Longer rivaroxaban course reduces risk of recurrent venous thromboembolism

5th December 2022

A longer course of rivaroxaban following an isolated distant deep vein thrombosis significantly reduces the risk of a recurrent thrombosis

Taking rivaroxaban for 12 weeks rather than 6, following an isolated deep vein thrombosis, significantly reduces the risk of a recurrent thromboembolic event over the next two years according to the results of a randomised, double-blind, placebo-controlled trial by Italian researchers.

An isolated distal deep vein thrombosis (DVT) accounts for between a quarter and a half of all leg DVTs. Moreover, left untreated, an isolated distal DVT can extend to the proximal veins or cause a pulmonary embolism in between 1% and 22% of cases. Treatment of an isolated DVT involves the use of anticoagulants both therapeutically and prophylactically although the duration of the therapy to prevent recurrent events is uncertain. In a meta-analysis of studies, it was clearly shown that anticoagulant therapy reduced the risk of venous thromboembolism in patients. However, the review also found that there was a lower rate of recurrent venous thromboembolism in patients who received longer than 6 weeks of anticoagulant therapy.

With a suggestion that longer duration anticoagulation appeared to reduce the risk of a recurrent thromboembolic event, in the present study, researchers compared the impact on recurrent events of either a 6- or 12-week course of rivaroxaban. They recruited patients diagnosed with a symptomatic isolated distal DVT of the leg and who were then given rivaroxaban 15 mg twice daily for three weeks and then 20 mg daily for a further three weeks. At this point, participants who had not developed any thrombotic and haemorrhagic events, were randomised 1:1 to either continue with rivaroxaban 20 mg daily or matching placebo for a further 6 weeks. The primary efficacy outcome was a recurrent venous thromboembolism during the follow-up and the primary safety outcome was major bleeding, after randomisation.

Rivaroxaban and recurrent thromboembolism

A total of 402 individuals with a mean age of 65 years (58% women) were included and randomised to rivaroxaban (200) or placebo and followed for 24 months.

A recurrent thromboembolism occurred in 11% of rivaroxaban patients and 19% of those assigned to placebo (relative risk, RR = 0.59, 95% CI 0.36 – 0.95, p = 0.03). A recurrent isolated distal DVT recurred significantly less frequently, occurring in 8% and 15% of the rivaroxaban and placebo groups respectively (p = 0.02). However, a proximal or pulmonary embolism occurred in an equally small number of patients in each group and there were no major bleeding events.

The authors concluded that giving rivaroxaban for 3 months in patients with and isolated distal DVT who did not experience any events during the first 6 weeks of therapy reduced the risk of recurrent venous thromboembolism.

Citation
Ageno W et al. Rivaroxaban treatment for six weeks versus three months in patients with symptomatic isolated distal deep vein thrombosis: randomised controlled trial. BMJ 2022

No benefit for COVID-19 inpatients from either colchicine or aspirin and rivaroxaban combined 

8th September 2022

COVID-19 inpatients failed to benefit from the use of colchicine or a combination of aspirin and rivaroxaban in comparison to usual care

Among COVID-19 inpatients, neither colchicine or a combination of aspirin and rivaroxaban provided any benefit in terms of the need for high flow oxygen, mechanical ventilation or death according to the findings of a study by researchers based at the Population Health Research Institute, Hamilton, Canada and presented at the ESC congress in Barcelona, Spain.

The use of anti-inflammatory treatments such as glucocorticoids for COVID-19 inpatients is associated with a lower risk of 28-day all-cause mortality.

Colchicine which is largely used in the treatment of gout, interferes with several inflammatory pathways, including inhibition of neutrophil chemotaxis, adhesion, and mobilisation, disruption of superoxide production and inflammasome inhibition and has possible antiviral properties.

However, to date studies with colchicine among COVID-19 inpatients have failed to reduce in-hospital mortality.

A further problem among hospitalised COVID-19 patients is hyper-coagulability accompanied by activation of blood coagulation, leading to a high risk of venous thromboembolism, especially among those admitted to an intensive care unit.

Aspirin and rivaroxaban are both effective antithrombotic drugs and in combination, have been found to result in better secondary cardiovascular prevention outcomes.

For the present trial, the Canadian team tested these two treatments: colchicine to target inflammation and the aspirin and rivaroxaban combination to target haemostatic activation. The overall aim was to prevent the need for increased respiratory support and death among COVID-19 inpatients.

The trial randomised COVID-19 inpatients to receive 28 days of treatment with: (1) colchicine (loading dose 1.2 mg, followed by 0.6 mg two hours later, then 0.6 mg twice daily for 28 days) versus control and (2) rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) versus control, using a factorial design.

Using this design, researchers were able to simultaneously evaluate the independent effects of colchicine and the aspirin-rivaroxaban strategy and any possible additive effects. 

The team set the main outcome for the comparison between colchicine and control as the need for high flow oxygen, mechanical ventilation or death. In contrast, for the aspirin-rivaroxaban combination, the outcome was major thrombosis, need for high flow oxygen, mechanical ventilation or death.

COVID-19 inpatients and treatment outcomes

The trial randomised 2,611 to colchicine versus control and 2,119 to rivaroxaban plus aspirin versus control.

Colchicine compared with control did not significantly reduce high flow oxygen, mechanical ventilation or death (28.2% vs. 27.2% events) giving a hazard ratio, HR of 1.04 (95% CI 0.90 – 1.28, p = 0.578).

Similarly, the combination of aspirin and rivaroxaban versus control did not significantly reduce major thrombosis, the need for high flow oxygen, mechanical ventilation or death (26.4% vs. 28.4% events), HR = 0.92 (95% CI 0.78 – 1.09, p = 0.324).

There was no evidence of benefit of either treatment in any of the major subgroups examined including the need for oxygen at baseline, admission to the intensive care unit at randomisation, COVID-19 vaccination status or time from COVID-19 symptom onset to randomisation.

The team also performed an updated meta-analysis of randomised trials of intensified anticoagulation versus control. Among 7,503 patients, intensified anticoagulation compared with control reduced venous thromboembolism by about one-half, whereas among 7,640 patients intensified anticoagulation compared with control did not reduce mortality.

There was statistical evidence of heterogeneity for the outcome of mortality which was driven by two smaller trials that suggested implausibly large reductions in mortality (46 – 77% relative risk reductions).

Lead author Dr Sanjit Jolly said: ‘The ineffectiveness of colchicine contrasts with a clear benefit of glucocorticoids, and raises several possibilities: concomitant use glucocorticoids negated any benefit of colchicine, colchicine is not sufficiently potent to suppress inflammation, or activation of the NLRP3 inflammasome does not play a major causal role in COVID-19 disease progression.’

They added: ‘The low rate of major thrombosis in the control group (<2%) suggests thrombosis is less of a problem than originally thought and that the lack of mortality benefit suggests that venous thromboembolism does not substantially contribute to mortality in hospitalised COVID-19 patients.’