Results
Question 1: In Ambulatory Cancer Patients, Should the Thrombotic Risk Be Evaluated
Using a Risk Score to Decide on the Use of Antithrombotic Prophylaxis?
Background
To date, the only validated prediction model of CAT is the Khorana risk score.[7] However, in recent years several studies in different types of cancer suggest that
this should not be the only tool to select candidate patients for antithrombotic prophylaxis
in the outpatient setting[8]
[9]
[10]
[11]:
-
A recent assessment questions the usefulness of the Khorana score, Vienna-CATS prediction
model, PROTECHT score, or CONKO score for this aim.[12]
-
Two recent models, COMPASS[13] and ONKOTEV,[14] which rely on clinical parameters only, seem to overcome the predictive ability
of the Khorana score. At 6 months, the area under the curve (AUC) of receiving operating
characteristics of the COMPASS risk assessment model was 0.85. The ONKO-TEV score
showed an AUC at 3 months of 71.9 versus 57.9% with the Khorana score. However, validation
is still required.
-
The addition of some biomarkers such as D-dimer or genomic risk profiles may help
improve the usefulness of VTE risk scores.[15]
[16]
-
A different strategy, based on tumor-specific assessment models, has been developed.
The Throly score, developed for patients with lymphomas, showed high negative predictive
value (NPV; 97%), although the positive predictive value (PPV) was 15%. Another new
risk model for prediction of VTE in gynecological cancer patients has also shown promising
results.[17]
[18]
Currently, routine thromboprophylaxis in ambulatory cancer patients is not recommended.
Better tools to stratify VTE risk are needed to favor a primary prevention strategy
in ambulatory cancer patients.
Suggestions
-
Assessment of thrombotic risk in cancer patients on ambulatory treatment is suggested,
with the purpose of identifying those who would, theoretically, benefit more from
antithrombotic prophylaxis.
-
Although Khorana's risk score is the only validated prediction model, it should not
be the only tool used to select the patients who will receive ambulatory antithrombotic
prophylaxis. Bleeding risk factors also have to be considered.
-
New predictive models including biomarkers such as D-dimer or genomic risk profile,
or tumor-specific scores, may help improve risk stratification.
Question 2: In Cancer Patients Who Are Hospitalized for an Acute Medical Illness,
When Is Pharmacological Antithrombotic Prophylaxis Contraindicated?
Background
Current guidelines agree that cancer patients who are hospitalized for any complication
related to their clinical condition are at very high VTE risk, recommending pharmacologic
prophylaxis with low-molecular-weight heparin (LMWH), unless contraindicated.[1]
[2]
[3]
[4]
[5] However, studies that specifically address the risk–benefit of thromboprophylaxis
in cancer inpatients are lacking. In fact, recommendations are based on the results
of trials whose cohorts consisted of heterogeneous groups of medical patients, among
which cancer patients were underrepresented (5–15%).[19]
[20]
[21]
[22]
[23] A recent meta-analysis restricted to the cancer subgroup of the aforementioned studies
did not confirm a positive effect of thromboprophylaxis.[24]
On the other hand, cancer patients also exhibit an increased bleeding tendency and
are considered as a high-risk population for hemorrhages. Therefore, a careful benefit–risk
balance for each individual patient is advisable. Although validated tools to assess
bleeding risk in cancer patients are lacking, several circumstances imply a contraindication
for pharmacologic thromboprophylaxis.
Suggestions
-
Settings where primary thromboprophylaxis with LMWH is contraindicated for cancer
inpatients:
-
When pharmacological thromboprophylaxis is contraindicated, alternative use of mechanical
measures is suggested.
-
Thromboprophylaxis with LMWH is not necessary in patients admitted to hospital for
scheduled oncological treatment who are not immobilized.
Question 3: Must the LMWH Dose Be Modified in Cancer Patients with Acute VTE Receiving
Antiangiogenic Drugs?
Background
Patients on anticoagulant therapy were explicitly excluded from most clinical studies
with antiangiogenic drugs.[25]
[26] Furthermore, in those studies that allowed participation of anticoagulated patients,
vitamin K antagonists (VKA) instead of LMWH (drug of choice for CAT treatment) were
mostly used. Certain evidence arises from several clinical trials evaluating bevacizumab:
The BEAT[27] and the BRITE[28] studies provided comparative analyses on the incidence of severe bleeding (SB [grades
3–5]) between anticoagulated and non-anticoagulated bevacizumab-treated patients.
Both studies showed higher SB rates among anticoagulated patients (4.3 vs. 2.4% in
BEAT and 6.0 vs. 2.2% in BRITE, respectively). In contrast, in the SAIL study the
SB rate in patients under anticoagulant therapy was null, compared with 4% in the
overall cohort.[29]
In the pivotal trial, the proportion of patients who maintained the study treatment
after suffering a VTE event and starting anticoagulant therapy was 6.5% in the bevacizumab
arm and 3.4% in the placebo arm.[26] SB episodes were experienced by 3.8 and 6.7% of those patients, respectively.[30] On the contrary, in the AVADO study, the incidence of SB among anticoagulated bevacizumab-treated
patients was 5% compared with 0% in anticoagulated placebo-treated patients, and 1.2%
in the bevacizumab group that did not receive anticoagulants.[31]
Data from 3,201 patients were collected.[32] Patients were allowed to continue with the study medication after an acute VTE event
if the following criteria were fulfilled: absence of active bleeding, maintenance
of stable anticoagulation for at least 2 weeks, and, in two of the three studies,
absence of major vessel invasion. The SB rates, obtained from 194 anticoagulated patients,
were similar in those treated with either bevacizumab or placebo (4.1 vs. 4.2%, respectively).
Finally, a meta-analysis including 10 studies and 6,055 bevacizumab-treated patients
found that 10.5% of those who suffered a VTE and started anticoagulant therapy did
not discontinue the antiangiogenic treatment.[33] In this subgroup, the bleeding rate was 1.9% (SB in 0.2% of cases), versus 1.2%
among patients who did not require anticoagulant treatment.
Suggestions
-
In the absence of bleeding, a reduction of the LMWH dose to be administered to a patient
developing an acute VTE event while on antiangiogenic treatment is not suggested.
Special caution is required in patients with central nervous system involvement.
-
Resumption of the antiangiogenic therapy, after starting anticoagulant therapy for
an acute VTE event, should be delayed for a reasonable period of 2 weeks to check
the absence of any bleeding complication before adding any further risk factor. In
case of life-threatening VTE, resumption of the antiangiogenic therapy is not recommended.
Question 4: In Patients with CAT Requiring Surgery or an Invasive Procedure, When
Should the Placement of an Inferior Vena Cava Filter Be Considered?
Background
The evidence supporting the use of inferior vena cava filters (IVCFs) in cancer patients
is scarce. While some studies suggested that IVCFs are safe and effective, others
found an increased risk of recurrent deep venous thrombosis (DVT; indeed, the cancer-related
hypercoagulability is not corrected by the IVCF), as well as no benefit regarding
pulmonary embolism (PE) incidence or short-term mortality.[34]
[35]
[36]
[37]
[38]
[39]
[40] Nevertheless, most guidelines recommend the use of IVCF in cancer patients with
proximal acute DVT or PE when anticoagulant therapy is contraindicated.[41]
[42]
[43]
[44] Such is the case of major surgery or invasive procedures. Lumbar puncture, spinal
anesthesia, or epidural catheter placement are considered as special procedures.[42] The use of IVCF would be particularly useful within the first 2 to 4 weeks after
the acute thrombotic event due to the high recurrence risk in that particular period.[45] The use of IVCF is not clearly supported in other scenarios.[45]
[46]
[47] Furthermore, other potential adverse events associated with its use, such as placement
or removal complications, migration, breakage, or thrombosis of the device, should
be taken into account.[41]
[44]
[45]
[46]
[47]
Moreover, anticoagulation should be restarted, and the IVCF removed, once the contingency
that led to its placement is resolved. The strategy of IVCF removal should be defined
prior to filter insertion.[41]
[43]
[44]
[45]
[46]
Suggestions
-
The use of a retrievable IVCF is suggested in cancer patients with acute proximal
lower limb DVT or PE who require surgery or an invasive procedure that contraindicates
anticoagulant therapy, particularly within the first 2 to 4 weeks after diagnosis.
After 4 weeks from the diagnosis of the thrombotic episode, the placement of an IVCF
is suggested in case of persistent proximal DVT (femoral or iliac veins).
-
While the IVCF remains placed, the use of (at least) prophylactic LMWH, if not contraindicated
by the bleeding risk, is suggested.
-
Full anticoagulant therapy should be restarted and IVCF removed as soon as the cause
leading to the placement of the filter is resolved.
Question 5: In Patients with CAT Who Require Extended Anticoagulant Therapy beyond
Six Months, What Is the Optimal Dose if LMWH Is Maintained?
Background
After completing 6 months of anticoagulant therapy for CAT, current clinical guidelines
recommend to continue anticoagulation in case of active cancer and/or ongoing chemotherapy
due to the high risk of recurrent VTE. However, since the observation period in available
randomized trials comparing VKA and LMWH in this setting lasted 6 months, the drug/dose
of choice for extended therapy is a matter of debate.[44]
[48]
Useful data are provided by a subgroup analysis of an observational study,[49] and two single-arm prospective studies designed to evaluate LMWH safety over a 12-month
period: the DALTECAN study,[50] in which dalteparin dose was reduced after the first month of treatment, and the
TICAT study,[51] in which tinzaparin was used at full dose throughout the study.
Until stronger evidence becomes available, the dose of LMWH for extended therapy beyond
6 months should be tailored considering several issues: severity of VTE, cancer type
and extension, ongoing anticancer therapies, bleeding risk, and patients' characteristics
and preferences, which may change over time.[52]
[53] Indeed, intrinsic differences in the dosing of the various LMWH must be taken into
account (as mentioned earlier, the standard therapeutic dose of dalteparin after the
first month of treatment is 150 IU/Kg instead of 200 IU/Kg, while for the other molecules
the full dose is maintained during the 6-month anticoagulation period).
Other options for extended therapy are VKA (although maintaining therapeutic INR ranges
may be difficult in cancer patients under active antineoplastic therapy) and direct
oral anticoagulants (DOACs). Very recently, two randomized clinical trials in patients
with CAT have compared the efficacy and safety of edoxaban and rivaroxaban, direct
factor Xa inhibitors, versus dalteparin using the CLOT trial scheme (200 UI/kg/day
the first month, 150 UI/kg/day afterward)[54]
[55]
[56] for a minimum observation period of 6 months. In the Hokusai-VTE cancer study, no
significant differences were observed in the rate of the primary composite endpoint
(recurrent VTE and/or major bleeding), albeit patients in the edoxaban arm had a lower
rate of VTE recurrence and a higher rate of major bleeding, especially gastrointestinal
bleeding.[54] Similarly, the 6-month cumulative VTE recurrence rate was higher with dalteparin
compared with rivaroxaban, although major bleeding was increased in the rivaroxaban
arm.[56] The results of other ongoing studies may confirm a role of DOACs as an alternative
for CAT extended therapy. However, current restraints by health authorities limit
its use in patients with VTE in Spain and other countries, making LMWH the drug of
choice for extended treatment of CAT.
Suggestions
-
When LMWH treatment for CAT is to be prolonged beyond 6 months, the characteristics
of each individual patient, of the underlying malignancy and its treatment and of
the index VTE, should be considered to decide the optimal dose. [Table 2] summarizes useful criteria to guide decisions.
Table 2
Criteria to decide LMWH dose when anticoagulant treatment for CAT is prolonged beyond
the first 6 mo
|
Full-dose LMWH[a]
|
Intermediate or prophylactic LMWH dose
|
LMWH dose increased 25%
|
|
VTE event
|
• Life-threatening symptomatic PE
|
• Incidental PE
• Isolated lower limb DVT
• Catheter-associated thrombosis
|
• VTE recurrence in spite of full-dose LMWH
|
|
Patient characteristics
|
• Obesity
• Immobilization
• Thrombophilia
• Venous insufficiency, varicose veins, postthrombotic syndrome
|
• Renal impairment
• Thrombocytopenia
|
|
|
Neoplasm
|
• Metastatic disease
• Tumor vessel compression
• High thrombotic risk cancer: lung, pancreas, gastroesophageal
|
• Cancers with lower thrombotic risk: breast, prostate
|
|
|
Cancer treatment
|
• Chemotherapy
• Erythropoietin
• Hormone therapy
|
• Immunotherapy
• Targeted therapies
|
|
|
Bleeding risk
|
Low:
• No bleeding history
|
High:
• Previous tumor bleeding
• Previous bleeding history due to any other cause
• Treatment with antiangiogenic drugs
• Concomitant treatment with antiplatelet drugs
|
|
Abbreviations: CAT, cancer-associated thrombosis; DVT, deep venous thrombosis; LMWH,
low-molecular-weight heparin; PE, pulmonary embolism; SVT, superficial vein thrombosis;
VTE, venous thromboembolism.
a For dalteparin, full doses after the first month of treatment, according to DALTECAN
and CLOT studies, is 150 IU/kg/24 hours.[47]
[52]
Question 6: Should Anticoagulant Treatment Be Prolonged Beyond 3–6 Months in Cancer
Patients with Catheter-Related DVT (CVC-DVT), When the Central Venous Line Is Maintained?
Is LMWH Prophylaxis Indicated in Patients with previous CVC-DVT if a New CVC Is Needed?
Background
Some guidelines have addressed the initial management of central venous catheter (CVC)-DVT
in cancer patients, although the strength of the evidence is limited.[43]
[44]
[57]
[58]
[59] In fact, the use of LMWH in this setting relies on general clinical trials of CAT.
In general, anticoagulation for a minimum period of 3 months is recommended, even
if the CVC is removed earlier. However, the CVC can be kept in place as long as it
is functional, not infected, and DVT-related symptoms improve adequately.
In certain sense, if the CVC is maintained (or a new CVC is placed) beyond the first
3 to 6 months of anticoagulation for a CVC-DVT episode, the scenario could be comparable
to a provoked VTE with a persistent risk factor. Therefore, the risk of recurrent
thrombosis without anticoagulant treatment would be relatively high. In a study from
the RIETE registry, the incidence of recurrent thrombosis after discontinuation of
anticoagulant therapy in patients with CVC-DVT was 3.4 events/100 patient-years, but
the proportion of patients in whom the central line remained inserted was not specified.[60] Another retrospective study suggested that after 3 months of LMWH, anticoagulation
can safely be discontinued in patients with CVC-DVT when cancer is in remission and
catheter is removed.[61] Two late recurrent VTE events (lower limb DVT) were observed in 16 patients in whom
the central line was kept and continued anticoagulation beyond 3 months. In both cases,
the patients were receiving only prophylactic doses of LMWH. No recurrent upper extremity
DVT was observed in this group. Given the low number of patients and events, no definite
conclusions regarding the optimal dose of LMWH for secondary prevention in this scenario
can be derived.
Suggestions
-
When the CVC is maintained after having completed 3 to 6 months of LMWH treatment
due to a CVC-DVT event in a cancer patient, prolongation of LMWH therapy using intermediate
or prophylactic doses is suggested. Treatment should be continued until CVC removal,
as long as patient's bleeding risk is not high.
-
In cancer patients with previous CVC-DVT history who require a new CVC, LMWH prophylaxis
for at least 30 days after placement is suggested. Prophylaxis for a longer period,
as long as the CVC remains inserted, may be considered, although patient's bleeding
risk and preferences should also be valued.
Question 7: How Should CAT Be Treated in Patients with Primary or Secondary Central
Nervous System Involvement?
Background
Anticoagulation is effective, and usually well tolerated, in patients with gliomas[62] or cerebral metastases.[63] Nevertheless, some data may favor treatment modifications under certain circumstances:
-
A retrospective study analyzed the outcomes of 364 patients with CAT, half of them
with primary or metastatic brain tumors, for a median time of 6 months.[64] There were no differences between groups in the incidence of VTE recurrence (11.0
vs. 13.5 cases per 100 patients-year, p = 0.26) or major bleeding (8.9 vs. 6.0 cases per 100 patients-year, p = 0.80).
-
Another retrospective study included 293 patients with cerebral metastases, 104 of
who received therapeutic doses of enoxaparin due to acute VTE.[63] There were no differences in the 1-year incidence of cerebral hemorrhage compared
with non-anticoagulated patients (total bleeding: 44 vs. 37%, respectively, p = 0.13). The risk of intracranial hemorrhage was fourfold higher for melanoma or
kidney cancer when compared with lung cancer, although the increased risk was not
associated with enoxaparin use.
-
A meta-analysis with 1,480 patients with central nervous system (CNS) malignancies
compared the risk of intracranial hemorrhage between those who received anticoagulant
therapy with LMWH or warfarin, and those who were not treated with anticoagulant drugs.[65] The odds ratio (OR) of intracranial hemorrhage in anticoagulated patients was 2.13
(95% confidence interval [CI]: 1.0–4.56). The risk was not increased in patients with
CNS metastases (OR: 1.07, 95% CI: 0.61–1.88), in contrast to those with cerebral glioma
(OR: 3.75, 95% CI: 1.42–9.95). However, the higher incidence of intracranial bleeding
did not seem to be associated with LMWH use (OR: 0.75, 95% CI: 0.24–2.33).
-
Finally, since brainstem hemorrhages are particularly serious, any condition involving
such area should be managed cautiously.
Suggestions
-
In general, in the absence of other contraindications, in patients with primary or
secondary neoplastic involvement of CNS, standard treatment of CAT with full-dose
LMWH according to guidelines is suggested. However, the following exceptions may be
considered:
-
In patients with secondary CNS involvement from melanoma or kidney cancer, and especially
when the VTE event is not severe, a 25 to 50% reduction of the LMWH dose could be
considered.
-
In cases of glioma in the brainstem, a 25 to 50% reduction in LMWH dose is suggested.
If disease control with local treatment is achieved, a subsequent LMWH dose increase
may be weighed.
Question 8: Should Incidental Splanchnic Venous Thrombosis Be Treated?
Background
The most relevant information comes from a recent international registry promoted
by the ISTH, although the study was not limited to cancer patients.[66]
[67] A total of 604 splanchnic venous thromboses (VTs), 177 (30%) of them incidental,
were consecutively included. Sixty-two of 177 (35%) incidental splanchnic VTs were
associated with nonhematologic cancer. In this latter group, one major bleeding event
(1.2 cases per 100 patients-year) and seven thrombotic recurrences (8.1 cases per
100 patients-year) were observed during follow-up.[67] However, additional analyses may be useful for the decision-making process:
-
The probability of being administered anticoagulant treatment was lower in both, patients
with cancer and patients with incidental thrombosis.[67]
-
Treatments given to patients with incidental splanchnic VT were markedly heterogeneous
regarding drug and duration. Patterns ranged from 6 months with parenteral anticoagulants,
especially LMWH, to 24 months with oral VKA.[67]
-
Patients with thrombocytopenia (platelet count ≤100 × 109/L) were less prone to receive anticoagulant treatment, and showed the highest rate
of major bleeding.[67] A thrombotic recurrent event was more frequently seen in male patients with incidental
thrombosis and shorter duration of the anticoagulant therapy.[66]
-
Regardless of cancer, the rate of recurrences during anticoagulant treatment was similar
in patients with symptomatic or incidental splanchnic VT.[67]
-
While on anticoagulant treatment, in patients with incidentally diagnosed splanchnic
VT, the rate of major bleeding did not exceed that of recurrent thrombosis, although
specific results in cancer patients are unknown.[67]
In another recent study from the RIETE group including 521 patients with splanchnic
VT, 309 (59%) incidental, most of them received anticoagulant therapy.[68] Compared with patients with symptomatic splanchnic VT, those with incidental splanchnic
VT had a nonsignificantly higher risk of symptomatic VTE recurrence (hazard ratio
[HR]: 2.04; 95% CI: 0.71–5.88) and a similar risk of major bleeding (HR: 1.12; 95%
CI: 0.47–2.63). Active cancer was associated with an increased risk of recurrence
(HR: 3.06; 95% CI: 1.14–8.17).
Although the quality of the evidence is low, international guidelines suggest that
in cancer patients with incidental splanchnic VT, anticoagulant treatment should be
considered in a case-by-case basis, taking into account clinical data suggestive of
chronic thrombus, such as collateral circulation or portal cavernomatosis.[42]
[58] No recommendation about the need of an upper gastrointestinal endoscopy to look
for esophageal varices that could be treated before starting anticoagulant therapy
is made. There are no specific recommendations according to the splanchnic vein involved
either. Nevertheless, anticoagulant therapy seems more warranted in patients with
portal thrombosis candidates for liver transplantation, or in those with superior
mesenteric vein thrombosis involving a large intestinal surface area.
Suggestions
-
Unless contraindicated, in cancer patients diagnosed with incidental splanchnic VT,
starting anticoagulant treatment is suggested.
-
Treatment should be individualized in cases with clinical data suggesting chronic
thrombosis, as well as in cases of isolated thrombosis of an intrahepatic portal segmental
branch.
-
Anticoagulant treatment should be maintained for at least 3 months.
Question 9: In Cancer Patients with Acute VTE, What Platelet Count Threshold Would
Imply Modifications in the LMWH Dose? Can Platelet Transfusions Avoid LMWH Dose Reductions?
Background
Full-dose anticoagulation with platelet counts higher than 50 × 109/L is universally accepted, also in the context of CAT. However, management with lower
counts is controversial. Both, the ISTH in 2013 and the 2015 Canadian Consensus Guidelines
recommended the following[41]
[69]:
-
For VTE diagnosed more than 30 days ago, anticoagulant dose should be reduced in case
of platelet counts lower than 50 × 109/L.
-
In the acute phase of VTE (i.e., the first 30 days since onset), transfuse platelets
to reach counts higher than 50 × 109/L, and anticoagulation should be kept at full therapeutic doses. This recommendation
is based on the higher risk of recurrence during the first month after VTE diagnosis.
However, there are some concerns regarding this last recommendation[70]
[71]:
-
First, sustaining an intensive platelet transfusion program to reach and maintain
the threshold of 50 × 109/L is not easy and in many cases results unsuccessful.
-
Second, transfusion may imply some safety concerns. In fact, an observational study
showed that platelet transfusion aimed to reach counts greater than 50 × 109/L to maintain anticoagulation, was not only unable to reduce the hemorrhagic risk
but was associated with frequent transfusion-related adverse effects.[72]
By contrast, some studies assessed other alternatives:
-
A recent observational study performed at the Memorial Sloan Kettering Cancer Center
validated a dynamic strategy of enoxaparin dose reduction with the purpose of avoiding
platelet transfusion. Such practice could be implemented at any VTE period, even in
the first month.[73] In this study, therapeutic doses of enoxaparin were administered in case of platelet
counts greater than 50 × 109/L, while half-dose was used with platelet counts between 25 and 50 × 109/L. Anticoagulant treatment was withheld if counts were less than 25 × 109/L. An IVCF was placed in 21 out of the 99 patients who participated in the study.
-
Likewise, an intermediate strategy has also been proposed, which encourages platelet
transfusion albeit with a lower threshold, 20 × 109/L.[71]
In the very recent update of the ISTH guidelines, the experts suggest a dose modification
strategy using 50% or prophylactic-dose LMWH for patients with platelet count of 25
to 50 × 109/L and acute CAT with lower risk of thrombus progression (i.e., distal DVT, incidental
subsegmental PE, or CVC-DVT). In case of higher risk of thrombus progression, platelet
transfusion to maintain a platelet count over 40 to 50 × 109/L and use of full-dose LMWH are recommended.[74]
Finally, in a novel study from the RIETE registry (R. Lecumberri, MD, PhD, May 2018,
unpublished data), the use of lower doses of LMWH in patients with acute CAT and severe
thrombocytopenia seemed to be effective and safe, leading to low early rates of major
bleeding and recurrent VTE, very close to those observed in cancer patients with normal
platelet counts, although cancer-related mortality was significantly increased.
Suggestions
-
In case of mild thrombocytopenia (platelet counts ≥50 × 109/L), keeping anticoagulant treatment at full therapeutic doses is suggested.
-
In case of thrombocytopenia with counts lower than 50 × 109/L but higher than 20 × 109/L, a 50% reduction in the LMWH dose is suggested.
-
In case of thrombocytopenia with counts equal or lower than 20 × 109/L:
-
If VTE was diagnosed more than 30 days ago, temporary interruption of anticoagulant
treatment is suggested.
-
If VTE diagnosis was less than 30 days ago (acute VTE), platelet transfusion aimed
to keep counts above 20 × 109/L, and anticoagulation using intermediate LMWH doses, is suggested.
-
In the acute phase of VTE, placement of an IVCF can be considered in case of platelet
counts equal or lower than 20 × 109/L or in patients with low cardiopulmonary reserve and counts ranging between 20 and
50 × 109/L, especially if thrombocytopenia is anticipated to continue for more than 5 to 7
days.
Question 10: In Patients with CAT Requiring Anticoagulant Treatment and Who Were under
Antiplatelet Therapy, When Should the Latter Be Maintained?
Background
Evidence on the need of maintaining or stopping antiplatelet therapy in patients with
CAT is lacking. However, some data from atrial fibrillation (AF) and coronary artery
disease patients may be useful:
-
The use of VKA to treat a VTE event in patients with cancer is associated with a 3-
to 6-fold higher hemorrhagic risk than that observed in patients without cancer.[75]
-
Many randomized clinical trials have shown that LMWH is safe and effective in acute
coronary syndrome (ACS) without ST elevation.[76]
-
In AF patients who have stable coronary disease and for whom anticoagulation is indicated,
oral anticoagulation therapy (mainly VKA) protects against ischemic stroke and coronary
events.[77]
-
In AF patients who have stable coronary disease, the combination of VKA and acetylsalicylic
acid (ASA), compared with VKA alone, does not reduce the risk of stroke or acute myocardial
infarction but increases the risk of severe bleeding by 1.5- to 2-fold.[78]
-
Adding clopidogrel to the combination of warfarin and ASA in patients who have suffered
an ACS markedly increases the rate of severe hemorrhage (4.6% at 30 days and 10.3%
at 6–12 months).[79]
-
In patients treated for an ACS and in those who have undergone the placement of a
coronary stent, the triple therapy consisting of oral anticoagulation, clopidogrel,
and aspirin seems to be justified during a limited period.[80] In patients with high bleeding risk, the triple therapy might be limited to the
first month after the ACS, and be followed by double therapy (VKA together with ASA
or clopidogrel) for up to 1 year.
On the other hand, in the field of myeloproliferative neoplasms, both arterial and
venous thrombotic complications are frequent. ASA is frequently used as primary prophylaxis
or as secondary prophylaxis after an arterial event. In spite of the benefit of aspirin
in reducing thrombotic complications, this benefit is probably overweighed by the
increase of bleeding risk due to the association of ASA plus anticoagulation in comparison
to anticoagulants alone.[81]
[82]
[83]
Suggestions
-
Since anticoagulation at therapeutic doses is effective to prevent coronary disease
progression, and the addition of antiplatelet drugs increases the hemorrhagic risk,
the indication of combined antiplatelet plus anticoagulant treatment for CAT should
be limited to exceptional situations involving a very high risk of coronary event.
-
Maintenance of antiplatelet therapy in patients who are going to start anticoagulant
therapy for CAT is justified in case of recent (<1 year) ACS event or placement of
a coronary stent.
-
In patients with CAT carrying stents in other vascular beds, maintenance of antiplatelet
treatment while on anticoagulant therapy should be decided in a case-by-case basis.
Question 11: In Cancer Patients Treated with LMWH, When Should Anti-factor Xa Activity
Be Monitored?
Background
In the pivotal studies comparing LMWH versus VKA in CAT, body weight–adjusted LMWH
doses were used.[55]
[84]
[85] Data from those studies ruled out a significant LMWH accumulation over time, since
anti-factor Xa activity (anti-Xa) remained stable.[86] Therefore, in spite of the higher risk of recurrence and bleeding in cancer patients,
there is no evidence to support routine monitoring of anti-Xa activity to adjust LMWH
dose.
-
However, patients with severe renal failure (creatinine clearance <30 mL/min) were
excluded from those clinical trials. Clinical practice guidelines suggest monitoring
anti-Xa activity when using therapeutic doses of LMWH in patients with severe renal
impairment, and also consider initial dose reduction when using enoxaparin or bemiparin.[87]
-
Due to variations in drug distribution, the suitability of monitoring anti-Xa activity
in patients with extreme body weight and pregnant women has also been suggested.[87]
-
Additionally, monitoring anti-Xa activity in high bleeding risk scenarios, for instance,
patients with thrombocytopenia, has also been proposed.[88] However, pharmacokinetics of LMWH would not be influenced under these conditions.
The same applies to patients who have suffered a recurrent event in spite of treatment
with LMWH. An empirical dose increase is recommended, although monitoring of anti-Xa
activity might help in optimizing treatment.
-
Importantly, the association between anti-Xa activity and either clinical efficacy
or bleeding risk has not been undoubtedly demonstrated.[89] Therefore, in the earlier two mentioned scenarios, decisions on LMWH dose should
not rely on anti-Xa assessment only.
Finally, the goals of anti-Xa activity for the different LMWH molecules have been
retrospectively established. When LMWH is administered in a once-daily regimen, the
goal of peak anti-Xa activity is generally around 1 IU/mL.
Suggestions
-
In patients with CAT, routine monitoring of anti-Xa activity is not required to adjust
LMWH dose.
-
Renal function should be assessed in patients receiving LMWH at therapeutic doses.
If creatinine clearance is less than 30 mL/min, LMWH dose adjustment according to
peak anti-Xa activity is suggested (sample withdrawn 4 hours after subcutaneous LMWH
administration). Repeated monitoring over time is advisable.
-
Monitoring anti-Xa activity in patients with extreme body weight (after several days
of treatment) and in pregnant women (once per trimester) is suggested.
-
Monitoring anti-Xa in patients with thrombocytopenia or with other hemorrhagic risk
factors is not suggested. The LMWH dose should not rely on this variable.
-
Monitoring anti-Xa activity is not suggested for prophylactic doses of LMWH.
Question 12: Should Thrombophilia Study Be Performed in Patients with CAT?
Background
Thrombophilia is mainly characterized by VTE at early ages (40–50 years), unprovoked
events, or triggered by weak stimuli, recurrences, thrombosis at unusual sites, or
strong family history of VTE.[90] The term “hereditary thrombophilia” usually includes deficiency of natural anticoagulants
(antithrombin, protein C, protein S), factor V Leiden, and prothrombin G20210A mutation,
while lupus anticoagulant or antiphospholipid antibodies are considered acquired thrombophilia.[90] The following points summarize some reasoning that does not support the search for
these abnormalities in the context of CAT, since the clinical usefulness and benefits
of such practice are rather limited or nonexistent.
-
VTE management is generally guided by the clinical features of the event. Thrombophilic
abnormalities do not usually change clinical decisions, except for antiphospholipid
syndrome and antithrombin deficiency, associated with high recurrence risk, which
may favor indefinite anticoagulant treatment. In fact, the main clinical practice
guidelines on VTE management do not consider that thrombophilic abnormalities are
relevant for initial treatment or duration of therapy.[43]
[91]
[92] Moreover, the selection of patients who would benefit from thrombophilia assessment
is under discussion, although identification of thrombophilic abnormalities could
influence decisions on anticoagulant treatment duration in patients with recurrent
VTE or with strong family history.[93]
[94]
[95]
[96]
-
Patients with cancer exhibit a higher VTE risk. Although a thrombophilic factor could
further increase the risk, VTE management in cancer patients is not influenced by
the existence of associated thrombophilia: initial recommended treatment is similar
to that used in nonthrombophilic cancer patients with VTE, and duration of therapy
is mainly influenced by persistence of cancer and/or active oncologic treatment.[42]
[43]
[44]
[91]
In sum, the existing literature does not provide evidence to justify, at first, a
study of thrombophilia in patients with CAT, and guidelines do not recommend to perform
it on a routine basis.
Suggestions
