Defining the patients who will benefit most for antithrombotic treatment with dual pathway inhibition

This commentary deals with the recent paper by Kaplovitch and colleagues entitled: Rivaroxaban and aspirin in patients with symptomatic lower extremity peripheral artery disease: a subanalysis of the COMPASS randomized clinical trial, recently published in JAMA Cardiology.

Summary. This paper reports a subanalysis of the participants with symptomatic lower extremity peripheral artery disease (LE-PAD) from the Cardiovascular Outcomes for People Using Anticoagulation StrategieS (COMPASS) trial, which randomised 27,395 patients with CAD and additional risk factors, and/or symptomatic PAD to aspirin only, aspirin plus rivaroxaban 2.5 mg twice daily (low-dose dual antithrombotic therapy [DATT]) or rivaroxaban 5 mg twice daily (only) [1]. Consistent with the findings from the total study population, low-dose DATT led to a significantly lower incidence of major adverse cardiovascular (MACE) or limb events (MALE) compared to aspirin alone (HR 0.71 [95% CI 0.57 to 0.87]), with a particularly impressive reduction in MALE (0.55 [0.35-0.85]), but at the expense of increased major bleeding (1.72 [1.06-2.77]). Furthermore, the investigators explored features of risk within this subgroup and how these influenced the magnitude of benefit from low-dose DATT over aspirin alone. They demonstrated a clear relationship between increasing severity of LE-PAD and ischaemic event rates. Those with prior amputation; Fontaine class III (pain at rest) or IV (necrosis and gangrene) ischaemia; or previous lower limb revascularisation, were at the highest risk for MACE or MALE. This also interacted with co-morbidities such as polyvascular disease, diabetes and heart failure, which all increased risk too. Risk of bleeding was also higher in those with high risk LE-PAD or high-risk co-morbidities. Moreover, though the relative risk reduction was broadly similar in the different risk groups, this meant the absolute risk reduction was of greater magnitude in those with the highest risk presentations, translating into particularly impressive net clinical benefits in these groups.

Junior commentary. Dr William Parker, MB, BChir, MRCP on behalf of the WGTYR

A central tenet that has underlined the optimisation of antithrombotic therapy in recent decades has been that patient groups at higher risk of ischaemic events will benefit proportionally more from greater intensity therapy than those at lower risk. Despite the fact that patients with lower extremity peripheral artery disease (LE-PAD) are at greater risk of atherothrombotic events than many other at-risk groups [2], it has been difficult to demonstrate that escalation of antithrombotic therapy beyond single antiplatelet therapy (SAPT) significantly reduces ischaemic events in patients with LE-PAD outside the setting of acute events. For example, use of the more potent and reliable P2Y12 inhibitor ticagrelor offered no benefit in preventing MACE over clopidogrel in the “Examining Use of tiCagreLor In peripheral artery Disease” (EUCLID) trial [3]. Similarly, the combination of aspirin and clopidogrel offered no significant benefit of reduction of MACE over aspirin alone in patients with LE-PAD participating in the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management, and Avoidance (CHARISMA) study [2]. However, the investigators in the Cardiovascular Outcomes for People Using Anticoagulation StrategieS (COMPASS) trial built upon the idea that adding an anticoagulant, even at low dose, to antiplatelet therapy can provide further anti-ischaemic benefit, for example in patients with a recent ACS event [4, 5]. Though we already had an idea of the magnitude of the benefit in patients of PAD-in-general from the main paper, the latest subgroup analysis provides further detailed insight into the LE-PAD subgroup [6]. Importantly, the investigators have shown that in this population, there was a clear and sizeable benefit of low-dose DATT over aspirin alone.
Furthermore, they have reinforced the relationship between magnitude of ischaemic risk and benefit from intensification of antithrombotic therapy in this group through demonstrating not only that severe features of LE-PAD were associated with increased risk of MACE and MALE, but also that these factors conferred a greater degree of absolute risk reduction when participants were receiving low-dose DATT compared to aspirin alone. As has been noted in many studies of antithrombotic therapy, those at the highest ischaemic risk also had the highest bleeding risk, however the net clinical benefit over any risk was impressive and surely enhances the case for the use of low-dose DATT in this group. This is particularly demonstrable with regards to balancing benefits against the most serious bleeding events of a fatal or critical nature.
The present analysis therefore strengthens the case for routine clinical use of low-dose DATT in patients with symptomatic PAD, alongside aggressive management of other risk factors. This rationale has also been recently corroborated by the Vascular Outcomes Study of Aspirin Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial, which randomised 6564 patients with PAD treated by revascularisation to low-dose DATT or aspirin alone and demonstrated a significant difference in ALI, major amputation, MI, ischaemic stroke or CV death: (HR=0.85 [0.76-0.96], p=0.009) [7].

Senior commentary. Dr. Christina Christersson, MD, PhD, FESC, on behalf of the WGT.

In the recent publication by E. Kapliovitch et al they performed a subgroup analysis of the patients with symptomatic lower extremity peripheral artery disease (LE-PAD) from the COMPASS trial, to quantify major vascular events and the response to antithrombotic treatment with dual pathway inhibition i.e. low dose rivaroxaban and aspirin compared to aspirin alone [8]. It is well known that a high proportion of patients with LE-PAD have a widespread atherosclerotic disease with an increased risk of cardiovascular events [9]. In the ELUCIDE trial the PAD patients with previous revascularization where the group with the highest risk of new cardiovascular events [10]. Similar results were found in this paper with the highest risk for MACE and MALE in LE-PAD patients with high-risk limb presentation or/and a high-risk comorbidity (poly vascular diseases, diabetes mellitus, heart failure or kidney disease). An important finding from the study is that the majority of the LE-PAD patients had at least one of these high-risk comorbidities and in these patients with high-risk limb presentation or/and high-risk comorbidities there was a 4.2% (95% C.I. 1.9-6.2%) absolute risk reduction for a vascular event by rivaroxaban and aspirin compared to aspirin alone. In atherosclerotic disease there is an ongoing activation of platelets as well as the coagulation system and biomarkers for thrombin generation and fibrin turnover are higher in patients with most widespread diseases [11]. Today single antiplatelet therapy is recommended in symptomatic LE-PAD and clopidogrel is preferred above aspirin [12,13]. However, it might be an advantage to inhibit not only activated platelets but also target the coagulation pathway in selected patients with LE-PAD. The concern of using dual pathway inhibition is the risk of bleeding. This increased bleeding risk is associated with the dose of the oral anticoagulant drug and the dose with enough effect for reducing cardiovascular events without too high bleeding risk is crucial. In this paper major bleeding was increased with the combination of low dose rivaroxaban and aspirin compared to aspirin alone, however the absolute numbers of fatal bleeding were low in the study. These findings emphasize that we have to put effort in risk evaluation of symptomatic LE-PAD patients, searching for comorbidities such as diabetes, heart failure, kidney disease and other vascular manifestations, since they contribute to an increased risk even without high-risk limb presentation. This approach will help us define the patients who will benefit most for antithrombotic treatment with dual pathway inhibition where the net clinical benefit will be the largest.