Sebastian Debus (University Heart Center, Hamburg-Eppendorf, Germany) is joined by Birgitta Sigvant (Uppsala University, Uppsala, Sweden) and Rupert Bauersachs (Clinic Darmstadt, Darmstadt, Germany) for a special ESVS Educational Webinar: “From Science to Practice: Impact of the VOYAGER PAD trial on interventions for PAD [peripheral arterial disease].”
Debus begins by discussing the current COVID-19 pandemic and notes that, during these times, “we cannot forget about our PAD patients”—of which there are more than 200 million globally—adding that it is a disease which is “a real burden” on the vascular field.
He goes on to outline the backdrop to the VOYAGER PAD trial, the results of which were released at the recent American College of Cardiology/World Congress of Cardiology’s virtual scientific sessions (ACC.20/WCC Virtual). The VOYAGER PAD trial investigated the efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic PAD undergoing peripheral revascularisation procedures of the lower extremities.
Debus explains that previous recommendations for antiplatelet monotherapy for cardiovascular risk prevention were on a “very weak basis” and comments that “we are very grateful” that there is now a large randomised controlled trial on PAD patients only and therefore a situation where surgically treated and percutaneously treated PAD patients can be compared.
Sigvant then goes on to explain some of the European, US and global guidelines on treatment, noting that “as we all know, the PAD population is a very frail population”. Among revascularised PAD patients, data shows that one in three critical limb ischaemia (CLI) patients in this group will be dead within two years and 12% will have lost their leg.
The European guidelines, which were published in 2018, recommend that for asymptomatic patients, antiplatelet therapy should not be used. For symptomatic patients, single antiplatelet therapy is recommended and, in terms of revascularisations, for patients treated percutaneously, dual antiplatelet is recommended compared with single antiplatelet therapy for the open surgery patients.
The US guidelines are similar for symptomatic patients, but there is a slight difference for the asymptomatic patients, in that the use of antiplatelets are considered to be reasonable, states Sigvant. She then goes on discuss the Global Vascular Guidelines on the management of the “most severe patient” group, the CLI patients, which recommend that all patients be on antiplatelet therapy and say that clopidogrel, aspirin or rivaroxaban could all be considered.
Sigvant concludes by noting that “there is a lack of high-quality evidence” from the randomised trial data behind all the aforementioned guidelines. There is also “a gap of knowledge both in asymptomatic patients and in the sickest, those with CLI”. As such, there is a need for an evidence-based approach for antithrombotic therapy for all PAD stages where MACE (major adverse cardiac events), MALE (major lower-extremity limb amputation) and bleeding should be weighted,” she adds.
Following Sigvant’s presentation, Rupert Bauersachs then proceeds to present the results of the VOYAGER PAD trial, the findings of which were published on the same day as the ACC.20/WCC Virtual presentation in the New England Journal of Medicine.
Agreeing with Sigvant, Bauersachs also says there is a “lack of data” and briefly touches on the previous CASPAR trial which did not find any benefit of dual antiplatelet treatment in these patients, but did find that there was an increase of severe bleeding by a factor of almost three.
The VOYAGER PAD trial looked at patients undergoing lower extremity revascularisation for ischaemic symptoms, and to see whether 2.5mg of rivaroxaban twice daily added to low-dose aspirin reduces the risk of major adverse limb and cardiovascular events compared to aspirin alone as well as to evaluate the safety of the drug.
The trial included more than 6,500 patients, randomised on a one-to-one ratio, with a median follow-up of 28 weeks. The new combined primary objective combined limb events, major amputation, myocardial infarction, ischaemic stroke and cardiovascular death into one endpoint.
Outlining the results, Bauersachs notes that it is “remarkable” that 19.9% of the patients that were just receiving aspirin had an incidence of the primary endpoint which fell to 17.3% in the rivaroxaban group after three years (hazard ratio [HR]: 0.85, p=0.0085).
There was a drop in the incidence of acute limb ischaemia (7.74 to 5.24), major vascular amputation (3.87 to 3.42), ischaemic stroke (3.01 to 2.70) and myocardial infarction (5.22 to 4.55). However, the rate of cardiovascular death increased from (6.43 to 7.05), yet this was not statistically significant.
In terms of secondary outcomes, unplanned limb revascularisation was more than 22% in the placebo group compared with 20% in the rivaroxaban group (HR: 0.88). Vascular hospitalisation for a coronary or peripheral thrombotic event also fell from 12.1% to 8.7% (HR: 0.72). Additionally, there was no significant difference in all-cause mortality.
In regards to safety, TIMI (Thrombolysis in Myocardial Infarction) major bleeding was numerically higher in the rivaroxaban cohort (2.7%) compared with the placebo cohort (1.9%) but not significant (HR: 1.43).
In summary, in symptomatic PAD patients after revascularisation, rivaroxaban 2.5mg twice daily compared to aspirin alone led to a “significant reduction in the risk for the primary endpoint,” with the added benefit that the reduction was established early and continued over time as well as indicating a consistent benefit across all major subgroups. There was a numerical increase in both TIMI major bleeding and International Society on Thrombosis and Hemostasis (ISTH) major bleeding but no increase bleeding to leading to irreversible harm.
The data are “very reassuring” says Bauersachs. Debus fully agrees, saying that “the fear we had during the study that we would have increased numbers of bleedings post-procedure just did not happen”. He does say however that this may be because “we did not start immediately after treatment,” but concludes that the results are “promising” and the real-life cohort of patients “really reflects our practice”. Sigvant however notes that there were “very few” women included in the trial, which she says is not the case in her daily practice experience. Responding, Bauersachs accepts that women are underrepresented in many cardiovascular trials and puts the lack of women in the VOYAGER PAD trial down to the proportion of women presenting with PAD tending to be older and thus many not meeting the inclusion criteria.
Debus then outlines the findings of the COMPASS trial and the differences between the two, including the fact that the patients in COMPASS were less severely affected (mostly claudicants) than in VOYAGER PAD. The results, however, were similar in that they showed a “strong and significant benefit” of rivaroxaban plus aspirin compared to aspirin alone.
Debus and Sigvant highlight two case studies before Bauersachs provides some insight on the data surrounding the use of clopidogrel that came out of the VOYAGAERPAD study—notably whether or not the efficacy and safety of rivaroxaban were consistent regardless of a background of clopidogrel use and to explore temporal patterns of bleeding in relationship to exposure and duration of clopidogrel.
The results show that “whether you use clopidogrel or not,” rivaroxaban works in “both ways exactly the same,” says Bauersachs. However, clopidogrel exposure was found to be associated with higher rates of bleeding overall, particularly with longer durations (e.g. more than 30 days).
Debus says that this “thrilling data must be received like an earthquake, especially to the endovascular community” and asks whether or not clopidogrel should be used at all. Bausersachs concludes: “If you do not find a reason for the clopidogrel, I would recommend to discontinue it because it increases the risk and has no proven benefit”.