Use of LMWH (Low molecular Weight Heparins ) in treating Venous Thromboembolism (VTE)

The risk of having Venous Thromboembolism (VTE) in cancer patients is high due to poor prognosis. VTE as such is an independent risk factor for cancer, and there is an increase in incidence by 7-fold to develop VTE in cancer patients. It is estimated that around 15-20% of patients with Pulmonary Embolism (PE) or Deep-Vein Thrombosis (DVT) are diagnosed with cancer too. When comparing the cause of death in cancer patients, VTE is ranked second and in hospitalised cancer patients, it is an independent risk factor for mortality. It has been observed that there is an increase in the incidence of VTE especially in cancer patients who are under chemotherapy regimen. VTE risk is increased in patients who undergo a progressed patient management along with the usage of the central venous catheter (CVC) plus chemotherapy or radiation or both together. It is to be kept in mind that bleeding is an independent risk factor for cancer patients. To optimize cancer-associated thrombosis (CAT), therapeutic management is essential, which benefits patients by preventing the recurrence of VTE by reducing the risk of bleeding.

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Management of CAT with Heparins

Low molecular weight Heparin (LMWH) is considered as the first choice of drugs by most academic institutions internationally for VTE in cancer. According to the guidelines for treating patients with VTE, it is recommended to treat with LMWH for 3-6 months. Efficacy of LMWH was seen as more superior than Vitamin K antagonist (VKA) in CAT patients reducing VTE as seen in 4 randomised controlled trials. The French drug agency recommendation in treating VTE in CAT patients was made by performing a meta-analysis in 4 clinical trials. Meta-analysis of these randomised controlled trials was done in which LMWH was compared to VKA, and the results stated LMWH given for long-term treatment would be two folds more efficacious than VKA in preventing recurrence of VTE. Recently the CATCH study results indicated that LMWH tinzaparin showed a superior efficacy than VKA in reducing the recurrence of VTE and bleeding, thus confirming LMWH should be the first line agent with CAT. The current guidelines suggest that 10-day initial treatment should be done by using Unfractionated Heparin (UFH) or weight-adjusted LMWH for 3-6 months. Patients with active cancer can be considered for therapy after six months, taking into account about the risk of bleeding and preference of the patient.

It remains unclear for the duration of treatment. The available data on usage of anti coagulation is limited to 6 months. As of today, there has been no RCT’s performed beyond six months on the utilization of LMWH. Two studies were conducted to answer this question but were closed due to poor patient recruitment. Therefore, there is no clarity on the duration of treatment. The French guidelines state that treatment can be extended more than six months if the patient has active cancer and there is a high chance of recurrence of VTE.


Non-adherence to clinical practice guidelines

Different medical groups & physicians from different countries have documented the consistency along with recommendations in long-term therapy of CAT. Various studies and reports for managing CAT patients. Patient adherence to clinical practice guidelines are done by two criteria, i.e. for long-term anti coagulation therapy the choice of LMWH and minimum duration of treatment for three months

RIETE registry, observations till December 2008 showed 53% of patients had LMWH for long-term anti coagulation therapy in CAT.

SWIVTER, a prospective multicentre study performed from January 2009 to May 2010 showed, 39% of cancer patients received LMWH for long-term treatment while 50% of patients were treated with VKA.

In a longitudinal retrospective cohort study, 1,089 cancer patients with VTE was observed, and it was seen that there was an increase in choosing LMWH as the first choice from 8% in 2000 to 31% in 2008. But it is still considered as insufficient.

CARMEN, a prospective survey from France, showed that 59% of cancer patients with VTE received long-term therapy of LMWH which was consistent with the recommendations & the centres where the review was done was previously sensitized about the problems of CAT. The disadvantage of this study was that it did not consider the duration of treatment.

RECOVERY is a Canadian prospective cohort study which stated severe deficiencies in LMWH usage in treating Cancer patients with VTE.

From the above experience, we can outline two factors. The patient data studied is highly variable & all studies found were prospective and observational. It is clear that all old studies have less than 50% of patients prescribed on LMWH along with long-term therapy for patients with CAT. When a physician faces a patient with CAT, he should take a decision based on clinical guidelines as well as the current physical status of cancer in the patient. There is an increase in the proportion of patients prescribed with LMWH for long-term therapy in cancer-associated VTE patients after CAT guidelines were published in 2008. A recent update from the RIETE registry in December 2013, showed that 66.4% of patients are prescribed with LMWH for long-term therapy in CAT patients. Overall, we see an increased proportion of patients prescribed with LMWH which strongly implies the impact of clinical guidelines on the physician’s practice.


Reasons for non-adherence to guidelines

As such, there is no documented data or any explanation as such as to why the treatment guidelines have not been followed, but in a real clinical scenario, factors that lead to poor adherence towards clinical guidelines may be considered as a strength of habit without any specific reasons. Lack of confidence and knowledge on treatment guidelines, safety concerns, especially the bleeding risk in which the dosing regimen has to be adapted as per the patient condition, unwillingness to have a daily injection, especially in patients who are fragile and organisational and medical care complexity.

For many years, efforts had been made by many international academic institutions to integrate the clinical practice with guidelines, but in case of CAT, it had limited impact. Adherence to treatment guidelines is not implied by long-term prescription of LMWH. In a hospital-based cohort of CAT, 204 patients were studied, in which 63% of patients received LMWH for a minimum of 3 months and was considered for long-term therapy, but 31% of patients were the only adherent to the treatment. This was due to the prescription of other drugs other than LMWH (45.3%) or giving an inappropriate dose (46.2%). Many other factors justify the circumstances in which deviation of treatment guidelines take place like biopsy, surgery, an active bleeding episode or any other supportive care. However, only 34% accounts for regimens with inappropriate dosing. TROPIQUE, an observational study had patients with an ECOG 3-4 index plus a history of bleeding episode was associated due to the poor adherence to treatment guidelines as they had to adapt to the schedule of LMWH injections.


Safety concerns and patient’s condition

The risk of getting heparin-induced thrombocytopenia in these type of patient populations is minimal. Regular biological check-ups are required for patients undergoing chemotherapy and also to detect any decrease in platelet count.

Non-adherence to treatment guidelines has a lot of influence in the extension of cancer. In concern of thrombocytopenia occurrence in haematological malignancy, usage of LMWH would be reluctant as it would increase bleeding risk.

On the other hand, a positive influence was seen in severity and extension of thromboembolic disease and malignancy due to the adherence to treatment guidelines. In the study mentioned above of 204 patients associated with CAT, adherence towards treatment guidelines was seen less in patients without metastases when compared to patients with metastatic cancer [HR 2.33 (95% CI 1.31 – 4.14), p =0.04]. Patients with PE, when compared to DVT, is seen to be treated (60% versus 40%, p = 0.016). RIETE registry data has shown that anticoagulant prescription was appropriate in metastatic cancer [OR 3.22 (95% CI 2.9-3.60)] and PE [OR 1.2 (95% CI 1.0-1,3)].

 

Complexity of medical care organisation and pathway 

A considerable variation is seen in therapeutic management which may be due to anticoagulant choice or duration of treatment or medical practice, qualifications and experience of the physician, geography or presence of any other anti-neoplastic agents.

The educational program for training on treatment guidelines for physicians, pharmacists and nurses is insufficient or poorly implemented as they lack consistency across disciplines. The pathway for medical care is involved in CAT patients, where both cancer and thrombosis have to be managed, and anticoagulants are considered less critical than anti-neoplastic treatment. On most occasions, there are no references to the management of thrombosis when an oncologist is a consulting physician. Therefore, when VTE is diagnosed, there is a massive risk as no one is accountable for the dose adaptation, prolongation or discontinuation and follow up of the anticoagulant therapy.

Many surveys are available which show variations in practice and the difficulties in approaching sizeable supportive care which mainly occurs in managing VTE in cancer patients. The primary challenge in oncology is that the therapy using anti-neoplastic agent progresses rapidly and requires highly trained professionals. The importance and severity of thromboembolism in cancer patients are perceived insufficiently and involves improvement plus awareness in various disciplines of medicine.

Another major factor that leads to deviation from treatment guidelines is the strength of habit. VKA has been choice of the drug by physicians for many decades in VTE due to its clinical familiarity. On most occasions, physicians give less importance on the tolerability and efficacy of anticoagulant agents in front of anti-neoplastic agents. Due to the absence of drug-drug interaction and regular blood check-ups, LMWH is less considered when compared to the tolerance level, and toxicity caused due to radiotherapy and chemotherapy.

Due to the daily injection of LMWH in patients, clinicians are mostly reluctant to use it. However, there is no supporting data to ascertain this assumption. Some studies have shown that acceptance for daily LMWH injections is quite high especially in CAT patients, but physicians undermine the capability of patient’s approval for long-term usage of sub-cutaneous injections. TROPIQUE, a prospective observational study of 409 CAT patients stated that treatment with LMWH for six months raised patient expectations & there was complete satisfaction shown by patients during the treatment.


Perception of patients with short or long-term prescription of LMWH

LMWH has been reported as an acceptable intervention for CAT patients, which may be considered as insignificant when compared to other adverse effects caused due to cancer-related treatment like chemotherapy and surgery. It was also found that Warfarin plays a significant role in reducing the quality of life of patients due to frequent INR monitoring, plus makes an uncertainty in the next dose of the drug to be given to the patient. LMWH, when provided for more than three months to a patient, is considered less distressing than the condition itself which is in turn, a “necessary evil”. Majority of patients adapt to daily injections thereby normalising it as their daily routine.


Learning from Patient

Many data on CAT associated patients suggest that they receive very less information about their distressing condition. It is required to give more information to the patients about the rationality of LMWH usage and also advice for self-injection. In another study on CAT patients, it was stated that anticoagulant treatment didn’t interact with any other chemotherapy, as it reduced the recurrence of VTE and also had a very low bleeding risk. In the matter of convenience, especially the use of oral drugs, once daily dose and reduction in INR monitoring, many patients have said it is not that important. This shows us that adherence to treatment guidelines will be improved by informing the patients properly about the rationality of the treatment.

 

Measures to be applied 

In the treatment of CAT, there is substantial evidence on the benefits of long-term therapy of LMWH, which proposes the importance of implementing the treatment guidelines. Guideline variation should be necessary due to the presence of bleeding risk, comorbidities like renal impairment or due to adverse reactions like thrombocytopenia. The training program should be designed giving particular attention to such exceptions. Treatment adaptation should not be legitimately considered as it may have a deviation from treatment guidelines.

Increase in thromboprophylaxis in hospitalised patients to reduce the incidence of hospital admitted PE and DVT rates. Increase in adherence to VTE treatment guidelines can be done by implementing continuous medical education in quality assurance programs, but this does not prevent VTE. Results from a prospective randomised study of patients admitted in internal medicine showed that summarising the treatment guidelines on the card which is associated with a training program has increased the adherence to treatment guidelines consistently.

The effectiveness is still unclear on educational programs given on treatment guidelines by many international consensus groups and experts of various disciplines.

There is an urgent requirement for ways to improve more adherence towards treatment guidelines as we have substantial evidence for the benefits it will have in preventing and treating CAT. It also requires a more precise understanding of the variation of treatment among the specialities, institutions and also keeping in mind the patient-related factors that can further lead to deviation in the treatment guidelines.

If all these factors can be worked on, it can help in the type of education or training that can be targeted to a suitable healthcare giver. A constructive dialogue between the oncologist and thrombosis expert and inclusion of patient factors is required to achieve this.


Take home message

VTE treatment in cancer patients is a significant medical need. Even though there is enormous evidence on the long-term use of LMWH, it is still an underused and real loss of chance(s) is/are seen.

Broader usage of LMWH should be considered keeping in mind the complexity of thromboembolic disorders in cancer patients, as it negatively impacts the prognosis. A room for deviation from treatment guidelines should be regarded as to adapt anticoagulant therapy in some legal conditions concerning of costs, geography and safety.

Treatment duration of LMWH has yet to be defined. CAT patients are recommended for a 6-month treatment. Due to the absence of data on the continuation of LMWH treatment after six months, it should be done by risk to benefit ratio in patients. Participation of both physicians and healthcare personnel, especially informing the patient about the rationality of treatment and giving appropriate training to the healthcare personnel can improve the management of CAT patients by adhering to the treatment guidelines. A drastic improvement in the usage of LMWH for long-term with acceptable recommendations due to the complexity of the thromboembolic disorder and its negative impact on the prognosis on cancer patients is an absolute requirement.

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