We read with great interest the study published on June 23, 2016 by Amato et al entitled
“Fondaparinux vs warfarin for the treatment of unsuspected pulmonary embolism in cancer
patients.”1 While we value the importance of this study in highlighting this important
topic, we have several issues to be addressed.
Venous thromboembolisms (VTEs), especially pulmonary embolism (PE), in asymptomatic
patients are well-described clinical entities that are usually underrecognized. It
is believed that most fatal PEs are not suspected clinically and are not treated.2,3
This issue is even more important in cancer patients where respiratory symptoms can
often be attributed to the cancer itself or its treatment.
We fully agree with the authors that incidental, or unsuspected PE, is not a benign
diagnosis especially in cancer patients. We previously reported our experience in
34 incidental PEs in such patients.4 Except for five (15%), all other patients were
anticoagulated; all with low-molecular-weight heparin (LMWH). With follow-up, two
patients developed recurrent PE, two others had clinical and echocardiographic evidence
of pulmonary hypertension, and nine (26%) died suddenly within 30 days of the diagnosis
of PE; two of these were among the five patients who were not anticoagulated.
In their introduction, the authors stated that “Warfarin is commonly used prophylactically
in patients with a high risk of thromboembolic events.” This statement is not accurate
as warfarin is not used for VTE prophylaxis. We assume that the authors meant active
treatment (not prophylaxis) of VTE.
Also, the authors stated that “Fondaparinux, is the newest agent with venous thromboembolism
(VTE) prophylaxis activity” and this statement is not accurate, either. Fondaparinux,
which was introduced and approved initially for VTE prophylaxis then for active treatment
of both deep vein thrombosis and PE for over 15 years now, is not new anymore.5,6
The “relatively new” oral anticoagulants, the direct thrombin inhibitors (dabigatran)
and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), are the
most recently introduced anticoagulants in clinical practice.7,8
The authors clearly stated that asymptomatic PE should be treated the same way symptomatic
PE is treated; a statement that is fully supported by many published guidelines, including
the American College of Chest Physicians.9 The authors also stated, based at least
on the CLOT trial,10 that LMWH (dalteparin) is superior to warfarin. Yet, the authors
used warfarin, not LMWH, to compare fondaparinux with.
Though we agree with the authors that the recently published CATCH trial failed to
show superiority of LMWH (tinzaparin) over warfarin in this setting,11 however, due
to many factors addressed by the authors in their paper, LMWHs are still the preferred
agents for active VTE treatment in cancer patients.
Additionally, the CATCH study showed that tinzaparin significantly reduced the risk
of clinically relevant nonmajor bleeding compared with warfarin. Together with the
adverse events data, CATCH demonstrated that tinzaparin, even when given at a full
therapeutic dose for up to 6 months, is a safe and convenient drug in cancer patients.
It should also be noted that the CATCH study results were published after enrolling
all patients in the current study under discussion.
More recently, our group participated in a pooled analysis of 926 cancer patients
from eleven cohorts, all with incidental PE. While VTE recurrence risk was comparable
under LMWH and warfarin (6.2% vs 6.4%; hazard ratio 0.9; 95% confidence interval 0.3–3.1),
the risk of major hemorrhage was higher under warfarin than under LMWH (13% vs 3.9%;
hazard ratio 3.9; 95% confidence interval 1.6–10).12
We believe that the era of having warfarin as a drug to compare new anticoagulants
within clinical trials, in cancer patients, is not attractive anymore. Researchers
are moving forward, comparing the new oral anticoagulants, such as rivaroxaban versus
LMWH, in a huge research program called the “CALLISTO”. This program is evaluating
cancer patient populations being treated for VTEs or at high risk for developing them.
Such a program will encompass the field of cancer-associated thrombosis through nine
studies, including seven clinical trials and two registries across various cancer
types, in >4,000 patients globally.13
Fondaparinux, on the other hand, has a major advantage over all other heparins, including
LMWH. Being a small molecule with just five sugars (pentasaccharide), it is rarely
associated with thrombocytopenia, thus allowing its clinical use in the treatment
of heparin-induced thrombocytopenia.14
In conclusion, we want to congratulate the authors for addressing such an important
topic, but we believe that such a study would have a better impact if the authors
chose one of the LMWHs to compare fondaparinux with. The real excitement in antithrombotic
therapy in cancer patients will be the introduction of oral direct thrombin and anti-Xa