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PAD: Rivaroxaban reduces VTE risk after revascularisation

Presented by
Dr Connie Hess; Prof. Judith Hsia
AHA 2020
Peripheral artery disease (PAD) is associated with a linearly increased risk of venous thromboembolism (VTE) after lower extremity revascularisation. A secondary analysis of the VOYAGER PAD study showed that adding low-dose rivaroxaban to aspirin reduced VTE risk by 39% [1]. In another analysis of VOYAGER PAD, rivaroxaban reduced the composite endpoint of major cardiovascular (CV) and limb events in PAD patients with chronic kidney disease (CKD) [2].

In the VOYAGER PAD study (NCT02504216), patients with lower extremity PAD undergoing revascularisation were randomised to rivaroxaban 2.5 mg twice daily plus aspirin (n=3,286) or placebo plus aspirin (n=3,278) [3]. The primary efficacy outcome of CV death, acute limb ischaemia, major amputation, myocardial infarction, or stroke occurred in 17.3% and 19.9%, respectively (HR 0.85; 95% CI 0.76–0.96; P=0.009).

Dr Connie Hess (University of Colorado, USA) presented the results of the prespecified secondary analysis with symptomatic VTE as its primary outcome [1]. Dr Hess explained that the risk of VTE and the effects of low-dose rivaroxaban in patients with symptomatic PAD undergoing revascularisation had not been described, and that it is unknown if the effect of rivaroxaban on VTE is modified by background dual antiplatelet therapy. Over a median of 28 months, 66 VOYAGER PAD participants presented with VTE. Compared with participants without VTE, they were slightly older, had greater body weight, more often had renal dysfunction, and had lower use of clopidogrel or statins. They were also more likely to have undergone prior endovascular revascularisation.

After 36 months, the rate of VTE was significantly lower in the rivaroxaban group versus the placebo group: 0.8% vs 1.66% (HR 0.61; 95% CI 0.37–1.00; P=0.047). In the placebo group, the VTE risk steadily accrued after randomisation at a rate of around 0.5% per year. The effect of rivaroxaban occurred early and was sustained over time (see Figure). The effect was also independent of baseline characteristics including age, weight, estimated glomerular filtration rate (eGFR), coronary artery disease, baseline statin, or baseline clopidogrel use. The hazard ratio for VTE with and without clopidogrel was 0.69 (95% CI 0.32–1.48) and 0.55 (95% CI 0.29–1.07), respectively (Pinteraction=0.67). Rivaroxaban was also associated with a 25% risk reduction versus placebo in the composite endpoint of acute venous and arterial thrombotic events (i.e. VTE, acute limb ischaemia, major amputation of vascular aetiology, myocardial infarction, or stroke). Cumulative incidence was 12.2% versus 16.2% (HR 0.75; 95% CI 0.65–0.86; P<0.0001). This translates into an absolute risk reduction of 4% over 3 years and a number needed to treat of 25.

Figure: VTE rate in the rivaroxaban versus placebo group after 3 years [1]
Figure kindly provided by Prof. Connie Hess.

Dr Hess concluded: “Rivaroxaban plus aspirin provides protection against the full spectrum of acute venous and arterial thrombotic events after lower extremity revascularisation, regardless of background therapy, and should be considered early to reduce this risk in patients with symptomatic PAD undergoing revascularisation.”

Another prespecified subgroup analysis of VOYAGER PAD presented at the AHA Scientific Sessions examined patients with CKD, a population at very high risk for adverse outcomes among patients undergoing lower extremity revascularisation for PAD [2]. Prof. Judith Hsia (University of Colorado, USA) explained that participants requiring dialysis or renal replacement therapy were excluded, as well as patients with an eGFR <15 mL/min/1.73m2 (i.e. CKD stage 5), as exposure to rivaroxaban is increased in these patients. The objectives of this subanalysis were to evaluate the extent to which PAD patients with CKD (defined as eGFR <60 mL/min/1.73m2) are at a higher risk for major CV and limb events, and to evaluate whether the efficacy and safety of rivaroxaban in this subpopulation are consistent with the overall cohort.

Of the 6,319 patients with baseline eGFR, 1,327 (21%) had CKD, of whom 1,284 had stage 3. As a group, they were older and more often female, and had a higher prevalence of hyperlipidaemia, diabetes, and hypertension. In the placebo group, major CV events, but not limb events, were more frequent among patients with CKD compared with patients without CKD. Rivaroxaban reduced the risk of the primary outcome (HR 0.85; 95% CI 0.76–0.96; P=0.009), with no heterogeneity by eGFR category (Pinteraction=0.62). In CKD patients, rivaroxaban was associated with a lower risk of limb events (HR 0.55; 95% CI 0.35–0.86; Pinteraction=0.18) but not with a lower risk of major CV events (HR 1.07; 95% CI 0.82–1.40; Pinteraction=0.52). TIMI major bleeding was numerically more frequent among patients with CKD (HR 1.86; 95% CI 0.92–3.79), with no heterogeneity by treatment group (Pinteraction=0.37).

Two additional sub-analyses of the VOYAGER PAD were presented during a late-breaking session at the AHA Scientific Session 2020 [3,4]. Prof. Marc Bonaca (University of Colorado, USA) presented a subgroup analysis on the risk profile of PAD patients who underwent endovascular lower-extremity revascularisation, and Prof. Manesh Patel (Duke Medical Center, USA) presented an analysis that included PAD patients who underwent lower extremity revascularisation for critical limb ischaemia.

    1. Hess CN, et al. Reduction in Venous Thromboembolism With Rivaroxaban versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD. Abstract 291, AHA Scientific Sessions 2020, 13–17 Nov.
    2. Hsia JA, et al. Rivaroxaban Reduces Major Cardiovascular and Limb Events in Patients With the High-risk Triad of Chronic Kidney Disease, Peripheral Artery Disease and Recent Lower Extremity Revascularization: Insights From VOYAGER PAD. Abstract 293, AHA Scientific Sessions 2020, 13–17 Nov.
    3. Bonaca MP, et al. N Engl J Med. 2020;382(21):1994-2004.
    4. Bonaca MP, et al. Efficacy and Safety of Rivaroxaban in Patients With PAD Undergoing Lower Extremity Revascularization for Critical Limb Ischemia: Insights From VOYAGER PAD. FS.03, AHA Scientific Sessions 2020, 13–17 Nov.
    5. Patel M, et al. Rivaroxaban Plus Aspirin versus Aspirin Alone After Endovascular Revascularization for Symptomatic PAD: Insights From Voyager PAD. FS.03, AHA Scientific Sessions 2020, 13–17 Nov.


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