Treatment of VTE in cancer patients

XXth IST, London 2013

Paolo Prandoni, MD, PhD University of Padua (Italy)

Anatomic theatre, Padua University

VTE and cancer: diagnostic aspects ●  Patients with active cancer should be promptly investigated

whenever clinical symptoms and signs suggestive of VTE arise

●  Clinical signs and symptoms of PE are often mimiked by those of the underlying malignancy

●  D-dimer is less likely to be useful than in cancer-free patients

●  DVT of the lower extremities is less likely to be present in patients with PE (Sorensen HT. et al. Circulation. 2011;124:1435-1441; Schwartz T, et al. Ann Vasc Surg. 2012;26:973-976.)

●  Areas of (relative) certainty (Asco Guidelines, JCO 2013; International Clinical Practice Guidelines, JTH 2013)

●  Areas of uncertainty (Guidance from the SSC of the ISTH, June 2013)

●  Potential role of new drugs ●  Management of incidental PE

VTE and cancer: diagnostic aspects

Treatment of CAT: areas of (relative) certainty

●  Cancer patients are less likely than patients without cancer to require

thrombolytic therapy (potential for bleeding, unlikelihood of long-term

complications in severely ill patients).

●  The treatment of SVT should not differ from that of non-cancer

patients.

●  The treatment of (catheter-induced) upper limb DVT should not differ

from that of DVT of the lower extremities.

●  Low-molecular-weight heparins represent the drugs of choice for the

initial and long-term treatment of upper or lower limbs DVT,

pulmonary thromboembolism and visceral thrombosis.

Asco Guidelines, JCO 2013; International Clinical Practice Guidelines, JTH 2013

Cumulative proportion of recurrent thromboembolism during VKA treatment

20

2 4 6 8 10 12

cancer

%

Months

Risk ratio=3.2; P<0.001

18

10

5

no cancer

Prandoni P, et al. Blood. 2002;100:3484-3488.

5

10

15

20

2 4 6 8 10 12

cancer no cancer

%

Months

HR=2.1; p=0.019

Cumulative proportion of major bleeding during VKA treatment

Prandoni P, et al. Blood. 2002;100:3484-3488.

Monreal M, Falgà C, Valdès M, Suarez C, Gabriel F, Tolosa C, Montes J,

for the RIETE registry

Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism*

J Thomb Haemost. 2006;4:1950-1956.

* during the first three months of conventional anticoagulation

Multivariate analysis on the risk of fatal PE (14 391 patients, of whom 2945 with cancer)

Variables OR (95% CI) P-value

Symptomatic PE 13.9 (6.3 – 30.0) < 0.001

Metastatic cancer 2.9 (1.8 – 4.8) < 0.001

Recent major bleeding 2.8 (1.2 – 6.3) 0.013

Renal insufficiency 2.6 (1.6 – 4.3) < 0.001

Immobility > 4 days 1.9 (1.1 – 3.2) 0.014

Multivariate analysis on the risk of fatal bleeding (14 391 patients, of whom 2945 with cancer)

Variables OR (95% CI) P-value

Immobility > 4 days 4.1 (1.4 – 7.1) < 0.001

Metastatic cancer 3.1 (1.8 – 4.8) 0.006

Recent major bleeding 3.0 (1.0 – 9.1) 0.058

Renal insufficiency 2.8 (1.3 – 5.8) 0.008

Body weight < 60 Kg 2.5 (1.1 – 5.3) 0.021

Treatment of CAT

•  All major consensus guidelines recommend

monotherapy with LMWH as the preferred treatment

for CAT

•  Recommendations are based on results of 3 open

label, randomized controlled trials

- CATHANOX: enoxaparin vs warfarin

- CLOT: dalteparin vs warfarin or acenocoumarol

- LITE: tinzaparin vs warfarin

Recurrent VTE Major bleeding

Dalteparin (N=336)OAT (N=336)

(%)

8.8%

17.4%

5.6%

3.6%

CLOT 2003

5

10

15

20

HR=0.48; P=0.0017

Lee AY, et al. N Engl J Med. 2003;349:146-153.

Implications for the detection of occult cancer

•  The strong advantage of LMWH over VKA adds to the still

unresolved issue on the need for cancer detection in patients

with otherwise unexplained VTE.

•  Indeed, the detection of cancer gives indication for

prolonging the initial LMWH treatment or shifting from VKA –

whenever initiated – to LMWH therapy

•  In addition, the use of LMWHs in subgroups of patients with

cancer may ultimately prolong survival

Duration of anticoagulation

• General expert/guidelines consensus: – minimum of 3 – 6 months – continue as long as cancer is active or chemotherapy is ongoing – discontinue if risk of serious bleeding is high or patient preference

•  Consider risk factors for recurrence and bleeding

•  Frequently evaluate patients and tailor therapy according to risk, benefits, preference

Thromb Haemost 2013

Treatment of CAT: areas of uncertainty

●  Management of recurrent cancer-associated thrombosis

despite anticoagulation

●  Management of cancer-associated thrombosis in patients

with thrombocytopenia

●  Management of cancer-associated thrombosis in patients

who are bleeding

Guidance from the SSC of the ISTH, June 2013

Management of recurrent CAT despite anticoagulation

●  Cancer patients with symptomatic recurrent VTE despite therapeutic

anticoagulation with VKA should be switched to therapeutic weight-

adjusted doses of LMWH [A]

●  Cancer patients with symptomatic recurrent VTE despite

anticoagulation with LMWH should continue with LMWH at a higher

dose, starting at an increase of approximately 25% of the current

dose or increasing it back up to the therapeutic weight-adjusted

dose if receiving non-therapeutic dosing [B]

Guidance from the SSC of the ISTH, June 2013: A=recommendation; B=suggestion

Management of CAT in patients with thrombocytopenia (1)

●  Full therapeutic doses of anticoagulation

without platelet transfusion should be given

in patients with CAT and platelet count ≥ 50

X 109/L [A]

Guidance from the SSC of the ISTH, June 2013: A=recommendation; B=suggestion

Management of CAT in patients with thrombocytopenia (2)

Acute CAT and platelet count < 50 X 109/L

● Full therapeutic doses of anticoagulation with platelet transfusion

should be given to maintain a platelet count ≥ 50 X 109/L [A]

● If platelet transfusion is not possible or contraindicated, the insertion

of a retrievable filter is suggested, as well as its removal when platelet

count recovers and anticoagulation can resume [B]

Guidance from the SSC of the ISTH, June 2013: A=recommendation; B=suggestion

Management of CAT in patients with thrombocytopenia (3)

Sub-acute or chronic CAT and platelet count <50 X 109/L

●  In patients with platelet count of 25 to 50 X 109/L subtherapeutic

or prophylactic doses of LMWH should be used [B]

●  In patients with platelet count < 25 X 109/L anticoagulation

should be discontinued [B]

Guidance from the SSC of the ISTH, June 2013: A=recommendation; B=suggestion

Management of CAT in patients who are bleeding (1) The panelists recommend:

●  Careful and thorough assessment of each bleeding episode,

including identification of the source, its severity or impact, and

reversibility [A]

●  Usual supportive care with transfusion and surgical intervention to

correct the bleeding source, whenever indicated and possible [A]

●  Withholding anticoagulation in patients having a major or life-

threatening bleeding episode [A]

Guidance from the SSC of the ISTH, June 2013: A=recommendation; B=suggestion

Management of CAT in patients who are bleeding (2)

●  The panel members suggest IVC filter insertion in patients with

acute CAT or sub-acute CAT who are having a major or life-

threatening bleeding episode [B]

●  They recommend against IVC filter insertion in patients with chronic

CAT [A]

●  They recommend initiating or resuming anticoagulation and

removing retrievable IVC filter (if inserted) once the bleeding

resolves [A]

Guidance from the SSC of the ISTH, June 2013: A=recommendation; B=suggestion

●  Paucity of clinical trial data

●  No comparison against long‐term LMWH

●  Liver and renal dysfunction is common in cancer

● Lack of experience on management for procedures and

thrombocytopenia

●  Drug interactions may be clinically important

●  Lack of measurement (therapeutic range) and antidote

Limitations of NOAs for treatment of CAT

Management of incidental PE in cancer patients

Incidental VTE

Frequent finding in oncology patients (2 to 6%) Clinical significance uncertain, but most are being treated

Khorana AA, et al. Cancer. 2007;110:2339-2346. Browne AM, et al. J Thorac Oncol. 2010;5:798-803. Douma RA, et al. Thromb Res. 2010;125:e306-309.

●  In patients who are incidentally found to have asymptomatic PE, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic PE (Grade 2B)

Recommendations on treatment of incidental VTE

ISSPE: accuracy of diagnosis

1.  We do not know the accuracy of detecting PE on CT-scans that

were not specifically ordered to diagnose PE

2.  Higher risk of false positive diagnosis compared to patients with

suspected PE

3.  In a series of 70 patients diagnosed with subsegmental PE, this

diagnosis was confirmed in only 51% by a reviewing radiologist

(Pena E, et al. J Thromb Haemost. 2012;10:496-498.)

4.  PE may not be acute but chronic

Withholding anticoagulation can be safe in ISSPE patients

1.  A total of 65 cases of untreated

subsegmental PE have been reported

2.  None of these patients developed

recurrent VTE

Donato AA, et al. Thromb Res. 2010;126:e266-270.

ISSPE: uncertainty of outcome

There is uncertainty on the outcome of patients with

incidental PE who receive anticoagulant

Cohort study of 51 patients with incidental PE: 5 (9.8%)

patients developed major bleeding of which 2 cases were

fatal

den Exter PL, et al. J Clin Oncol. 2011;29:2405-2409.

Instead of instant initiation of therapy consider:

1. Clinical evaluation:

- are symptoms of PE present?

- is there evidence of DVT?

- what is the bleeding risk with anticoagulation?

2. Evaluation of imaging studies:

- review CT critically, is the diagnosis accurate?

- is there the involvement of at least one segmental vessel?

- compare with recent CT-scans, are the findings new?

Treatment of CAT: main conclusions

1.  LMWH is the “best” agent available for initial and long-term treatment

2.  Duration of treatment is dependent on status of patients, treatment, other risk

factors and patients preference

3.  LMWH dose adjustment is effective in treating recurrent thrombosis and in

patients with bleeding or thrombocytopenia. IVC filters should be discouraged

4.  Novel anticoagulants should be investigated more carefully before routine usage

in cancer patients

5.  Incidentally detected sub-segmental PE is unlikely to require full-dose

anticoagulation