c ancer -a ssociated t hrombosis : w hat you need to know anne mcleod
TRANSCRIPT
CANCER-ASSOCIATED THROMBOSIS: WHAT YOU NEED TO KNOW
Anne McLeod
OBJECTIVES To discuss the risk of thrombosis in
cancer patients
To discuss signs and symptoms of thrombosis
To discuss treatment of thrombosis in cancer pts
WHY SHOULD YOU CARE ABOUT CAT?
Cancer increases the risk of VTE ~4-7x
Diagnosis of venous thromboembolism (VTE) is associated with worsened mortality and morbidity in patients with cancer
Active cancer accounts for 20% of new VTEs
VTE IN CANCER PATIENTS
VTE is a major complication of cancer affecting 5-20% of pts
Second leading cause of death
Autopsy rates of VTE in cancer patients~ 50%
National Hospital Discharge Survey
Stein AJM 2006 119,60-68
827,000 of 40, 787,000 cancer pts also had a diagnostic code for VTE
CONSEQUENCES OF VTE IN CANCER PTS
Hospitalized cancer pts with VTE have greater inpatient mortality and longer admissions
Risk of fatal PE in cancer surgery is 3X greater than similar noncancer surgery
Khorana JCO 24:484, 2006
Gallus Thromb Haemost 78:126, 1997
CONSEQUENCES OF VTE IN CANCER PTS
Cancer patients with VTE have increased risk of recurrent VTE, bleeding complications, morbidity and utilization of health care resources
Newer anticancer drugs particularly antiangiogenic drugs more thrombogenic
Khorana JCO 27: 4919 2009
Fatal PE, Deaths and Bleeding after Cancer Surgery
Haas – Thromb Haemost 2005;94:814
Non-cancer Cancer Outcome (N=16,954) (N=6,124) RR P
Fatal PE* 0.09 % 0.33 % 3.7 0.0001
Death 0.7 % 3.1 % 4.5 0.0001
Abn bleeding 0.04 % 0.29% 7.3 0.0001
• double-blind RCT of LDH TID vs certoparin QD
* autopsy-proven
0 5 10 15 20
100
80
60
40
20
Years after Diagnosis
Surv
ival, %
of
pati
ents
VTE, CANCER AND SURVIVAL
Sorensen - NEJM 2000;343:1846
1- yr survival
Cancer at time of VTE 12%
Cancer without VTE 36% p< .001
RISK FACTORS FOR VTE IN CANCER PTS
Patient-related factors• Older Age• Race (> African Americans)• Comorbid conditions (obesity, medical illness)• Prior VTE• Elevated prechemotherapy plt count• Inherited thrombophilia
RISK FACTORS FOR VTE IN CANCER PTS
Cancer-related factors- tumours can produce procoagulants• Type of cancer
• Initial 3-6 mons after diagnosis
• Metastatic disease
CANCER AND VTEMETASTATIC DISEASE AND VTEMetastatic Disease increases VTE risk 4-
13X
Incidence of VTE / 100 pt-yr
Pancreas 20.0Stomach 10.7Bladder 7.9Renal 6.0Lung 5.0
Chew et al. Arch Int Med. 2006;166: 458-64
Levitan Medicine 1999 78:295
RISK FACTORS FOR VTE IN CANCER PTS
Treatment-related factors• Current hospitalization- lines procedures
immobility
• Active chemotherapy
• Active hormonal therapy
• Antiangiogenic therapy (thalidomide, lenolidomide, becacizumab)
• Erythropoietin stimulating agents
Volume 25 Number 34 December 1 2007
ASCO RECOMMENDATIONS #1
Should hospitalized pts with cancer receive anticoagulation for VTE prophylaxis? YES
3 large RCTs in “acute medical pts” ~15% cancer pts
Bleeding complication rate was low
ARE GUIDELINES BEING USED?
ACCP guidelines recommend prophylaxis for acutely ill hospitalized medical and surgical cancer pts
FRONTLINE Survey in Oncologist 2003 found >50% of oncology surgeons but only 5% of medical oncologists reported use of primary prophylaxis for high risk pts
Kakkar, A. K. et al. Oncologist 2003;8:381-388
Medical Inpatients
Service Total no. of patients
(2009) (2010)
No. of pts excluded1
(2009) (2010)
Prophylaxis indicated
(2009) (2010)
AppropriateProphylaxis
(2009)
AppropriateProphylaxis
(2010)
Cardiac Surgery 19 21 6 8 13 13 12 (92%) 12 (92%)
Cardiology 37 17 28 10 9 7 3 (33%) 5 (71%)
Endocrinology 0 2 NA 0 NA 2 NA 2 (100%)
General Medicine 130 146 35 31 95 115 91 (96%) 90 (78%)
General Surgery 40 39 7 7 33 32 33 (100%) 30 (94%)
Gastroenterology 2 0 0 NA 2 NA 0 (0%) NA
Gynecology 31 12 17 6 14 6 9 (64%) 6 (100%)
Gyne. Oncology 11 7 0 0 11 7 10 (91%) 7 (100%)
Neurology 1 0 NA 0 1 NA 1 (100%) NA
Nephrology 10 11 6 4 4 7 0 (0%) 3 (43%)
Neurosurgery 19 20 7 7 12 13 10 (83%) 9 (69%)
Med. Oncology 36 38 10 15 26 23 14 (54%) 12 (52%)
Rad. Oncology 11 17 1 2 10 15 7 (70%) 8 (53%)
Ophthalmology 1 0 NA 0 1 NA 0 (0%) NA
Orthopedics 75 90 18 20 57 70 55 (96%) 69 (99%)
Otolaryngology 4 11 1 7 3 4 3 (100%) 3 (75%)
Plastics – Burn 8 10 1 0 7 10 7 (100%) 10 (100%)
Plastic Surgery 4 2 1 1 3 1 3 (100%) 1 (100%)
Respirology 2 0 1 NA 1 NA 0 (0%) NA
Trauma 25 21 6 1 19 20 17 (89%) 19 (95%)
Urology 12 9 3 1 9 8 5 (56%) 5 (63%)
Vascular Surgery 8 13 1 4 7 9 7 (100%) 9 (100%)
Combined 486 486 149 124 337 362 287 (85%) 300 (83%)
Table 3: Appropriate Thromboprophylaxis by Clinical Service 1 = includes patients on therapeutic anticoagulants and those for whom thromboprophylaxis was not indicated
WHERE IS THE LESION?
Under recognition of risk factors?
Because many pts are elderly?
Because of the risk of bleeding?
Because of the risk of HIT?
ASCO RECOMMENDATIONS #2
Should ambulatory pts with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy?
NO
PREVENTION OF THROMBOEMBOLISM IN CANCERMEDICAL ONCOLOGY PTS
Levine 1994 Stage IV Breast – RRR 85%
Hass 2005 TOPIC Breast/Lung -NS
Perry 2007 PRODIGE – Gliomas - NS
Agnelli 2008 PROTECHT Metastatic Ca- RRR
47%
Prevention of Thromboembolism in Cancer
Stage IV breast cancer patients receiving CTX Double-blind RCT Very low-dose warfarin: 1 mg x 6 wks INR 1.3-1.9
Placebo Warfarin
No. 159 152
Thromboembolism 4.4 % 0.6 % p = 0.03
Major bleeding 1.3 % 0.6 % NS
All bleeding 3.1 % 5.3 % NS
Levine - Lancet (1994)
PREVENTION OF THROMBOEMBOLISM IN CANCERTOPIC STUDIES
Advanced Cancer on ChemoRxLMWH vs. placebo x 6 months Dopplers q 4
weeks
TOPIC 1- Breast Ca Placebo LMWH p
VTE 3.9% 4%
Bleeding 0% 1.7%
TOPIC 2 - Lung Ca
Overall VTE 8.3% 4.5% .07
Stage IV VTE 10.1% 3.5% .03
Bleeding 2.2% 3.7%
Haas et al J Throm Haemos 2005; 3 (suppl) OR 059
PREVENTION OF THROMBOEMBOLISM IN CANCERPROTECHT STUDY 2009 OCT;10(10):943-9
Metastatic or locally advanced Ca (lung,
gastrointestinal, pancreatic, breast, ovarian, or head
and neck) on ChemoRx
RCT double-blind clinical outcome
LMWH vs placebo 2:1 randomization while on
ChemoRx
maximum 4 months 1,150 pts LMWH 769: Placebo
381
Primary Efficacy Endpoint: Composite of
Venous/Arterial Thromboembolic events- 2% treated
vs 3.9% untreated
Safety: Major Bleeding –NS difference
Lancet Oncol. 2009 Oct;10(10):943-9
ASCO RECOMMENDATIONS #2
Except pts receiving thalidomide or lenolidamide with chemo or dexamethasone should
Studies to identify better markers of increased risk ambulatory pts needed
ASCO RECOMMENDATIONS #3
Should pts with cancer undergoing surgery receive perioperative VTE prophylaxis?
YES1) All pts undergoing major surgical intervention
for malignant disease should be considered for prophylaxis
2) Patients undergoing laporotomy, laparoscopy or thoracotomy lasting greater the 30 mins
ASCO RECOMMENDATIONS #3
3) Prophylaxis should be commenced preoperatively, or as early as possible in the postoperative period
4) Mechanical methods may be added to pharmacologic methods, but should not be used as monotherapy for VTE prevention unless contraindicated because of active bleeding
ASCO RECOMMENDATIONS #3
5) A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy
6) Prophylaxis should be continued for at least 7-10 days postop. Consider up to 4 wks in major abdo or pelvic surgery in pts with high-risk features such as residual disease, obese or previous VTE
ASCO RECOMMENDATION # 4
What is the best treatment for patinets with cancer and with established VTE to prevent recurrent VTE?
In general LMWH
ASCO RECOMMENDATION #5
Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?
COCHRANE DATABASE SYSTEMATIC REVIEW JULY 2007 Five RCTs (UFH or LMWH)
Heparin associated with a statistically and clinically significant survival benefit (HR=0.77 CI 0.65 to 0.91)
Subgroup analyses: limited small cell lung CA had a clear survival benefit (HR=0.56 CI 0.65 to 0.83)
ASCO RECOMMENDATION #5
Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?
Recommendations:
1) NO2) Pts should be encouraged to
participate in trials
WHY TREAT?
To prevent fatal PE
To prevent recurrence
To prevent post-thrombotic syndrome
TREATING PATIENTS WITH VTE
Does the patient need treatment? Small subsegmental PE? PICC line clots? Is it real? VOMIT Is patient symptomatic- then treat
Lovenox 1.5 mg/kg od or 1 mg/kg bid Check plt count and creatinine clearance may
need dose adjustment in renal dysfunction Weight based dosing even in obese pts
If can’t anticoagulate use TEDS stockings and TE service should assess role of IVC filter
INCIDENCE OF CVC-RELATED DVT
Rate of thrombosis requiring PICC removal – 3.4% 1.1/1,000 catheter days - no prophylaxis (n=351)
Walshe – J Clin Onc 2002; 20:3276
Symptomatic thrombosis - 4%0.3 /1,000 device days PICCs, Porta- caths, Hickman
catheters – 444 pts
A. Lee - J Clin Onc 2006; 24:1404
Clinically Important CVC-related DVT 2 - 4%
Preventing Central Venous Catheter Thrombosis in Cancer (RCTs)
Warfarin 1 mg/day
DVT sympt DVT
Study Endpoint No. control warf control warf
Bern, 1990 venogram D90 82 38 % * 10 % 25 % 10 %
Couban, 2002 sympt. DVT 255 NR NR 4 % 5 %
Heaton, 2002 sympt. thromb 88 NR NR 12 % 18 %
Preventing Central Venous Catheter Thrombosis in Cancer (RCTs)LMWH
DVT
Study Endpoint No. control LMWH P
Monreal, 1996 venogram Day 90 29 62 % * 6 % 0.002
Reichardt, 2002 clinical 425 3.4 % 3.7 % 0.9
CVC-related Thrombosis in Cancer Pts
• Rate of clinically-important symptomatic DVT appears
to have decreased ~ 4%
• Rate of thrombosis requiring PICC removal – 3.4%
• Primary prophylaxis with Minidose warfarin or
LMWH
appear to NOT be effective nor necessary in
general
Apixaban
Idraparinux
Rivaroxaban
Dabigatran
Questions?