinical finding Point total

Clinical S/S of DVT (minimum of leg swelling and pain with palpation of the deep vein) 3

PE as or more likely than an alternative diagnosis 3 HR > 100 1.5 Immobilization or surgery in the previous 4 weeks 1.5 Previous DVT/PE 1.5 Hemoptysis 1 Malignancy (on Treatment, Treated in the last 6 mo or palliative) 1

Point total

Probability of PE

Point total

Low < 2 Moderate 2.0-6.0 High > 6.0 PE unlikely ≤ 4.0

PE likely > 4.0

Wells PS, et al. Lancet. 1997;350(9094):1795-8

Coagulation disorder

Diagnosis of PE Overview

Wells PS, et al. J Thromb Thrombolysis 2006;21:31-40.

Coagulation disorder

VTE initial prophylaxis

Adult inpatient with diagnosis of or suspicion of cancer

Yes

Mechanical

No

Pharmacological ± Mechanical

Coagulation disorder

Facts about VTE

Kirwan CC, et al. BMA 2003;327:597-8. Kakkar AK, et al. Oncologist 2003;8:381-8.

FRONTLINE Survey: No thromboprophylaxis: Surgical cancer: 50% !!! Medical cancer: 95% !!!

Why Such a Lack of Compliance ? Underestimation of risk Failure to assess clinical sings and risk Concern regarding anticoagulation-associated bleeding Inconvenience of available agents Lack of awareness of currently available clinical guideline Resistance to changing established practice pattern

Coagulation disorder

Antithrombotic Therapy: Choices

Pharmacologic (Prophylaxis & Treatment)

Low Molecular Weight Heparin (LMWH)

Nonpharmacologic (Prophylaxis)

Unfractionated Heparin (UH)

Oral Anticoagulants

Elastic Stockings

Inferior Vena Cava Filter

Intermittent Pneumatic Compression (IPC)

New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?

Electrical calf Stimulation (ECS)

Coagulation disorder

Non-pharmacologic Prophylaxis

High risk hemorrhagic complication

Adjunct to pharmacological therapy

Intermittent Pneumatic Compression Elastic stocking

Electrical calf stimulation

Coagulation disorder

Pharmacologic Prophylaxis

Aspirin

Warfarin

Unfractionated heparin (UFH)

Low molecular weight heparin (LMWH)

Fondaparinux

Coagulation disorder

Aspirin

Limited evidence in cancer In general; Should not be used

as a 1st pharmacological modality

Geerts WH, et al. Chest 2008;133:381s-453s.

Coagulation disorder

Warfarin: Oral Vitamin K antagonist

Rapidly absorption Long t1/2 36-42 hrs Inter-individual variation Narrow therapeutic window Drug-Drug interaction

Zacharski LR, et al. Oncologist 2005;10:72-9. Hutten BA, et al. J Clin Oncol 2000;18:3078-83.

Retrospective study in 2000 Cancer VS non-cancer Intervention: Warfarin 3 mos (keep INR 2-3) Results: Tumor increased incidence of

Recurrence: 27.1/100 vs 9.0/100 pt-yr Bleeding: 13.3/100 vs 2.1/100 pt-yr

Coagulation disorder

Warfarin: Mechanism of action

Martin JH. Aust Prescr 2009;32:76-80

Coagulation disorder

Warfarin: Interindividual Variability

Redman AR, Pharmacotherapy, 2001; 21:235–242

Coagulation disorder

Unfractionated Heparin

Sulphated-mucopolysaccharides 3000-30,000 Dal (mean 15,000 Dal) Continuous infusion or SQ

Hirsh J, et al. Chest 2008;133:141s-159s.

Important Limitations: High protein binding Non-linear pharmacokinetic Heparin-induced thrombocytopenia (HIT) Osteoporosis Narrow therapeutic window:

aPTT monitoring

Coagulation disorder

UFH: MOA

Coagulation disorder

Weitz JI. N Engl J Med 1997;337:688-98.

Low Molecular Weight Heparin

Enzymatic depolymerization 4000-5,000 Da Dalteparin, Enoxaparin, Tinzaparin, Nadroparin, Bemiparin Once daily, Fixed or Wt-base Regular monitoring is not indicated

Excepts in obese, renal insufficiency

Hirsh J, et al. Chest 2008;133:141s-159s.

Benefits: Improve anticogulant effect Improve PK profile Reduced propensity:

Osteoporosis HIT

Coagulation disorder

LMWH: MOA

Weitz JI. N Engl J Med 1997;337:688-98.

Coagulation disorder

Fondaparinux

AT-binding polysaccharide Act through AT-mediating selective inhibition of factor Xa Fixed dose 2.5 mg S.Q. Regular monitoring is not indicated

Hirsh J, et al. Chest 2008;133:141s-159s.

Coagulation disorder

Fondaparinux

http://www.ashpmedia.org/popup/anticoagulation_additional.html

Coagulation disorder

VTE Prophylaxis and Treatment

Prophylaxis in

Hospitalized Patient

Prophylaxis in

ambulatory patients

Prophylaxis in patients undergoing

surgery

Treatment of VTE and

prevention of recurrent

Coagulation disorder

Standard Treatment of VTE Can We Do Better Than This?

Vitamin K antagonist (INR 2.0 - 3.0)

> 3 months

LMWH or UFH

5 to 7 days Initial treatment

Long-term therapy

Coagulation disorder

Gap of Knowledge before 2003

This multicenter, RCT was conducted to compare the efficacy of dalteparin, an LMWH, with short-term dalteparin followed by long-term oral anticoagulation with a coumarin in preventing recurrent VTE in patients with cancer

Short-term LMWH treatment, followed by

long-term oral anticoagulation, was the standard of care for prevention of recurrent VTE in patients with cancer. While providing some efficacy, oral anticoagulation is associated with a number of limitations, some of which are specific to patients with cancer.

Lee AYY, et al. N Engl J Med 2003;349:146-53.

Coagulation disorder

CLOT Trial

Lee AYY, et al. N Engl J Med 2003;349:146-53.

5 to 7 days

Dalteparin 200 IU/kg OD

Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo

Control Group

Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo

Experimental Group

1 month 6 months

Coagulation disorder

Sample: acute, symptomatic DVT, PE, or both

CLOT Trial

End points:

Primary end point:

The first episode of objectively documented, symptomatic, recurrent DVT, PE, or both during the 6-month study period

Secondary outcomes:

Clinically overt bleeding and death

Lee AYY, et al. N Engl J Med 2003;349:146-53.

Coagulation disorder

Primary efficacy outcome

Lee AYY, et al. N Engl J Med 2003;349:146-53.

Coagulation disorder

Probability of symptomatic recurrent VTE

Lee AYY, et al. N Engl J Med 2003;349:146-53.

52% reduced risk for recurrent VTE 9% and 17% in the dalteparin and oral anticoagulant groups

Coagulation disorder

Secondary Outcome

Safety

There was no significant difference between the dalteparin and oral anticoagulant groups (p=0.27) in

Rate of major bleeding (6% vs 4%, respectively)

Or any bleeding (14% vs 19%, respectively)

Lee AYY, et al. N Engl J Med 2003;349:146-53. Lee AYY. et al. J Clin Oncol; 23:2123-2129 2005

Coagulation disorder

Secondary Outcome

Mortality

During the 6 month treatment period:

130 and 136 patients died in the dalteparin and oral anticoagulant groups, respectively (p=0.53)

Lee AYY, et al. N Engl J Med 2003;349:146-53. Lee AYY. et al. J Clin Oncol; 23:2123-2129 2005

Coagulation disorder

CLOT Trial: Conclusions

Lee AYY, et al. N Engl J Med 2003;349:146-53.

An only-dalteparin regimen was more effective than a regimen consisting of short-term dalteparin followed by oral anticoagulation in reducing the risk of recurrent VTE The two regimens produced approximately equivalent risks for hemorrhagic complications Long-term self-injection of LMWH was acceptable to patients enrolled in this study

Coagulation disorder

ONCENOX study

Patients were randomized to receive 1 of 3 treatment regimens: Low-dose enoxaparin:

BID enoxaparin (1.0 mg/kg) for 5 d OD enoxaparin (1.0 mg/kg) for 175 d High-dose enoxaparin:

BID enoxaparin (1.0 mg/kg) for 5 d OD enoxaparin (1.5 mg/kg) for 175 d Oral anticoagulation:

BID enoxaparin (1.0 mg/kg) for 5 d until stable INR 2-3 on oral warfarin begun on day 2 of enoxaparin

The efficacy and safety of extended-duration (6 month) low- or high-dose enoxaparin, compared with initial enoxaparin followed by warfarin in the secondary prevention of VTE in patients with cancer was examined in the ONCENOX study

Deitcher SR, et al. Clin Appl Thromb Hemost 2006;12:389-96.

Coagulation disorder

ONCENOX: Clinical Outcomes

The incidence of recurrent VTE (ITT population):

There was no difference between the low- and high-dose enoxaparin groups

Major hemorrhagic events:

1 patient (3%) in the warfarin group

2 (6%) in the low-dose enoxaparin group

4 (11%) in the high-dose enoxaparin group

Deitcher SR, et al. Clin Appl Thromb Hemost 2006;12:389-96.

These data suggest

that enoxaparin,

administered for

6 months in patients

with cancer, is safe

Coagulation disorder

Treatment and 2nd prevention of VTE

Acute Continue

Heparin or LMWH together with a VKA (e.g. warfarin) untill an INR of 2.0-3.0 is achieved

VKA (e.g. warfarin) INR 2.0-3.0

3-6-12 months or lifelong

Risk of VTE (5-7%/year) vs. Risk of bleeding (3-4%/year)

How long?

Coagulation disorder

Case study: Furby

Coagulation disorder

FB is an elderly man with a long history of prostate cancer.

Until recently, his prostate cancer was managed with antiandrogen therapy.

There is evidence of disease progression, and he now has metastatic prostate cancer.

The plan was to start chemotherapy. He was recently D/C from the hospital after it was

discovered he had spinal cord compression, and he has severely limited mobility.

Case study: Furby

Coagulation disorder

Additionally, he was found to have a lower extremity DVT.

His family has a number of questions about his medications, and is very concerned that he will be on a "blood thinner."

They have done some research, and their understanding is that he will continue on anticoagulation therapy for 3 months.

Question: What is the duration of therapy for

anticoagulation in the patient with VTE and cancer?

Case study: Discussion

Coagulation disorder

There is not one correct answer for this question. The duration of anticoagulation therapy is

determined on an individual case basis. Consider base on risk versus benefit issues. At any time, if the risk of anticoagulation therapy

outweighs its perceived benefit, the therapy should be discontinued.

Therefore, in counseling FB and his family, it is

important to discuss that a definitive answer may

not be appropriate.

Case study: Why???

Coagulation disorder

FB require anticoagulation therapy because of his disease state (advanced).

Although FB will be receiving CMT to decrease disease progression (not to cure the cancer). It is likely that FB will remain on anticoagulation

therapy for the rest of his life, unless there is a change in status that makes the risk of anticoagulation outweigh the benefit.

Case study: Discussion

Coagulation disorder

Patients with curable cancers may not require anticoagulation therapy longer than the time recommended for individuals without cancer. Unfortunately, this is not the situation with FB.

Patients with VTE associated with a CVC will

require anticoagulation therapy for the duration of the time they have the device in place. Again, this is considered on an individual basis.

Case study: Nong Neoi

Coagulation disorder

NN a 45-year-old man with history of NHL.

He was initially treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with CR.

After 6 cycles, he had no evidence of cancer.

Unfortunately, recent follow-up imaging scans show a recurrence of cancer and an incidental finding of a PE.

Case study: NN

Coagulation disorder

The plan is to begin anticoagulation therapy as well as therapy for recurrent NHL.

The oncologist has told NN he will receive 2 cycles of chemotherapy and then proceed with an autologous SCT.

Question: What are appropriate options for

management of this PE in NN?

Case study: Discussion

Coagulation disorder

Acute Management: An incidental finding of PE requires treatment,

and anticoagulation should be started immediately.

Therapy could include UFH, but as this would require hospitalization, LMWH is probably a better option.

Case study: Discussion

Coagulation disorder

Chronic Management: Chronic therapy with LMWH offers many

benefits, including the ability to easily hold anticoagulation for a short period of time when needed for procedures e.g, placement of CVC, BM biopsy

Another beneficial effect of chronic therapy with LMWH is a lack of drug–drug interactions.

Case study: Rum phoung

Coagulation disorder

RP is a 35-year-old woman with lung cancer.

She was recently diagnosed with a thrombosis associated with her infusion port and was started on LMWH.

She has limited insurance coverage at this time, and the plan is to start warfarin for chronic anticoagulation.

Question:

Case study: Discussion

Coagulation disorder

Concurrent LMWH with warfarin until the INR is within the targeted therapeutic range.

Initiation with warfarin 3-5 mg for 1 to 2 days, and subsequent dosing is based on INR response.

Lower doses are suggested for Older, debilitated, malnourished, have liver disease and/or

dysfunction, or are taking medications known to increase sensitivity to warfarin

Case study: VKAs

Coagulation disorder

Assessment (before start VKAs) Nutritional status Concurrent dietary intake of vitamin K,

Nutritional supplements Vitamins Diet

Concomitant drug therapy Liver function

Case study: Line Pop

Coagulation disorder

LP is a 39-year-old man with head and neck cancer receiving radiation therapy.

He has had extensive surgery, and his oral intake is limited to nutritional supplements.

Other medical problems include history of DVT in his left leg, hypertension, and liver dysfunction secondary to chronic alcohol use.

Case study: LP

Coagulation disorder

He has been managed with LMWH, but he has requested that he be changed to another therapy.

He has continued on LMWH and was started on warfarin 2 mg po daily.

Two days after initiation of warfarin, his INR is 2.9 with a target goal of 2 to 3.

Question:

Case study: Discussion

Coagulation disorder

Concurrent warfarin with LMWH at least 4-5 days.

INR is 2.9 after only 2 days of warfarin, and the full effect of these doses has not been seen.

Dose of warfarin should be decreased even though his INR is in the goal range.

It is important to closely monitor INR.

Initial Warfarin Dosing Guideline

Coagulation disorder

www.hematology.org/practiceguidelines

Warfarin Dosing at Steady State

Coagulation disorder

HASHTI 1. Hold further doses of

anticoagulant 2. Consider Antidote 3. Supportive treatment: volume

resuscitation, inotropes as needed

4. Local or surgical Hemostatic measures: topical agents (aminocaproic acid, tranexamic acid)

5. Transfusion (red cells, platelets, FFP as indicated)

6. Investigate for bleeding source

www.hematology.org/practiceguidelines

Case study: Discussion

Coagulation disorder

There is an opportunity to talk with LP to determine what the impact of diet, concomitant drug therapy, and/or other modifiable factors have on the apparent low warfarin dose requirement. Assess amount of nutritional supplementation

(and vitamin K content in supplementation) Obtain a complete medication history Evaluate alcohol use

Case study: Po Po

Coagulation disorder

PP is a 57-year-old man with a history of a neuroendocrine tumor of the pancreas.

He has been receiving monthly injections of

octreotide with relatively good management of diarrhea.

About 1 week ago, he noted new-onset shortness of breath and was found to have a PE.

Case study: PP

Coagulation disorder

He was started on LMWH for initial treatment, but then bridged to warfarin therapy as he refused to subcutaneously self-administer any medication chronically.

His INR has been erratic, and his dose of warfarin has been modified weekly. He is very upset that he is still having his blood work done once weekly.

Question:

Case study: Discussion

Coagulation disorder

Dietary changes, including vitamin K containing vegetables, liver, nutritional supplement, etc.

Changes in bowel function, especially in relation to monthly octreotide injections, as some patients will have an increase in diarrhea for the days to 1 week prior to scheduled dose of octreotide.

Adherence to the dosing regimen prescribed.

Nutescu EA, et al. Expert Opin Drug Saf. 2006;5(3):433-451.

Case study: Discussion

Coagulation disorder

Alcohol use (eg, chronic alcohol use may increase warfarin requirements and episodic alcohol use may increase INR for individuals on warfarin).

Use of OTC medications and complementary medications including acetaminophen and multivitamins.

Nutescu EA, et al. Expert Opin Drug Saf. 2006;5(3):433-451.

Case study: Be Be

Coagulation disorder

BB is a 44-year-old woman with MBC who has a relatively recent history of DVT managed with warfarin 7.5 mg po daily.

Her INRs have ranged from 1.9 to 2.3 over the last few weeks.

She was doing well until recently when she experienced confusion and severe headaches.

Subsequent evaluation demonstrated multiple brain lesions consistent with brain metastases.

Case study: BB

Coagulation disorder

She is scheduled to start RT and was started on dexamethasone 4 mg po every 8 hours.

Her INR today was 5.6 when she had blood work prior to radiation.

The INR results were not reported until BB left the

physician's office, and she is now at home. Question:

Case study: Discussion

Coagulation disorder

Reversal of warfarin is based on S/S, INR, and the patient's risk of bleeding.

It is important to assess whether the INR is stable or is escalating secondary to recent changes in medications (eg, dexamethasone).

Case study: Discussion

Coagulation disorder

PP has not reported bleeding, but this should be evaluated.

She is not currently receiving therapy that will cause thrombocytopenia and has no known risk for bleeding that we are aware of at this time.

One possible consideration is the risk of gastric irritation with dexamethasone.

Case study: Discussion

Coagulation disorder

The recent addition of dexamethasone may have a significant impact on INR for a patient on warfarin.

As this medication is likely to be continued, and eventually tapered, it will be important to closely monitor INR with dexamethasone dose changes.

Consideration of holding the dose of warfarin should be determined by both the clinical situation as well as the INR.

Case study: Discussion

Coagulation disorder

The use of oral phytonadione 1 to 2.5 mg may be used in patients with high risk of bleeding.

Although phytonadione has been given subcutaneously to manage elevated INRs, the absorption is erratic and delayed.

The use of intravenous phytonadione, given slowly to avoid anaphylaxis, should be considered when there is serious bleeding

Case study: Discussion

Coagulation disorder

Bennett CL, et al. JAMA.2008;299(8):914-924.

8th, 9th ACCP: Long-term treatment

Geerts WH, et al. Chest 2008;133(6 suppl):381s-453s. Kahn SR, et al. Chest. 2012;141(2):S195-226.

Initial management of DVT

Coagulation disorder

8th, 9th ACCP: Long-term treatment

Geerts WH, et al. Chest 2008;133(6 suppl):381s-453s.

2nd prevention in patients with cancer LMWH for the first 3 to 6 months

Duration of therapy Warfarin or LMWH:

Indefinitely or until the cancer is resolved

Coagulation disorder

Geerts WH, et al. Chest 2008;133(6 suppl):381s-453s. Kahn SR, et al. Chest. 2012;141(2):S195-226.

Prevention of VTE in Nonsurgical Patients

Coagulation disorder

Kahn SR, et al. Chest. 2012;141(2):S195-226.

Cancer in Outpatient Setting

Cancer patient w/o additional VTE risk factors, suggest against routine use of prophylactic LMWH/LDUH (2B) or prophylactic VKAs (1B)

Solid tumor outpatients with additional VTE risk factors and low bleeding risk, suggest prophylactic-dose LMWH or LDUH (2B)

LDUH: low-dose unfractionated heparin; LMWH: low-molecular weight heparin

Prevention of VTE in Nonsurgical Patients

Coagulation disorder

Kahn SR, et al. Chest. 2012;141(2):S195-226.

Cancer in Outpatient Setting: Remarks Additional risk factors for VTE in cancer outpatients

Previous venous thrombosis

Immobilization

Hormonal therapy

Angiogenesis inhibitors

Thalidomide

Lenalidomide

Antithrombotic Therapy for VTE

Coagulation disorder

Kahn SR, et al. Chest. 2012;141(2):S195-226.

Long term PE treatment Cancer patients with PE, suggest LMWH over

VKA therapy (2B). If not treated with LMWH, suggest VKA over

dabigatran or rivaroxaban (2C)

Anticoagulant regimens: Recommendation

NCCN Clinical Practice Guideline in Oncology. VTE 2012. Lyman GH, et al. J Clin Oncol 2007;25:5490-505.

Management Phase Dosage Prophylaxis(duration: until ambulatory or D/C)

UFH Dalteparin Enoxaparin Fondaparinux Tinzaparin

5000 U SC q 8 hr 5000 U SC daily 40 mg SC daily 2.5 mg SC daily 4500 U SC or 75 U/kg SC daily

Treatment: initial (5-7 days for minimum)

UFH Dalteparin Enoxaparin Fondaparinux Tinzaparin

80 U/kg IV push then 18 U/kg/hr 100 U/kg SC q 12 hr; 200 U/kg SC daily 1 mg/kg SC q 12 hr; 1.5 mg/kg SC daily < 50 kg: 2.5-5 mg SC daily; 50-100 kg: 5-7.5 mg SC daily > 100 kg: 7.5-10 mg SC daily 175 U/kg SC daily

Treatment: long term(3-6 mo for DVT, 6-12 mo for PE)

Dalteparin(preferred in advanced or metastatic cancer) Warfarin

200 U/kg SC daily X 1 mo 150 U/kg SC daily 5-10 mg PO daily

Issues ASCO ACCP NCCN Prophylaxis in hospitalized All pts High risk pts, bed ridden All pts without CI

Prophylaxis in ambulatory Not recommend for routine LMWH or warfarin recommend in MM receiving thalidomide or lenalidomide + CMT or dexamethasone

LMWH or warfarin recommend in MM receiving thalidomide or lenalidomide + CMT or dexamethasone

Prophylaxis in undergoing surgery

Major surgery: low dose UFH or LMWH without CI, ASAP in postoperative period

Higher-risk surgery: low dose UFH TID or LMWH or Fondaparinux without CI,

Treatment of VTE and prevention of recurrence

LMWH initial 5-10 days with cancer established VTE,

6mo treatment in active cancer,

Vena cava filter only indicated in anticoagulant CI and resistant anticoagulation therapy

LMWH for 1st 3-6 mo of long term coagulation therapy

Subsequent treatment by warfarin or LMWH until cancer is resolved

Evaluation risk-benefit ratio periodically

Initial treatment: LMWH or Fondaparinux LMWH without warfarin if

prefer for proximal DVT , PE in active cancer

LMWH or warfarin (INR 2-3)

Minimum duration 3-6 mo (DVT), 6-12 mo in PE Lifelong for active cancer

or persistent risk factors

Guideline Summary

Lyman GH, et al. Am J Hematol 2007;82:777-82. Geerts WH, et al. Chest 2008;133(6 suppl):381s-453s. NCCN Guideline. VTE 2012.

Take Home Messages

Coagulation disorder

Management of VTE remains a challenge LMWH preferred use as the initial treatment and

secondary prevention

Minimum of 6 months and longer duration if the cancer remains active

Both recurrent thrombosis and bleeding remain problems

Need to make research more for the advent of new anticoagulants

Thank you!