Circulation

ORIGINAL RESEARCH ARTICLE

Effect of Rivaroxaban and Aspirin in Patients With

Peripheral Artery Disease Undergoing Surgical
Revascularization: Insights From the VOYAGER
PAD Trial
E. Sebastian Debus , MD, PhD; Mark R. Nehler, MD; Nicholas Govsyeyev , MD; Rupert M. Bauersachs, MD;
Sonia S. Anand, MD; Manesh R. Patel , MD; Fabrizio Fanelli , MD; Warren H. Capell, MD; Taylor Brackin, MS;
Franz Hinterreiter, MD; Dainis Krievins, MD; Patrice Nault, MD; Gabriele Piffaretti , MD; Alexei Svetlikov, MD;
Nicole Jaeger, MS; Connie N. Hess, MD; Henrik H. Sillesen, MD; Michael Conte, MD; Joseph Mills , MD;
Eva Muehlhofer, MD; Lloyd P. Haskell, MD; Scott D. Berkowitz, MD; William R. Hiatt, MD; Marc P. Bonaca, MD

BACKGROUND: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of
adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid]
Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban
significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent
surgical LER.

METHODS: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER
to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The
Downloaded from http://ahajournals.org by on December 8, 2023

primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke,
or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International
Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were
adjudicated by a blinded independent committee.

RESULTS: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with
placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (P-interaction, 0.43). After
surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%)
patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81
[95% CI, 0.67–0.98]; P=0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International
Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity
for Thrombolysis in Myocardial Infarction major bleeding (P-interaction, 0.17) or International Society on Thrombosis and
Haemostasis major bleeding (P-interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety
outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year
cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39–1.95]; P=0.75) Among surgical
patients, the composite of fatal bleeding or intracranial hemorrhage (P=0.95) and postprocedural bleeding requiring
intervention (P=0.93) was not significantly increased.

CONCLUSIONS: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although
bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding,
intracranial hemorrhage, or postprocedural bleeds requiring intervention.

Correspondence to: E. Sebastian Debus, MD, PhD, University of Heart and Vascular Center Hamburg, Department of Vascular Medicine, Building O70, Martinistr. 52,
20246 Hamburg, Germany. Email s.debus@uke.de
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.121.054835.
For Sources of Funding and Disclosures, see page 1114.
© 2021 American Heart Association, Inc.
Circulation is available at www.ahajournals.org/journal/circ

1104 October 5, 2021 Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835

 Debus et al Surgical Reconstruction for PAD (VOYAGER Trial)

REGISTRATION: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.

ORIGINAL RESEARCH
Key Words: lower extremity revascularization ◼ major adverse limb events (MALE) ◼ peripheral artery disease ◼ revascularization
◼ rivaroxaban, major adverse cardiovascular events (MACE)

ARTICLE
Editorial, see p 1117

Clinical Perspective Nonstandard Abbreviations and Acronyms

What Is New? ALI acute limb ischemia
• Rivaroxaban 2.5 mg twice daily plus aspirin reduces CASPAR Clopidogrel and Acetylsalicylic Acid in
major adverse limb and cardiovascular events in bypass Surgery for Peripheral Arterial
surgically treated patients with peripheral artery Disease
disease relative to aspirin alone. CFA common femoral artery
• Although rivaroxaban increased bleeding, there was CLTI chronic limb threatening ischemia
no increase in postprocedural take-back bleeding, COMPASS Cardiovascular Outcomes for People
intracranial bleeding, or fatal bleeding, and the Using Anticoagulation Strategies
overall rates of bleeding were low. DAPT dual antiplatelet therapy
• The strategy of rivaroxaban plus aspirin after surgi-
cal revascularization is associated with a favorable ISTH International Society on Thrombosis
benefit/risk profile and a net benefit. and Haemostasis
LER lower extremity revascularization
What Are the Clinical Implications? MACE major adverse cardiovascular events
• Patients with peripheral artery disease are at high MALE major adverse limb events
risk of limb and cardiovascular events in spite of the MI myocardial infarction
use of available risk reduction therapies, and strate- PAD peripheral artery disease
gies to reduce this risk are needed.
PFA profunda femoris artery
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• In contrast with previous trials of anticoagulation

with warfarin, which have not shown benefit, the
VOYAGER PAD trial (Vascular Outcomes Study of
ASA [Acetylsalicylic Acid] Along With Rivaroxaban
in Endovascular or Surgical Limb Revascularization
for PAD) has now demonstrated a robust benefit
and net benefit for the combination of rivaroxaban
2.5 mg twice daily with aspirin in surgical patients.
• Rivaroxaban 2.5 mg twice daily plus aspirin there-
fore should be considered after surgical revas-
cularization and for long-term use after surgical
revascularization.
SFA superficial femoral artery
TIMI Thrombolysis in Myocardial Infarction
VKA vitamin K antagonist
in the first 30 days; however, nearly 1 in 4 patients will
develop a major adverse limb event by 1 year.9–11
Surgical LER is associated with a prothrombotic state,
particularly early after intervention, with disturbances of
coagulation and fibrinolytic systems.12,13 Nearly 15% of
LER bypass grafts fail within the first 4 weeks, and graft
stenosis or occlusion ranges from 30% to 50% within 3

P
eripheral artery disease (PAD) affects >200 million
people globally and is characterized by lower extrem-
ity morbidity ranging from intermittent claudication
to chronic limb threatening ischemia.1 Despite best prac-
tice with secondary preventive therapies, patients with
PAD remain at heightened risk for severe atherosclerotic
complications, with nearly 1 in 10 having a cardiovascular
or severe limb event annually.2–7 Although endovascular
and surgical lower extremity revascularization (LER) are
effective at providing immediate symptomatic relief and
preventing limb loss in patients with chronic limb threat-
ening ischemia in the short-term, the risk of recurrent
limb events after intervention remains elevated.8 Surgi-
cal LER is a durable approach that is accompanied by
a modest risk for major adverse cardiovascular events
to 5 years.14–17 The risk is higher with alloplastic grafts,
conduits <3 mm in diameter, and distal targets below
the knee.18 Although numerous antithrombotic strate-
gies are used as adjunctive therapy, there is a lack of
high-level evidence supporting an optimal strategy in
patients who have undergone a surgical LER. The CAS-
PAR trial (Clopidogrel and Acetylsalicylic Acid in Bypass
Surgery for Peripheral Arterial Disease) showed no ben-
efit of dual antiplatelet therapy (DAPT) with aspirin and
clopidogrel versus aspirin alone in patients undergoing a
below-knee bypass although an increase in major bleed-
ing was evident.19 Vitamin K antagonists (VKAs) have
shown benefit for graft patency, although the largest
multicenter randomized trial evaluating the efficacy of
VKAs compared with aspirin after infrainguinal bypass

Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835 October 5, 2021 1105

 Debus et al
surgery failed to show any difference in overall graft
occlusion rates, and patients treated with VKAs experi-
ORIGINAL RESEARCH
enced more major bleeding.20,21 More effective adjunc-
tive strategies are urgently needed in patients with PAD
ARTICLE
undergoing surgical LER, because they remain at high
risk of major vascular events despite currently available
best medical therapy.
The COMPASS trial (Cardiovascular Outcomes for
People Using Anticoagulation Strategies) demonstrated
that rivaroxaban 2.5 mg twice daily plus aspirin reduced
cardiovascular and limb ischemic risk in patients with
chronic PAD. Although there was a significant increase
in major bleeding, no increase in severe bleeding includ-
ing fatal or critical organ bleeding was observed, mak-
ing the net clinical benefit favorable.22,23 The VOYAGER
PAD trial (Vascular Outcomes Study of ASA [Acetylsali-
cylic Acid] Along With Rivaroxaban in Endovascular or
Surgical Limb Revascularization for PAD) further dem-
onstrated the benefit of rivaroxaban plus aspirin with a
significant reduction in the primary composite outcome
of acute limb ischemia, major amputation for vascular
causes, myocardial infarction (MI), ischemic stroke, or
death from cardiovascular causes in a broad popula-
tion of patients with PAD undergoing LER.24 Bleeding
was increased; however, there was a net benefit overall.
Patients treated with surgical LER may have a further
heightened risk of ischemic events and also bleeding,
particularly early after surgery.25 Therefore, these pre-
specified analyses were conducted to examine the ben-
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efit-risk profile of rivaroxaban 2.5 mg twice daily versus
placebo on top of background antiplatelet therapy in
patients undergoing surgical LER.
METHODS
The data, analytic methods, and study materials will not be
made available to other researchers for purposes of reproduc-
ing the results or replicating the procedure. Previous publi-
cations detail the design of VOYAGER PAD and the primary
results.24,26 Briefly, the patients were randomized after LER
for symptomatic PAD to rivaroxaban 2.5 mg twice daily or
matching placebo on top of background antiplatelet therapy
(aspirin to be used in all and clopidogrel at the treating phy-
sician’s discretion), and patients were followed for a median
of 28 months. The primary end point was a composite of
acute limb ischemia, major (above-ankle) amputation of a
vascular cause, MI, ischemic stroke, or cardiovascular death.
The principal safety outcome was Thrombolysis in MI (TIMI)
major bleeding, and International Society on Thrombosis and
Haemostasis (ISTH) bleeding was a secondary safety out-
come. Postprocedural bleeding requiring intervention was
prespecified and categorized during the trial. A postprocedural
bleeding event was defined as an unanticipated bleeding com-
plication after any revascularization for patients on study drug
that required an intervention to control bleeding. All efficacy
and safety outcomes were adjudicated by a blinded indepen-
dent clinical events committee. The definitions for all the trial
outcomes have been published previously.24,26 The protocol
1106 October 5, 2021 Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835
Surgical Reconstruction for PAD (VOYAGER Trial)
was approved by the ethics committee at each participating
site and according to local regulations. The present prespeci-
fied analyses focus on patients with surgical qualifying LER.
Study Population
Inclusion and exclusion criteria for the VOYAGER trial have
been described previously.24 Briefly, eligible patients were at
least 50 years old and had documented symptomatic lower-
extremity PAD. All patients required a successful LER, and the
first dose of study drug could be initiated up to 10 days after
procedure at the physician’s discretion to account for variability
in the timing of achieving acceptable postoperative bleeding
risk. Patients were excluded if they were clinically unstable,
were at heightened bleeding risk, or were taking prohibited
concomitant medications such as full-dose oral anticoagulation.
Clopidogrel as an adjunct to the study antithrombotic regimen
could be administered for up to 60 days after a qualifying LER
at the discretion of the investigator. All patients provided written
informed consent.
Qualifying Surgical Revascularization
The qualifying LER was performed for symptomatic PAD with
claudication, rest pain, or ischemic ulceration, evidence of occlu-
sive disease on imaging, and an abnormal ankle-brachial index.
Index arterial lesions undergoing treatment were required to be
distal to the external iliac artery. Randomization was performed
after technically successful lower extremity revascularization
on the basis of procedural imaging or postprocedure clinical
assessment. The qualifying procedure was categorized as sur-
gical or endovascular for stratification at randomization (hybrid
LER was classified as endovascular to allow for substratifica-
tion by clopidogrel exposure). Surgical LER included endarter-
ectomy or lower extremity bypass. The stratification with the
interactive voice web response system (IxRS) was slightly dif-
ferent than the actual LER performed because several cases
were found to have initially been misclassified (Table I in the
Data Supplement). In the present analyses, the LERs were
grouped by the actual procedure performed before randomiza-
tion so as not to underestimate any increased bleeding hazard
related to early use of rivaroxaban after surgical incision.
Statistical Analysis
The primary efficacy outcome was assessed among all ran-
domized patients regardless of whether they received study
treatment (intention-to-treat analysis set) in a time-to-event
analysis beginning from randomization until the global efficacy
cutoff date looking at the first occurrence of any component
of the primary efficacy outcome composite. Safety outcomes
were assessed as on-treatment analyses among all random-
ized patients who had received at least 1 dose of study drug
grouped according to treatment as received (safety analysis
set) in time-to-event analyses beginning from randomization
through 2 days after treatment discontinuation, after which
elimination of rivaroxaban was expected. The subgroup of
surgical LER was selected for evaluation of the consistency
of the primary and secondary efficacy and safety outcomes.
Sensitivity analyses of the primary efficacy and principal safety
outcomes were performed where deaths that were not part of
a given outcome were treated as competing terminal events.
 Debus et al
The prespecified approach to the benefit-risk analyses involved
pairwise comparisons of key on-treatment efficacy and safety
outcomes to determine a risk difference or excess number
of events, defined as the difference in incidence rates times
a hypothetical population size of 10 000 patients. The excess
number of events intended to be reduced (benefits) and events
that may be caused (risks) was compared between the rivar-
oxaban and placebo treatment groups.
Cumulative incidence on the basis of Kaplan-Meier estima-
tion was reported at 3 years. Hazard ratios and 95% CIs were
generated with the use of a Cox proportional hazards model with
treatment as the only model term (reported P values are 2-sided
and were obtained through a log-rank test with treatment as the
only factor). Assessing heterogeneity across subgroup levels,
interaction P values were generated on the basis of the main
effects model by adding the corresponding treatment interac-
tion term. The plausibility of the proportional hazards assump-
tion was confirmed by visually comparing the plot of the log of
cumulative hazard between treatments and by adding a treat-
ment by logarithm-transformed time interaction into the model.
Confidence limits presented for incidence rates are performed
using the SAS generalized linear model procedure, whereas
confidence limits presented for differences in incidence rates
use the nonlinear mixed models procedure with Wald CIs on the
basis of Poisson regression. For assessing baseline characteris-
tics, reported P values were generated by a Fisher’s exact test,
Monte Carlo estimate for the exact test, or Monte Carlo estimate
for the Wilcoxon exact test. Number needed to treat (NNT) and
number needed to harm were calculated as the reciprocal of the
absolute risk reduction. All analyses were performed with the
use of SAS software, version 9.4 (SAS Institute Inc, Cary, NC).
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RESULTS
Characteristics of Qualifying Revascularization
A total of 6564 patients underwent randomization. Of
these, 2185 patients (33%) underwent surgical LER,
and 4379 (67%) were treated with an endovascular or
hybrid procedure. Among the patients who underwent
surgical LER, 1124 (51%) received a bypass procedure
alone, 737 patients (34%) underwent femoral endarter-
Figure 1. Breakdown of qualifying revascularization.
Shown are the breakdowns of qualifying revascularization procedures actually performed by surgical or endovascular/hybrid. The surgical
revascularizations are further broken down into the type of surgical procedure performed.
Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835
Surgical Reconstruction for PAD (VOYAGER Trial)
ectomy alone, and 324 (15%) had a combination of both
(Figure 1). Endarterectomy involved the common femoral
ORIGINAL RESEARCH
artery in 89.8% of cases, with the inclusion of the super-
ficial femoral artery in 319 (43.3%) patients, the profunda
ARTICLE
femoris artery in 157 (21.3%), or limited to the common
femoral artery in 186 (25.2%; Table II in the Data Supple-
ment). The popliteal artery was a less frequent endarter-
ectomy location and was the target vessel in 75 (10.2%)
patients. For surgical bypass procedures, a prosthetic graft
(773 patients; 53.4%) was the most common conduit, and
the above-knee popliteal the most common distal target
(834 patients; 57.6%; Table II in the Data Supplement).
The median time frame from qualifying revascularization to
study drug initiation was 6 days among patients who un-
derwent surgical LER compared with 4 days among those
who underwent endovascular LER (P<0.0001). The me-
dian duration of treatment was 789 days among patients
who underwent surgical LER with similar treatment dura-
tion among those randomized to rivaroxaban or placebo
(785 versus 795).
Baseline Characteristics
Patient characteristics of the surgical and endovascu-
lar LER groups are presented in Table III in the Data
Supplement. Patients who underwent surgical LER were
younger and had fewer medical comorbidities such as
diabetes and chronic kidney disease than patients with
endovascular LER. However, patients who underwent
surgical LER had more severe limb disease and were
more likely to have critical limb ischemia (30.8% versus
19.7%, respectively; P<0.0001), and more likely to have
a history of a previous surgical LER (16.6% versus 6.8%,
respectively; P<0.0001) and have a target lesion length
≥15 cm. Among patients who underwent surgical LER,
the ankle brachial index was 0.47 (0.35–0.60) at screen-
ing and 0.90 (0.74–1.00) 1 month after the qualifying
revascularization. Patients who underwent surgical LER
were less likely to be on clopidogrel at randomization
October 5, 2021 1107
 Debus et al
(14.1% versus 68.6%, respectively; P<0.0001) and
were less likely to be treated with statins (76% versus
ORIGINAL RESEARCH
82%; P<0.0001) than patients with endovascular LER.
There were no significant differences in patient charac-
ARTICLE
teristics among patients who underwent surgical LER
randomized to rivaroxaban or placebo (P>0.05 for all
comparisons; Table 1).
Outcomes After Surgical LER
The cumulative incidence for the primary efficacy out-
come at 3 years after a surgical LER was 23.9% for
patients randomized to placebo. Of the primary out-
come components in the placebo group, major adverse
limb events occurred most frequently with a cumulative
incidence of 14.4% at 3 years, with the cumulative in-
cidence of acute limb ischemia and major vascular am-
putation of 11.3% and 6.3%, respectively. Cumulative
incidence at 3 years for MI and ischemic stroke was
4.2% and 2.9%, respectively, whereas the rate of car-
diovascular death was 8.4% (Table 2).
Efficacy of Rivaroxaban
The benefit of rivaroxaban versus placebo for the primary
composite outcome was consistent regardless of qualify-
ing LER (P-interaction, 0.43). For patients who underwent
surgical LER, the primary composite outcome occurred
in 199 patients in the rivaroxaban group and in 242 pa-
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tients in the placebo group with cumulative incidence at
3 years of 19.7% and 23.9%, respectively (hazard ratio
[HR], 0.81 [95% CI, 0.67–0.98]; P=0.026; Figure 2 and
Table 2). Similarly, the 3-year cumulative incidence of the
primary composite outcome for patients with endovascu-
lar LER was 16.1% in the rivaroxaban group and 17.8%
in the placebo group (HR, 0.89 [95% CI, 0.76–1.03];
P=0.12). Accounting for noncardiovascular deaths as
competing terminal events, the benefit of rivaroxaban on
the primary efficacy outcome in patients who underwent
surgical LER is essentially unchanged (HR, 0.81 [95%
CI, 0.67–0.97]; P=0.025). Frequency of drug discontinu-
ation was lower in the surgical subgroup (28.4%) versus
the endovascular subgroup (33.6%). When analyzed as
on treatment, the relative risk reduction with rivaroxaban
in the surgical subgroup was numerically greater than
that observed with the intention to treat (HR, 0.71 [95%
CI, 0.57–0.87]; P=0.0013).
Among patients who underwent surgical LER, the
benefit was apparent early after the qualifying revascular-
ization with a NNT of 24 (absolute risk reduction, 4.2%)
at 3 years. Among the primary end point components,
there appeared to be a consistent benefit of rivaroxaban
(Table 2); however, acute limb ischemia (ALI) was most
frequent and appeared to have the greatest influence on
the primary composite outcome in favor of rivaroxaban
(Figure 3; HR, 0.70 [95% CI, 0.53–0.93]; P=0.014).
1108 October 5, 2021 Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835
Surgical Reconstruction for PAD (VOYAGER Trial)
Similar to the primary efficacy outcome, the com-
posite of event free survival (ALI, major amputation of
vascular causes, MI, ischemic stroke, or all-cause mor-
tality) was significantly reduced with rivaroxaban versus
placebo, with cumulative incidences at 3 years of 23.5%
and 27.5%, respectively (HR, 0.83 [95% CI, 0.70–0.99];
P=0.039) and a NNT of 25 (Figure 4). The end point of
all-cause mortality had a point estimate with directional
benefit in favor of rivaroxaban versus placebo but was
not statistically significant (Table 2; HR, 0.86 [95% CI,
0.67–1.12]; P=0.27).
Safety of Rivaroxaban
In the overall trial, the principal safety outcome of TIMI
major bleeding and secondary safety outcome of ISTH
major bleeding on treatment were increased with rivar-
oxaban compared with placebo. There was no apparent
heterogeneity in qualifying LER type for TIMI major bleed-
ing (P-interaction, 0.17). Among patients who underwent
surgical LER, the incidence of TIMI major bleeding was
11 (1.0%) in the rivaroxaban group and 13 (1.2%) in
placebo, with cumulative incidence at 3 years of 1.3%
and 1.4%, respectively (HR, 0.88 [95% CI, 0.39–1.95];
P=0.75; Figure 5 and Table 3). The cumulative incidence
of TIMI major bleeding at 3 years among patients with
endovascular LER was 3.3% and 2.1% for those taking
rivaroxaban versus placebo, respectively (HR, 1.66 [95%
CI, 1.06–2.59]; P=0.025). Within the surgical subgroup,
bleeding risk of rivaroxaban appeared to be consistent
in those initiated <6 days from the procedure versus ≥6
days (P-interaction, 0.68). Accounting for nonbleeding
deaths as competing terminal events, the effect of riva-
roxaban on the principal safety outcome in patients who
underwent surgical LER is largely unchanged (HR, 0.86
[95% CI, 0.39–1.93]; P=0.72). Among patients who un-
derwent surgical LER, the incidence of intracranial hem-
orrhage was 2 (0.19%) in the rivaroxaban group and 3
(0.27%) in the placebo group, whereas incidence of fatal
bleeding was 3 (0.28%) and 3 (0.27%), respectively.
There was no evidence of heterogeneity in qualifying
LER type for ISTH major bleeding (P-interaction, 0.73).
Among patients who underwent surgical LER, the incidence
of ISTH major bleeding was 33 (3.1%) in the rivaroxaban
group and 26 (2.4%) in placebo; cumulative incidence at
3 years was 4.0% and 2.8%, respectively (HR, 1.32 [95%
CI, 0.79–2.20]; P=0.29; Figure 5 and Table 3). The cumu-
lative incidence of ISTH major bleeding at 3 years among
patients with endovascular LER was 6.9% and 4.7%,
respectively (HR, 1.46 [95% CI, 1.09–1.96]; P=0.012). A
total of 28 patients (1.3%) experienced bleeding related to
any revascularization while on study drug that required an
unplanned take-back procedure. After the qualifying revas-
cularization, 11 patients (0.5%) experienced take-back
bleeds requiring unplanned intervention. There was no
significant difference in postprocedural take-back bleeding
 Debus et al Surgical Reconstruction for PAD (VOYAGER Trial)

Table 1. Baseline Characteristics in Patients Who Table 1. Continued

Underwent Surgical Lower Extremity Revascularization*

ORIGINAL RESEARCH
Rivaroxaban Placebo
Rivaroxaban Placebo Characteristic (N=1084) (N=1101)
Characteristic (N=1084) (N=1101)

ARTICLE
 Performed for mild to moderate clau- 182 (16.8) 169 (15.3)
Median age, y (IQR) 65.0 66.0 dication
(60.0–71.0) (60.0–72.0)
Performed for severe claudication 541 (49.9) 574 (52.1)
Female sex, No. (%) 221 (20.4) 227 (20.6)
Performed for ischemic rest pain 185 (17.1) 195 (17.7)
Median body mass index (IQR)† 25.6 25.7
 Performed for ischemic ulceration of 144 (13.3) 134 (12.2)
(23.2–28.6) (23.0–28.7)
toes
Race/ethnicity, No. (%)‡
Target lesion length (cm)∥
White 964 (88.9) 996 (90.5)
≥15 478 (44.1) 479 (43.5)
Asian 87 (8.0) 76 (6.9)
5 to <15 395 (36.4) 394 (35.8)
Black 15 (1.4) 4 (0.4)
<5 170 (15.7) 176 (16.0)
Other 18 (1.7) 25 (2.3)
Medication, No. (%)
Geographic region, No. (%)
Aspirin at baseline 620 (57.2) 645 (58.6)
North America 68 (6.3) 69 (6.3)
Clopidogrel at randomization 153 (14.1) 156 (14.2)
Western Europe 232 (21.4) 235 (21.3)
Dual antiplatelet therapy 125 (11.5) 112 (10.2)
Eastern Europe 623 (57.5) 640 (58.1)
β-Blocker 429 (39.6) 440 (40.0)
Asia Pacific 86 (7.9) 77 (7.0)
Statin 820 (75.7) 844 (76.7)
South America 75 (6.9) 80 (7.3)
ACE inhibitor/ARB 658 (60.7) 638 (58.0)
Risk factors, No. (%)
ABI indicates ancle brachial index; ACE, angiotensin converting enzyme;
Hypertension 882 (81.4) 878 (79.8)
ARB, angiotensin receptor blocker; GFR, glomerular filtration rate; IQR, inter-
Hyperlipidemia 564 (52.0) 558 (50.7) quartile range; LER, lower extremity revascularisation; PAD, peripheral artery
disease; and PTA, percutaneous transluminal angioplasty.
Current smoker 401 (37.0) 402 (36.5)
*There were no significant differences between groups; P>0.05 for all com-
Diabetes mellitus 343 (31.6) 326 (29.6) parisons
†The body mass index is the weight in kilograms divided by the square of the
 Estimated GFR <60 mL per min/1.73 156 (14.4) 169 (15.4) height in meters.
m2
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‡Race was reported by the patient. Other race/ethnicity indicates American In-
Known carotid artery disease 87 (8.0) 98 (8.9) dian or Alaska Native, Hispanic, Latino, Native Hawaiian or Other Pacific Islander.
§This excludes 53 patients with missing disease severity (26 rivaroxaban, 27
Symptomatic coronary artery disease 334 (30.8) 312 (28.3) placebo) and 8 patients with disease severity exceeding ischemic ulceration of
Myocardial infarction 124 (11.4) 102 (9.3) toes (6 rivaroxaban, 2 placebo).
∥This excludes 93 patients with missing lesion lengths (41 rivaroxaban, 52
Percutaneous coronary intervention 104 (9.6) 94 (8.5) placebo).
Coronary artery bypass graft 70 (6.5) 66 (6.0)
Atrial fibrillation 37 (3.4) 27 (2.5) between rivaroxaban and placebo after any revasculariza-
Heart failure 102 (9.4) 108 (9.8)
tion (1.3% versus 1.3%) or the qualifying revascularization
(0.7% versus 0.3%; Table 3).
PAD history
Median ABI at screening (IQR) 0.48 0.47
(0.35–0.60) (0.35–0.59) Risk Benefit
 Median ABI at 1 mo after procedure 0.90 0.90
(IQR) (0.73–1.00) (0.74–1.00)
We estimate that for every 10 000 patients who were
treated for 1 year after surgical LER, rivaroxaban at a
Critical limb ischemia at baseline, No. (%) 337 (31.1) 335 (30.4)
dose of 2.5 mg twice daily added to aspirin would pre-
Previous amputation, No. (%) 60 (5.5) 64 (5.8)
vent 301 primary efficacy outcome events including 33
Previous major amputation 10 (0.9) 13 (1.2) MI events, 66 ischemic strokes, 141 ALI events, and 52
Previous minor amputation 42 (3.9) 39 (3.5) major amputations at the cost of 37 ISTH major bleed-
 History of previous limb revasculariza- 326 (30.1) 315 (28.6) ing events and no excess of fatal bleeds (Figures 6 and
tion, No. (%) 7). Similarly, rivaroxaban plus aspirin would prevent 168
Peripheral PTA 181 (16.7) 194 (17.6) hospitalizations for a coronary or lower extremity throm-
Surgical bypass 185 (17.1) 178 (16.2) botic event and 306 occurrences of event-free survival.
Median days from LER to randomization 6.0 (4.0–8.0) 6.0 (4.0–8.0)
(IQR)
Qualifying revascularization, No. (%)§ DISCUSSION
Patients with symptomatic PAD undergoing LER are at
(Continued ) high risk of atherothrombotic events, particularly morbid

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 Debus et al Surgical Reconstruction for PAD (VOYAGER Trial)

Table 2. Primary and Secondary Efficacy Outcomes in Patients Who Underwent Surgical LER
ORIGINAL RESEARCH

Rivaroxaban (N=1084) Placebo (N=1101) Hazard ratio (95% CI)

Patients with K-M estimate Patients with K-M estimate

ARTICLE

Outcome event, No. (%) at 3 y, % event, No. (%) at 3 y, % P value

Primary efficacy outcome: acute limb ischemia, major 199 (18.4) 19.7 242 (22.0) 23.9 0.81 (0.67–0.98) 0.026
amputation for vascular causes, myocardial infarction,
ischemic stroke, or death from cardiovascular causes
Major adverse limb event 117 (10.8) 11.4 147 (13.4) 14.4 0.79 (0.62–1.00) 0.052
Acute limb ischemia 80 (7.4) 7.7 113 (10.3) 11.3 0.70 (0.53–0.93) 0.014
Major amputation for vascular causes 63 (5.8) 6.2 67 (6.1) 6.4 0.94 (0.67–1.33) 0.74
Major adverse cardiovascular event 104 (9.6) 11.0 122 (11.1) 12.7 0.86 (0.66–1.11) 0.24
Myocardial infarction 37 (3.4) 3.6 37 (3.4) 4.2 1.00 (0.64–1.58) 0.99
Ischemic stroke 17 (1.6) 1.7 29 (2.6) 2.9 0.59 (0.32–1.07) 0.078
Death from cardiovascular causes 62 (5.7) 6.9 80 (7.3) 8.4 0.78 (0.56–1.08) 0.13
Secondary efficacy outcomes
Acute limb ischemia, major amputation for a vascular 175 (16.1) 17.2 220 (20.0) 22.0 0.78 (0.64–0.95) 0.015
cause, myocardial infarction, ischemic stroke, or death
from coronary heart disease
Unplanned index-limb revascularization for recurrent 149 (13.7) 15.1 169 (15.3) 16.7 0.87 (0.70–1.09) 0.23
limb ischemia
Hospitalization for coronary or peripheral event of a 117 (10.8) 11.3 150 (13.6) 15.2 0.77 (0.60–0.98) 0.034
thrombotic nature
Acute limb ischemia, major amputation for a vascular 237 (21.9) 23.5 279 (25.3) 27.5 0.83 (0.70–0.99) 0.039
cause, myocardial infarction, ischemic stroke, or death
from any cause
Acute limb ischemia, major amputation for a vascular 200 (18.5) 19.8 243 (22.1) 24.0 0.81 (0.67–0.97) 0.026
cause, myocardial infarction, stroke from any cause, or
death from any cause
Downloaded from http://ahajournals.org by on December 8, 2023

Death from any cause 108 (10.0) 11.8 125 (11.4) 12.9 0.86 (0.67–1.12) 0.27
Death from cardiovascular causes 62 (5.7) 6.9 80 (7.3) 8.4 0.78 (0.56–1.08) 0.13
Venous thromboembolism 8 (0.7) 0.8 17 (1.5) 1.9 0.47 (0.20–1.09) 0.070

limb events such as ALI and major vascular amputation.
The current analyses provide several novel observations
on those treated with surgical LER from a large, modern,
well-characterized randomized trial. First, patients selected
for surgery differed from those selected for endovascular
revascularization in that they had fewer medical comorbid-
ities but had more severe limb disease. Second, patients
with PAD undergoing surgical revascularization are at high
risk of the primary end point with nearly 1 in 4 experienc-
ing at least 1 event at 3 years—much of that driven by limb
events. Third, in patients selected for surgery, the efficacy
and safety of rivaroxaban versus placebo for the primary
efficacy and safety outcome were consistent regardless
of revascularization approach; however, because of their
high limb risk profile, those treated with surgical LER ap-
peared to derive a particularly robust benefit risk profile.
Postprocedural bleeding after any revascularization while
on study drug requiring unplanned intervention was rare
overall and not increased with rivaroxaban.
Although several large trials are currently ongoing
to identify the optimal revascularization strategy,27–29
the postintervention antithrombotic regimen remains
highly variable among surgeons, with supportive data
largely based on small observational or randomized tri-
als. A Cochrane review recommended single antiplate-
let treatment with aspirin or clopidogrel for all patients
with symptomatic PAD before surgical LER.30 Improved
graft patency was observed in patients receiving aspirin
versus placebo. The effect of DAPT versus aspirin alone
was evaluated in 851 patients after below-knee bypass
in the CASPAR trial. Patency rates were no different in
either group after a mean follow-up of 2 years, but bleed-
ing complications were higher in the DAPT group.19 A
recent observational study did not show any difference
between DAPT and aspirin monotherapy on bypass graft
patency, although there was improvement in patency
with DAPT among those with a prosthetic bypass on
subgroup analysis.31 Although 309 (14.1%) patients
who underwent surgical LER in the VOYAGER trial also
received clopidogrel, there was no interaction for efficacy
or safety with concomitant clopidogrel use in the overall
trial population.32 Two studies compared aspirin with a
VKA in patients receiving surgical LER with bypass.33,34
Both studies demonstrated no difference in patency or
amputation rates, and bleeding rates were significantly
higher in the VKA group in both studies. A major issue

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 Debus et al Surgical Reconstruction for PAD (VOYAGER Trial)

ORIGINAL RESEARCH
ARTICLE
Figure 2. Efficacy of rivaroxaban on the primary composite efficacy outcome in patients who underwent surgical lower
extremity revascularization.
Shown is the curve for the Kaplan-Meier cumulative incidence of the primary efficacy outcome at 3 years. Rivaroxaban is represented by purple
curve, placebo by red curve. ARR indicates absolute risk reduction; HR, hazard ratio; and NNT, number needed to treat.

in both trials was maintaining correct anticoagulation
effect, which is not an issue with low-dose rivaroxaban.
Rivaroxaban plus aspirin has emerged as a promising
strategy to reduce both cardiac and limb ischemic events
in patients with symptomatic PAD. The COMPASS trial
randomized 27 395 patients with stable atherosclerotic
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vascular amputation.22,23 These results form the basis of
current guidelines for patients with symptomatic PAD
or patients with chronic limb threatening ischemia.35–37
Patients with PAD who have undergone a LER are at par-
ticularly high risk for major adverse cardiovascular events
and major adverse limb events, including a 4-fold risk of

vascular disease, including 7470 with PAD, and demon-
strated that rivaroxaban 2.5 mg twice daily plus aspirin
compared with matching placebo plus aspirin resulted in a
significant 28% reduction in major adverse cardiovascular
events and a 31% reduction in major adverse cardiovas-
cular events or major adverse limb events including major
ALI and ?30% increased risk of MI compared with patients
with PAD with stable disease.38 The VOYAGER PAD trial
enrolled a broad population of patients with PAD undergo-
ing LER and found that compared with placebo, the addi-
tion of rivaroxaban 2.5 mg twice daily to aspirin reduced
the primary composite outcome of ALI, major amputation

Figure 3. Efficacy of rivaroxaban on acute limb ischemia in patients who underwent surgical lower extremity revascularization.
Shown is the curve for the Kaplan-Meier cumulative incidence of the acute limb ischemia primary end point component at 3 years. Rivaroxaban is
represented by purple curve, placebo by red curve. ARR indicates absolute risk reduction; HR, hazard ratio; and NNT, number needed to treat.

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 Debus et al Surgical Reconstruction for PAD (VOYAGER Trial)
ORIGINAL RESEARCH
ARTICLE

Figure 4. Efficacy of rivaroxaban on event-free survival in patients who underwent surgical lower extremity revascularization.
Shown is the curve for the Kaplan-Meier cumulative incidence of the event-free survival secondary efficacy outcome at 3 years. This end point is a
composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or all-cause mortality. Rivaroxaban
is represented by purple curve, placebo by red curve. ARR indicates absolute risk reduction; HR, hazard ratio; and NNT, number needed to treat.

for vascular causes, MI, ischemic stroke, or death from
cardiovascular causes by ?15% over 3 years, an effect
primarily driven by a significant reduction in ALI.24
Current practice guidelines recommend aspirin or
clopidogrel monotherapy for patients with symptomatic
PAD regardless of clinical setting.39 Recommendations
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than limb outcomes.19,39–41 Subgroup analyses of the sur-
gical LER VKA trials have led to some recommendations
of VKA therapy in selected conduit and target artery set-
tings. Additional adjuncts to surgical LER include bypass
graft surveillance. In the VOYAGER PAD trial, graft sur-
veillance was at the discretion of the site investigator

for more intensive regimens including DAPT with aspi-
rin and a ADP Receptor P2Y12 inhibitor or vorapaxar
are given a class IIb recommendation.39,40 Although the
use of DAPT is common after endovascular LER, data
are largely extrapolated from observational or coronary
populations, in which efficacy has been demonstrated for
cardiovascular risk and coronary stent thrombosis rather
and therefore not randomized or systematically collected.
Although this practice is widespread in modern vascular
surgery, the data to support this are modest. Randomized
trials had small sample sizes with conflicting conclusions,
and a recent review was inconclusive for benefit.42–45 Per
historical reports, the time frame for most intensive graft
surveillance and failure (30 days to 24 months) coin-

Figure 5. Safety outcomes in patients who underwent surgical lower extremity revascularization.
Shown are safety outcomes for on-treatment rivaroxaban or placebo use. TIMI major bleeding is the primary safety outcome. ISTH major bleeding
is the secondary safety outcome. Rivaroxaban is represented by purple bars, placebo by red bars. BARC indicates bleeding academic research
consortium; HR, hazard ratio; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis; KM, Kalplan Meier; and
TIMI, Thrombolysis in Myocardial Infarction.

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 Debus et al Surgical Reconstruction for PAD (VOYAGER Trial)

Table 3. Safety Outcomes in Patients Who Underwent Surgical Lower Extremity Revascularization*

ORIGINAL RESEARCH
Rivaroxaban (N=1072) Placebo (N=1099) Hazard ratio (95% CI)

Patients with K-M estimate at Patients with K-M estimate at

ARTICLE
Outcome event, No. (%) 3 y, % event, No. (%) 3 y, % P value
Primary safety outcome: TIMI major 11 (1.0) 1.3 13 (1.2) 1.4 0.88 (0.39–1.95) 0.75
bleeding
Intracranial hemorrhage 2 (0.2) 0.2 3 (0.3) 0.4 0.69 (0.12–4.14) 0.68
Fatal bleeding 3 (0.3) 0.3 3 (0.3) 0.3 1.04 (0.21–5.13) 0.97
Intracranial or fatal bleeding 5 (0.5) 0.6 5 (0.5) 0.6 1.04 (0.30–3.58) 0.95
Secondary safety outcomes
ISTH major bleeding 33 (3.1) 4.0 26 (2.4) 2.8 1.32 (0.79–2.20) 0.29
BARC major bleeding† 27 (2.5) 3.3 25 (2.3) 2.7 1.12 (0.65–1.93) 0.68
Bleeding requiring unplanned take back procedure
Any revascularization 14 (1.3) 14 (1.3) 1.04 (0.49–2.17) 0.93
Qualifying revascularization 8 (0.7) 3 (0.3) 2.76 (0.73–10.40) 0.12

BARC indicates Bleeding Academic Research Consortium; ISTH, International Society on Thrombosis and Haemostasis; and TIMI, Thrombolysis in Myocardial
Infarction.
*Safety analyses included all patients who underwent randomization and had received at least 1 dose of trial medication.
†BARC major bleeding is defined as grade 3b or higher.

cides with the separation of curves seen for surgical LER
in VOYAGER PAD.
The NNT to prevent an ischemic event in surgical LER
at 6 months and 3 years needs context as well: intensive
blood pressure control in patients with high cardiovascu-
lar risk had a NNT of 61 at 3 years to prevent 1 primary
composite end point event (MI, other acute coronary
Downloaded from http://ahajournals.org by on December 8, 2023
heart disease, and stroke) over 10 years with the use
of high-intensity statin therapy.47 It is further comparable
with the NNT with asymptomatic carotid revasculariza-
tion to prevent 1 stroke at 10 years.48 In comparison,
rivaroxaban plus aspirin after surgical LER is far more
efficacious than these therapies given the effect is seen
within the first year and continues to increase to year 3.

syndrome, stroke, heart failure, or cardiovascular death)
compared with standard blood pressure control.46 The
3-year NNT of 24 among patients who underwent surgi-
cal LER is superior to any currently recommended anti-
thrombotic regimen for patients who underwent surgical
LER and comparable with the NNT to prevent 1 athero-
sclerotic cardiovascular event (nonfatal MI, fatal coronary
Data from the COMPASS trial suggest that rivaroxaban
plus aspirin in stable but symptomatic patients provides
consistent and sustainable benefit over time, suggest-
ing long-term use in patients after revascularization for
symptomatic PAD, extending 3 years.
Limitations of the study include that it is a subgroup
analysis of a randomized trial, although the analysis was

Figure 6. Risk-benefit analysis over time in patients who underwent surgical lower extremity revascularization.
Shown are pairwise comparisons of on-treatment primary efficacy and primary safety outcomes among patients who actually underwent a
qualifying surgical revascularization to determine the risk difference of rivaroxaban use in a hypothetical population size of 10 000 patients.
The differences in cumulative incidences were determined from Kaplan-Meier analyses and calculated across time after the qualifying surgical
revascularization. Primary efficacy outcome events represented by blue line. Primary safety outcome events represented by red lines.

Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835 October 5, 2021 1113

 Debus et al
ORIGINAL RESEARCH
ARTICLE
Figure 7. Risk-benefit analysis in patients who underwent surgical lower extremity revascularization by incidence rates.
Shown are pairwise comparisons of on-treatment primary efficacy and primary safety outcomes and their components among patients who
actually underwent a qualifying surgical revascularization to determine the incidence rate difference of rivaroxaban use in a hypothetical
population size of 10 000 patients. The differences in incidence rates were determined from Kaplan-Meier analyses.
prespecified. The indications and conduct of surgical
revascularization were left to the investigators; however,
this is unlikely to bias the observations for rivaroxaban
because allocation was randomized.
In conclusion, in symptomatic PAD after LER, nearly
1 in 5 patients will develop cardiovascular or limb isch-
emic events at 3 years—a risk that is even higher (1 in
Downloaded from http://ahajournals.org by on December 8, 2023
4) after surgical LER. The addition of rivaroxaban 2.5 mg
twice daily to aspirin in patients with symptomatic PAD
undergoing surgical LER reduced cardiac and limb risk,
with robust benefits apparent early and consistent over
time. There was no significant increase in the principal
safety outcome of TIMI major bleeding among patients
who underwent surgical LER, no increase in fatal bleed-
ing or intracranial hemorrhage, and no apparent increase
in procedural or take-back bleeding. Compared with pla-
cebo, rivaroxaban 2.5 mg twice daily in addition to aspirin
in patients receiving surgical LER for symptomatic PAD
is a new adjunctive therapy that reduces cardiovascular
and limb risk as well as event-free survival.
ARTICLE INFORMATION
Received March 18, 2021; accepted June 23, 2021.
Affiliations
Department of Vascular Medicine, Vascular Surgery–Angiology–Endovascular
Therapy, University of Hamburg-Eppendorf, Hamburg, Germany (E.S.D.). CPC
Clinical Research, Aurora, CO (M.R.N., N.G., W.H.C., T.B., N.J., C.N.H., W.R.H., M.P.B.).
Division of Vascular Surgery, Department of Surgery (M.R.N., N.G.), Division of En-
docrinology (W.H.C.), and Division of Cardiology (C.N.H., W.R.H., M.P.B.), Depart-
ment of Medicine, University of Colorado School of Medicine, Aurora. Department
of Vascular Medicine, Klinikum Darmstadt, Darmstadt, and Center for Thrombosis
and Hemostasis, University of Mainz, Germany (R.M.B.). Population Health Re-
search Institute, Hamilton Health Sciences and McMaster University, Ontario,
Canada (S.S.A.). Duke Clinical Research Institute, Division of Cardiology, Duke
University, Durham, NC (M.R.P.). Vascular and Interventional Radiology Depart-
ment, Careggi University Hospital, University of Florence, Italy (F.F.). Department
1114 October 5, 2021 Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835
Surgical Reconstruction for PAD (VOYAGER Trial)
for Vascular Surgery Krankenhaus Barmherzige Brüder Linz, Austria (F.H.). Pauls
Stradins University Hospital, University of Latvia, Riga (D.K.). Vascular and Endo-
vascular Surgery, McGill University Montreal, Quebec, Canada (P.N.). Vascular Sur-
gery, Department of Medicine and Surgery, University of Insubria School of Medi-
cine, Varese, Italy (G.P.). The I.I. Mechnikov North-Western State Medical University,
Department of Cardiovascular Surgery, St. Petersburg, Russia (A.S.). Department
of Vascular Surgery, Rigshospitalet, Institute of Clinical Medicine, University of
Copenhagen, Denmark (H.H.S.). Division of Vascular and Endovascular Surgery,
University of California, San Francisco (M.C.). Division of Vascular Surgery and En-
dovascular Therapy, Baylor College of Medicine, Houston, TX (J.M.). Bayer, Wup-
pertal, Germany (E.M.). Janssen Research and Development, Raritan, NJ (L.P.H.).
Thrombosis Group Head, Clinical Development, Bayer US, Whippany, NJ (S.D.B.).
Acknowledgments
Co-Author and chair of the Voyager trial, Will Hiatt, died December 8, 2020. Marc
P. Bonaca, MD, MPH, was supported by the American Heart Association Stra-
tegically Focused Research Network in Vascular Disease under award Nos.
18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH
Clinical Project). The content is solely the responsibility of the authors and does
not necessarily represent the official views of the American Heart Association.
Sources of Funding
VOYAGER PAD was supported by a grant from Bayer AG and Janssen Research
& Development, LLC.
Disclosures
Dr. Bonaca reports grants from grant support to CPC Clinical Research from
Bayer AG, and grants from grant support to CPC Clinical Research from Jans-
sen Pharmaceuticals, during the conduct of the study; and grants from Amgen,
grants from AstraZeneca, grants from Merck, grants from NovoNordisk, grants
from Pfizer, and grants from Sanofi, outside the submitted work. Dr. Bauersachs
reports personal fees from Bayer, during the conduct of the study; and personal
fees from Bristol Myers Squibb, personal fees from Daiichi-Sankyo, and personal
fees from Pfizer, outside the submitted work. Dr. Anand reports personal fees
from Bayer AG, and personal fees from Janssen, during the conduct of the study;
and personal fees from Bayer AG, and personal fees from Janssen, outside the
submitted work. Dr. Debus reports grants and personal fees from Bayer AG,
grants from Cook LTD, and grants from Terumo Aortic, during the conduct of
the study. Dr. Nehler reports grants from Bayer, and grants from Janssen, during
the conduct of the study; and other support from CPC Research, outside the
submitted work. Dr. Patel reports grants and personal fees from Bayer, and grants
and personal fees from Janssen, during the conduct of the study; and grants
and personal fees from AstraZeneca, grants from the National Heart, Lung, and
Blood Institute, grants from Medtronic, grants from Phillips Healthcare, and grants
and personal fees from Heartflow, outside the submitted work. Dr. Capell reports
grants from Bayer and Janssen to CPC Clinical Research, during the conduct of
 Debus et al
the study. Dr. Hess reports grants from Bayer, during the conduct of the study;
and grants from Merck, and grants from Amgen, outside the submitted work. Dr.
Sillesen reports research grants and personal fees from Bayer, research and per-
sonal fees from Philips Ultrasound, research grants from Cook Medical, and per-
sonal fees from Novo Nordisk. Dr. Conte reports an advisory role to SymicBio and
Abbott Vascular. Dr. Mills reports stock in Nangio TX and serves as a consultant
for Innomed. Dr. Muehlhofer is employed by Bayer AG. Dr. Haskell reports other
support from Janssen Pharmaceuticals LLC, during the conduct of the study; and
other support from Johnson & Johnson, outside the submitted work. Dr. Berkow-
itz reports personal fees from Bayer US during the conduct of the study and out-
side of the submitted work from employment as a clinical research physician. Dr.
Hiatt has passed away. He reported grants from Bayer, and grants from Janssen,
during the conduct of the trial. Dr. Svetlikov reports personal fees from Bayer AG,
during the conduct of the study. Dr. Nault reports grants from Bayer, during the
conduct of the study. The other authors report no conflicts.
Supplemental Materials
Data Supplement Tables I–III
REFERENCES
1. Fowkes FG, Aboyans V, Fowkes FJ, McDermott MM, Sampson UK, Criqui
MH. Peripheral artery disease: epidemiology and global perspectives. Nat
Rev Cardiol. 2017;14:156–170. doi: 10.1038/nrcardio.2016.179
2. Alonso-Coello P, Bellmunt S, McGorrian C, Anand SS, Guzman R, Criqui MH,
Akl EA, Vandvik PO, Lansberg MG, Guyatt GH, et al. Antithrombotic ther-
apy in peripheral artery disease: Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines. Chest. 2012;141(Suppl):e669S–e690S. doi:
10.1378/chest.11-2307
3. Bonaca MP, Storey RF, Theroux P, Steg PG, Bhatt DL, Cohen MC, Im K,
Murphy SA, Magnani G, Ophuis TO, et al. Efficacy and safety of ticagrelor
over time in patients with prior MI in PEGASUS-TIMI 54. J Am Coll Cardiol.
2017;70:1368–1375. doi: 10.1016/j.jacc.2017.07.768
4. Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clément D, Collet
JP, Cremonesi A, De Carlo M, Erbel R, Fowkes FG, et al; European Stroke
Organisation; ESC Committee for Practice Guidelines. ESC guidelines
Downloaded from http://ahajournals.org by on December 8, 2023
on the diagnosis and treatment of peripheral artery diseases: document
covering atherosclerotic disease of extracranial carotid and vertebral,
mesenteric, renal, upper and lower extremity arteries: the Task Force on
the Diagnosis and Treatment of Peripheral Artery Diseases of the Euro-
pean Society of Cardiology (ESC). Eur Heart J. 2011;32:2851–2906. doi:
10.1093/eurheartj/ehr211
5. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA,
Drachman DE, Fleisher LA, Fowkes FGR, Hamburg NM, Kinlay S, et al.
2016 AHA/ACC guideline on the management of patients with lower
extremity peripheral artery disease: executive summary: a report of the
American College of Cardiology/American Heart Association Task Force on
Clinical Practice Guidelines. J Am Coll Cardiol. 2017;69:1465–1508. doi:
10.1016/j.jacc.2016.11.008
6. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG;
TASC II Working Group. Inter-society consensus for the management of
peripheral arterial disease (TASC II). J Vasc Surg. 2007;45(suppl S):S5–67.
doi: 10.1016/j.jvs.2006.12.037
7. Sigvant B, Hasvold P, Kragsterman B, Falkenberg M, Johansson S,
Thuresson M, Nordanstig J. Cardiovascular outcomes in patients with pe-
ripheral arterial disease as an initial or subsequent manifestation of athero-
sclerotic disease: results from a Swedish nationwide study. J Vasc Surg.
2017;66:507–514.e1. doi: 10.1016/j.jvs.2017.01.067
8. Hess CN, Huang Z, Patel MR, Baumgartner I, Berger JS, Blomster
JI, Fowkes FGR, Held P, Jones WS, Katona B, et al. Acute limb isch-
emia in peripheral artery disease. Circulation. 2019;140:556–565. doi:
10.1161/CIRCULATIONAHA.119.039773
9. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes
FG, Gillepsie I, Ruckley CV, Raab G, et al; BASIL Trial Participants. By-
pass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL): multi-
centre, randomised controlled trial. Lancet. 2005;366:1925–1934. doi:
10.1016/S0140-6736(05)67704-5
10. Conte MS, Bandyk DF, Clowes AW, Moneta GL, Seely L, Lorenz TJ, Namini
H, Hamdan AD, Roddy SP, Belkin M, et al; PREVENT III Investigators. Re-
sults of PREVENT III: a multicenter, randomized trial of edifoligide for the
prevention of vein graft failure in lower extremity bypass surgery. J Vasc
Surg. 2006;43:742–751; discussion 751. doi: 10.1016/j.jvs.2005.12.058
Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835
Surgical Reconstruction for PAD (VOYAGER Trial)
11. Conte MS, Geraghty PJ, Bradbury AW, Hevelone ND, Lipsitz SR, Moneta GL,
Nehler MR, Powell RJ, Sidawy AN. Suggested objective performance goals
ORIGINAL RESEARCH
and clinical trial design for evaluating catheter-based treatment of criti-
cal limb ischemia. J Vasc Surg. 2009;50:1462–143.e1-3. doi: 10.1016/j.
jvs.2009.09.044
ARTICLE
12. Collins P, Ford I, Greaves M, Macaulay E, BriCttenden J. Surgical revascu-
larisation in patients with severe limb ischaemia induces a pro-thrombotic
state. Platelets. 2006;17:311–317. doi: 10.1080/09537100600746540
13. Pärsson H, Holmberg A, Siegbahn A, Bergqvist D. Activation of coagulation
and fibrinolytic systems in patients with CLI is not normalized after surgi-
cal revascularisation. Eur J Vasc Endovasc Surg. 2004;27:186–192. doi:
10.1016/j.ejvs.2003.10.015
14. Conte MS, Belkin M, Upchurch GR, Mannick JA, Whittemore AD, Donaldson
MC. Impact of increasing comorbidity on infrainguinal reconstruction:
a 20-year perspective. Ann Surg. 2001;233:445–452. doi: 10.1097/
00000658-200103000-00021
15. Mills JL. Mechanisms of vein graft failure: the location, distribution, and
characteristics of lesions that predispose to graft failure. Semin Vasc Surg.
1993;6:78–91.
16. Shah DM, Darling RC 3rd, Chang BB, Fitzgerald KM, Paty PS, Leather
RP. Long-term results of in situ saphenous vein bypass. Analysis of
2058 cases. Ann Surg. 1995;222:438–446; discussion 446-8. doi:
10.1097/00000658-199510000-00003
17. Taylor LM, Jr., Edwards JM and Porter JM. Present status of reversed
vein bypass grafting: five-year results of a modern series. J Vasc Surg.
1990;11:193–205; discussion 205-6. doi: 10.1067/mva.1990.17235
18. Venermo M, Sprynger M, Desormais I, Björck M, Brodmann M, Cohnert
T, De Carlo M, Espinola-Klein C, Kownator S, Mazzolai L, et al. Follow-up
of patients after revascularisation for peripheral arterial diseases: a con-
sensus document from the European Society of Cardiology Working
Group on Aorta and Peripheral Vascular Diseases and the European So-
ciety for Vascular Surgery. Eur J Prev Cardiol. 2019;26:1971–1984. doi:
10.1177/2047487319846999
19. Belch JJ, Dormandy J, Biasi GM, Biasi BM, Cairols M, Diehm C, Eikelboom
B, Golledge J, Jawien A, Lepäntalo M, et al; CASPAR Writing Committee.
Results of the randomized, placebo-controlled Clopidogrel and Acetylsali-
cylic Acid in Bypass Surgery for Peripheral Arterial Disease (CASPAR) trial.
J Vasc Surg. 2010;52:825–833, 833.e1. doi: 10.1016/j.jvs.2010.04.027
20. Geraghty AJ, Welch K. Antithrombotic agents for preventing thrombosis
after infrainguinal arterial bypass surgery. Cochrane Database Syst Rev.
2011;6:CD000536. doi: 10.1002/14651858.CD000536.pub2
21. Group DBS. Efficacy of oral anticoagulants compared with aspirin after in-
frainguinal bypass surgery (the Dutch Bypass Oral Anticoagulants or Aspirin
Study): a randomised trial. Lancet. 2000;355:346–351.
22. Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, Aboyans
V, Alings M, Kakkar AK, Keltai K, et al; COMPASS Investigators. Rivaroxaban
with or without aspirin in patients with stable peripheral or carotid artery
disease: an international, randomised, double-blind, placebo-controlled trial.
Lancet. 2018;391:219–229. doi: 10.1016/S0140-6736(17)32409-1
23. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska
O, Diaz R, Alings M, Lonn EM, Anand SS, et al; COMPASS Investigators.
Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl
J Med. 2017;377:1319–1330. doi: 10.1056/NEJMoa1709118
24. Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR,
Fanelli F, Capell WH, Diao L, Jaeger N, et al. Rivaroxaban in peripheral artery
disease after revascularization. N Engl J Med. 2020;382:1994–2004. doi:
10.1056/NEJMoa2000052
25. Spence J, LeManach Y, Chan MTV, Wang CY, Sigamani A, Xavier D, Pearse
R, Alonso-Coello P, Garutti I, Srinathan SK, et al. Association between
complications and death within 30 days after noncardiac surgery. CMAJ.
2019;191:E830–E837. doi: 10.1503/cmaj.190221
26. Capell WH, Bonaca MP, Nehler MR, Chen E, Kittelson JM, Anand SS,
Berkowitz SD, Debus ES, Fanelli F, Haskell L, et al. Rationale and design for
the vascular outcomes study of ASA along with rivaroxaban in endovascular
or surgical limb revascularization for peripheral artery disease (VOYAGER
PAD). Am Heart J. 2018;199:83–91. doi: 10.1016/j.ahj.2018.01.011
27. Hunt BD, Popplewell MA, Davies H, Meecham L, Jarrett H, Bate G, Grant
M, Patel S, Hewitt C, Andronis L, et al; BASIL-3 Collaborative Group.
BAlloon versus Stenting in severe Ischaemia of the Leg-3 (BASIL-3):
study protocol for a randomised controlled trial. Trials. 2017;18:224. doi:
10.1186/s13063-017-1968-6
28. Menard MT, Farber A, Assmann SF, Choudhry NK, Conte MS, Creager MA,
Dake MD, Jaff MR, Kaufman JA, Powell RJ, et al. Design and Rationale of the
Best Endovascular Versus Best Surgical Therapy for Patients With Critical
October 5, 2021 1115
 Debus et al
Limb Ischemia (BEST-CLI) Trial. J Am Heart Assoc. 2016;5:e003219. doi:
10.1161/JAHA.116.003219
ORIGINAL RESEARCH
29. Popplewell MA, Davies H, Jarrett H, Bate G, Grant M, Patel S, Mehta S,
Andronis L, Roberts T, Deeks J, et al; BASIL-2 Trial Investigators. Bypass
Versus Angio Plasty in Severe Ischaemia of the Leg - 2 (BASIL-2) trial:
ARTICLE
study protocol for a randomised controlled trial. Trials. 2016;17:11. doi:
10.1186/s13063-015-1114-2
30. Bedenis R, Lethaby A, Maxwell H, Acosta S, Prins MH. Antiplatelet agents
for preventing thrombosis after peripheral arterial bypass surgery. Co-
chrane Database Syst Rev. 2015;2:CD000535. doi: 10.1002/14651858.
CD000535.pub2
31. Belkin N, Stoecker JB, Jackson BM, Damrauer SM, Glaser J, Kalapatapu
V, Golden MA, Wang GJ. Effects of dual antiplatelet therapy on graft pa-
tency after lower extremity bypass. J Vasc Surg. 2021;73:930–939. doi:
10.1016/j.jvs.2020.06.127
32. Hiatt WR, Bonaca MP, Patel MR, Nehler MR, Debus ES, Anand SS, Capell
WH, Brackin T, Jaeger N, Hess CN, et al. Rivaroxaban and aspirin in periph-
eral artery disease lower extremity revascularization: impact of concomitant
clopidogrel on efficacy and safety. Circulation. 2020;142:2219–2230. doi:
10.1161/CIRCULATIONAHA.120.050465
33. Johnson WC, Williford WO; Department of Veterans Affairs Cooperative
Study #362. Benefits, morbidity, and mortality associated with long-term
administration of oral anticoagulant therapy to patients with peripheral
arterial bypass procedures: a prospective randomized study. J Vasc Surg.
2002;35:413–421. doi: 10.1067/mva.2002.121847
34. Dagher NN, Modrall JG. Pharmacotherapy before and after revascular-
ization: anticoagulation, antiplatelet agents, and statins. Semin Vasc Surg.
2007;20:10–14. doi: 10.1053/j.semvascsurg.2007.02.006
35. Authors/Task Force M, Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F,
Danchin N, Deaton C, Escaned J, Hammes HP, et al. ESC guidelines on dia-
betes, pre-diabetes, and cardiovascular diseases developed in collaboration
with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular
diseases of the European Society of Cardiology (ESC) and developed in col-
laboration with the European Association for the Study of Diabetes (EASD).
Eur Heart J. 2013;34:3035–3087. doi: 10.1093/eurheartj/eht108
36. Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, Mills JL,
Ricco JB, Suresh KR, Murad MH, et al; GVG Writing Group for the Joint
Guidelines of the Society for Vascular Surgery (SVS), European Society
Downloaded from http://ahajournals.org by on December 8, 2023
for Vascular Surgery (ESVS), and World Federation of Vascular Societies
(WFVS). Global vascular guidelines on the management of chronic limb-
threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1–S109.
e33. doi: 10.1016/j.ejvs.2019.05.006
37. Frank U, Nikol S, Belch J, Boc V, Brodmann M, Carpentier PH, Chraim A,
Canning C, Dimakakos E, Gottsäter A, et al. ESVM guideline on periph-
eral arterial disease. Vasa. 2019;48(suppl 102):1–79. doi: 10.1024/0301-
1526/a000834
38. Bonaca MP, Bhatt DL, Storey RF, Steg PG, Cohen M, Kuder J, Goodrich
E, Nicolau JC, Parkhomenko A, López-Sendón J, et al. Ticagrelor for
prevention of ischemic events after myocardial infarction in patients with
peripheral artery disease. J Am Coll Cardiol. 2016;67:2719–2728. doi:
10.1016/j.jacc.2016.03.524
1116 October 5, 2021 Circulation. 2021;144:1104–1116. DOI: 10.1161/CIRCULATIONAHA.121.054835
Surgical Reconstruction for PAD (VOYAGER Trial)
39. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA,
Drachman DE, Fleisher LA, Fowkes FG, Hamburg NM, Kinlay S, et al. 2016
AHA/ACC guideline on the management of patients with lower extremity
peripheral artery disease: a report of the American College of Cardiology/
American Heart Association Task Force on Clinical Practice Guidelines. Cir-
culation. 2017;135:e726–e779. doi: 10.1161/CIR.0000000000000471
40. Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, Cohnert T, Collet
JP, Czerny M, De Carlo M, Debus S, et al; ESC Scientific Document Group.
2017 ESC guidelines on the diagnosis and treatment of peripheral arterial
diseases, in collaboration with the European Society for Vascular Surgery
(ESVS): document covering atherosclerotic disease of extracranial carotid
and vertebral, mesenteric, renal, upper and lower extremity arteries Endorsed
by: the European Stroke Organization (ESO) The Task Force for the Diag-
nosis and Treatment of Peripheral Arterial Diseases of the European Soci-
ety of Cardiology (ESC) and of the European Society for Vascular Surgery
(ESVS). Eur Heart J. 2018;39:763–816. doi: 10.1093/eurheartj/ehx095
41. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel
in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects
of clopidogrel in addition to aspirin in patients with acute coronary syn-
dromes without ST-segment elevation. N Engl J Med. 2001;345:494–502.
doi: 10.1056/NEJMoa010746
42. Abu Dabrh AM, Mohammed K, Farah W, Haydour Q, Zierler RE, Wang Z,
Prokop LJ, Murad MH. Systematic review and meta-analysis of duplex
ultrasound surveillance for infrainguinal vein bypass grafts. J Vasc Surg.
2017;66:1885–1891.e8. doi: 10.1016/j.jvs.2017.06.113
43. Davies AH, Hawdon AJ, Sydes MR, Thompson SG; VGST Participants. Is
duplex surveillance of value after leg vein bypass grafting? Principal re-
sults of the Vein Graft Surveillance Randomised Trial (VGST). Circulation.
2005;112:1985–1991. doi: 10.1161/CIRCULATIONAHA.104.518738
44. Lundell A, Lindblad B, Bergqvist D, Hansen F. Femoropopliteal-crural graft
patency is improved by an intensive surveillance program: a prospec-
tive randomized study. J Vasc Surg. 1995;21:26–33; discussion 33. doi:
10.1016/s0741-5214(95)70241-5
45. Zierler RE, Jordan WD, Lal BK, Mussa F, Leers S, Fulton J, Pevec W, Hill A,
Murad MH. The Society for Vascular Surgery practice guidelines on follow-
up after vascular surgery arterial procedures. J Vasc Surg. 2018;68:256–
284. doi: 10.1016/j.jvs.2018.04.018
46. Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco
MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, et al. A randomized
trial of intensive versus standard blood-pressure control. N Engl J Med.
2015;373:2103–2116. doi: 10.1056/NEJMoa1511939
47. Mortensen MB, Nordestgaard BG. Statin use in primary prevention of
atherosclerotic cardiovascular disease according to 5 major guidelines
for sensitivity, specificity, and number needed to treat. JAMA Cardiol.
2019;4:1131–1138. doi: 10.1001/jamacardio.2019.3665
48. Halliday A, Harrison M, Hayter E, Kong X, Mansfield A, Marro J, Pan
H, Peto R, Potter J, Rahimi K, et al; Asymptomatic Carotid Surgery
Trial (ACST) Collaborative Group. 10-Year stroke prevention after suc-
cessful carotid endarterectomy for asymptomatic stenosis (ACST-1):
a multicentre randomised trial. Lancet. 2010;376:1074–1084. doi:
10.1016/S0140-6736(10)61197-X