DEBATE: Should VTE treatment continue beyond 6 months? Evidence supporting anticoagulation discontinuation

During the 11th ICTHIC, Agnes YY Lee and Marcello Di Nisio debated whether anticoagulation treatment should be continued in patients with cancer-associated thrombosis (CAT) beyond 6 months of therapy. Here, we summarize the evidence suggesting that venous thromboembolism (VTE) treatment should be discontinued after 6 months of therapy.

The reasons suggesting continuing anticoagulation are reported in the article “DEBATE: Should VTE treatment continue beyond six months? The evidence behind the decision to continue anticoagulation.”

Is the risk of recurrent VTE truly elevated beyond 6 months in all patients?

It is essential to identify a population that might benefit from treatment withdrawal. A better understanding of the risk of recurrent VTE beyond 6 months, taking into consideration the type of recurrence (for example, pulmonary embolism or distal deep vein thrombosis), could help in deciding the duration of anticoagulation therapy.

Two studies (DALTECAN and TiCAT) followed patients that received low-molecular-weight heparin (LMWH) treatment for up to 1 year.

The DALTECAN study shows a higher risk of recurrent VTE and major bleeding during the first month (5.7% for recurrent VTE and 3.8% for major bleeding). The risk of recurrent VTE persists at around 4% up to 12 months while the risk of major bleeding diminishes (1.1% at 6 months and 0.7% at 12 months) [1].

However, in the TiCAT study, the risk of recurrent VTE between 7 and 12 months is lower at around 1%. In addition, the risk of clinically relevant bleeding increases with time, reaching approximately 7% at 12 months [2].

The disparity between these estimates might be caused by the differences in the two populations analyzed in the two studies, which might act as confounding factors.

In some patients, anticoagulation can be safely interrupted

In the DACUS study, patients with active cancer and the first episode of VTE were treated with LMWH for 6 months. Those with residual vein thrombosis were randomly assigned to continue LMWH for an additional 6 months or to discontinue it [3].

Among the patients that didn’t have residual vein thrombosis, the risk of VTE and major bleeding was lower at six and 12 months compared with patients with residual vein thrombosis who continued or discontinued anticoagulation after 6 months [3].

These data indicate that it could be possible to identify a subgroup of patients in which anticoagulation could be safely interrupted.

In the SELECT-D trial, a quite small study with only 92 patients, after 6 months of trial treatment for VTE, patients with active cancer and residual deep vein thrombosis or index pulmonary embolism were randomized to a further 6 months of rivaroxaban or placebo [4].

The study showed a significant reduction of recurrent venous thromboembolism with rivaroxaban (4.3% with rivaroxaban compared to 13.0% with placebo). However, this reduction came at the cost of an increased risk of major bleeding and clinically relevant nonmajor bleeding (8.6% vs 0% events in rivaroxaban and placebo group, respectively) [4].

Interestingly, the group of patients who did not experience residual vein thrombosis did not experience bleeding or thrombosis for up to 12 months. Therefore, it can be observed once again that there is a group of patients with a lower risk of recurrence who would not benefit from the anticoagulation extension.

In addition, it is important to consider that bleeding caused by the anticoagulation therapy might potentially affect patient quality of life and cancer treatment interruptions.

A very recent meta-analysis looked at the incidence of recurrent VTE and major bleeding during the period beyond 6 months. Unfortunately, it was impossible to pull the data because the studies were extremely heterogeneous in terms of cancer types and type of VTE included (some include only deep vein thrombosis, some other incidental or symptomatic) [5].

Looking at the data of recurrent VTE between 6 and 12 months, the range varied between 1 and 12 %. Some studies even reported a rate below 1% [5]. This underscores that some of these patients have a low risk for recurrence.

Looking at bleeding events, data were heterogeneous but not as much for recurrence. And combining the risk of major bleeding and clinically relevant nonmajor bleeding (CRNMB) can be obtained a quite high incidence of bleeding complications (major bleeding: 1.7–4.8% [I²:30%]; CRNMB: 2.0–4.8% [I²: 64%]; at 6–12 months after index VTE) [5].

Factors to consider in anticoagulation decision-making

Considering retrospective and prospective cohort studies or even registry data, the efficacy and safety of anticoagulation beyond six months have not always been convincing. In some studies, we can see some paradoxical results, which might be the effect of residual confounding [6,7].

Other studies suggested that the equilibrium between recurrence and major bleeding is not so straightforward. In real life, patients might have a higher risk for bleeding complications than those seen in selected patient populations [8,9].

Cancer site

One of the reasons this variable risk-to-benefit ratio might be the cancer site. For example, some cancer types have a bleeding risk that clearly outweighs that of recurrent VTE (e.g., prostate cancer), while in other types of cancer (e.g., breast cancer), these two outcomes occur at similar frequencies [10].

Therefore, cancer type could be taken into account when considering if to stop coagulation, even though it is not known if the cancer stage has any effect.

Type of CAT

Another point to consider when evaluating the extension beyond six months is the type of CAT. For example, if the thrombosis is completely resolved and the disease is stable, or in the case of distal vein thrombosis, it might be considered to extend the coagulation only up to 3 months or stop anticoagulation and continue to follow up.

In case of single or multiple subsegmental pulmonary embolisms or if thrombosis was caused by a major transient risk factor (such as surgery or trauma) or by a catheter that has been removed, it might not be necessary to extend coagulation beyond 6 months.

Finally, is it necessary to extend anticoagulation in case of an unusual site and incidental VTE, representing up to 50% of thrombosis diagnoses in cancer patients?

A recent meta-analysis compared the recurrence of VTE and bleeding rate between incidental events and symptomatic events. Patients with incidental VTE had a 40% lower risk compared to symptomatic at six months while having a numerically higher rate number of bleeding events [11].

This might be a further factor to consider when planning to extend anticoagulation beyond 6 months in patients with incidental VTE.

Bleeding risk factors

Several risk factors might be associated with an increased risk for bleeding complications in cancer patients. Some are general risk factors (such as age or immobility), while others are cancer-related (e.g., metastatic disease, genitourinary cancer, and much more). These factors might be useful for identifying subgroups that have a higher risk of VTE or might benefit from interrupting anticoagulation [12].

A sub-analysis of the CLOT trial compared the recurrent and major bleeding events in patients with normal renal function or renal impairment (the proportion of patients with severe renal insufficiency was really low) [13].

Compared to the group with normal renal function, the risk of major bleeding was higher in moderate renal impaired patients, more than double in the deltaparin group and almost three-times in the warfarin group (deltaparin group: 4.1% vs 9.5% in normal and renal impaired groups, respectively; warfarin group: 2.2% vs 6.2% in normal and renal impaired groups, respectively) [13].

Case-fatality rate

A study indicated that the case-fatality rate of recurrent VTE is as high as 50%, but the heterogeneity of the study included was very high (I²: 77.3%): some studies had a case fatality rate of 0%, while others showed an increase of 50% [15].

The same heterogeneity can be seen for the case-fatality rate of recurrent major bleeding (I²: 85.2%) [15].

End-of-life care

A multicenter observational study assessed the bleeding risk of patients in a real-world practice setting of hospital palliative care. 91% of patients had cancer, and 5.7% received therapeutic anticoagulation. At 3 months, the incidence of clinically relevant bleeding was as high as 9.8%. But most importantly, the case-fatality rate of bleeding was as high as 71.9% [15].

This study is a further reminder that the use of thromboprophylaxis in palliative care patients should consider the high risk of bleeding in these patients.

Recommendations for an anticoagulation extension cannot be generalized, but the stage and the characteristic of the patient should be evaluated to weigh the importance of bleeding events or recurrent thrombosis.

Guidelines and anticoagulation use

Current guidelines suggest long-term anticoagulation or indefinite anticoagulation, but the level of certainty they are based on is low or very low. The ASCO guidelines suggest an individualized approach and extend anticoagulation only in those patients where the risk of recurrence outweighs the risk of bleeding [16].

A study shows that the use of anticoagulation drops rapidly in the first month, and, at 12 months, only 20–40% of patients are still on anticoagulation [17].

Indeed, in many of these patients, the risk-benefit was probably not favorable to continue anticoagulation. This might be due to cancer-related complications, costs, and patient preferences.

Another study confirms these results both for LMWH and DOACS. At 6 months, the use of LMWH drops between 10 and 20%, while the use of DOACS drops around 35%. At 18 months, less than 5% of the patients use LMWH or DOACS [18].

Conclusion

When evaluating the extension of anticoagulation beyond 6 months, several factors need to be considered, such as the stage of the disease, the risk of bleeding, and patient preferences.

A paper highlights the group of patients that could likely benefit from anticoagulation discontinuation, which includes [19]:

• Patients whose cancer is in complete remission
• Patients that are not receiving cancer treatment
• Patients that have a lower risk of recurrence (breast cancer and prostate cancer)
• Patients with high bleeding risk
• Patients that are approaching the end of life
• Patients with severe thrombocytopenia.

Heterogeneous data exist on the risk-to-benefit ratio of extended anticoagulation beyond 6 months. Therefore, the guideline’s suggestions to continue anticoagulation must be individualized since they are based on Expert Opinions and low evidence.

Finally, in the real-world setting, bleeding might be higher than seen in randomized clinical trials where there was a careful selection of patients.

References

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