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Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease - VOYAGER PAD

Contribution to literature:.

Highlighted text has been updated as of October 23, 2023.

The VOYAGER PAD trial showed that rivaroxaban/aspirin was superior to aspirin alone at preventing major adverse limb and cardiovascular events.

Description:

The goal of the trial was to evaluate rivaroxaban/aspirin compared with placebo/aspirin among patients with lower extremity peripheral artery disease (PAD) undergoing revascularization.

Study Design

Patients with lower extremity PAD undergoing revascularization were randomized to rivaroxaban 2.5 mg twice daily/aspirin (n = 3,286) versus placebo/aspirin (n = 3,278).

• Total number of enrollees: 6,564
• Duration of follow-up: median 28 months
• Median patient age: 67 years
• Percentage female: 26%
• Percentage with diabetes: 40%

Inclusion criteria:

• Age ≥50 years
• Lower extremity PAD (documented by ischemic symptoms, imaging evidence of disease, and abnormal ankle-brachial index)
• Successful lower extremity revascularization

Exclusion criteria:

• Revascularization for asymptomatic disease
• Recent revascularization (<10 days), acute limb ischemia (<2 weeks), or acute coronary syndrome (<30 days)
• Current major tissue loss
• Need for antiplatelet or anticoagulation therapy other than aspirin and/or clopidogrel
• Need for long-term dual antiplatelet therapy
• High-risk for bleeding

Other salient features/characteristics:

• Indication for revascularization; claudication = 77%, critical limb ischemia = 23%
• Type of revascularization: surgical = 35%, endovascular or hybrid = 66%
• Median ankle-brachial index = 0.56

Principal Findings:

The primary efficacy outcome, cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke, occurred in 17.3% of the rivaroxaban/aspirin group compared with 19.9% of the placebo/aspirin group (p = 0.0085). This association was similar among various tested subgroups.

The primary safety outcome, Thrombolysis in Myocardial Infarction (TIMI) major bleeding, occurred in 2.7% of the rivaroxaban/aspirin group compared with 1.9% of the placebo/aspirin group (p = 0.069). Among diabetics, TIMI major bleeding occurred in 2.4% of the rivaroxaban/aspirin group compared with 1.0% of the placebo/aspirin group (p for interaction = 0.033).

Secondary outcomes:

• Acute limb ischemia: 5.2% of the rivaroxaban/aspirin group compared with 7.8% of the placebo/aspirin group (p < 0.05)
• International Society on Thrombosis and Haemostasis (ISTH) major bleeding: 5.9% of the rivaroxaban/aspirin group compared with 4.1% of the placebo/aspirin group (p = 0.0068)
• Intracranial hemorrhage: 0.6% of the rivaroxaban/aspirin group compared with 0.9% of the placebo/aspirin group (p = 0.5)
• Primary outcome for rivaroxaban/aspirin versus placebo/aspirin among those who underwent lower extremity revascularization for critical limb ischemia: HR 0.85, 95% CI 0.69-1.05, and among those who underwent lower extremity revascularization for noncritical limb ischemia: HR 0.86, 95% CI 0.74-0.99 (p for interaction 0.94)

Study medication and baseline clopidogrel use:

• Baseline clopidogrel: primary efficacy outcome for rivaroxaban plus aspirin vs. aspirin alone, hazard ratio = 0.85
• No baseline clopidogrel: primary efficacy outcome for rivaroxaban plus aspirin vs. aspirin alone, hazard ratio = 0.86 (p for interaction = 0.92)

Coronary artery disease (CAD) subgroups:

• PAD without CAD: Cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke occurred in 16.1% of the rivaroxaban group compared with 17.9% of the placebo group (absolute risk reduction [ARR] 1.8%, p = not significant).
• PAD with CAD: Cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke occurred in 18.9% of the rivaroxaban group compared with 24.3% of the placebo group (ARR 5.4%, p < 0.05, p for interaction = 0.29).
• PAD without CAD: TIMI major bleeding occurred in 1.7% of the rivaroxaban group compared with 1.5% of the placebo group (p = nonsignificant).
• PAD with CAD: TIMI major bleeding occurred in 2.4% of the rivaroxaban group compared with 1.1% of the placebo group (p for interaction = 0.13).

Long-term safety of drug-coated devices (n = 1,342; drug-coated stent, drug-coated balloon, and both):

• Weighted all-cause mortality: 12.1% in the drug-coated device group vs. 12.6% in the nondrug-coated device group (p = 0.66)
• Weighted all-cause mortality for drug-coated balloon vs. PTA: 7.4% in the drug-coated device group vs. 9.7% in the nondrug-coated device group (p = not significant)
• Weighted all-cause mortality for drug-eluting stent vs. bare-metal stent: 8.2% in the drug-coated device group vs. 9.9% in the nondrug-coated device group (p = not significant)

Effect of rivaroxaban vs. placebo on cardiovascular death, acute limb ischemia, major amputation of vascular etiology, myocardial infarction, or ischemic stroke according to drug-coated devices:

• Drug-coated device: 13.5% in the rivaroxaban group vs. 15.0% in the nondrug-coated device group
• Nondrug-coated device: 14.4% in the rivaroxaban group vs. 16.0% in the nondrug-coated device group (p for interaction = 0.88)

Outcomes among subjects who underwent endovascular lower extremity revascularization (67% endovascular revascularization):

• Among the endovascular revascularization group, the primary efficacy outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death: 14.0% in the rivaroxaban group vs. 15.7% in the placebo group (p = 0.12; p for interaction vs. surgical revascularization group = 0.43)
• Among the endovascular revascularization group, the primary safety outcome of TIMI major bleeding: 2.3% in the rivaroxaban group vs. 1.4% in the placebo group (p = 0.02; p for interaction vs. surgical revascularization group = 0.17)

Outcomes among subjects who underwent surgical lower extremity revascularization (of the total randomized, 33% underwent surgical revascularization):

• Among the surgical revascularization group, the primary efficacy outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death: 18.4% in the rivaroxaban group vs. 22.0% in the placebo group (p = 0.026; p for interaction vs. endovascular revascularization group = 0.43)
• Among the surgical revascularization group, the primary safety outcome of TIMI major bleeding: 1.0% in the rivaroxaban group vs. 1.2% in the placebo group (p = 0.75; p for interaction vs. endovascular revascularization group = 0.17)

Total events (considers first and subsequent events):

• Total primary endpoints, rivaroxaban vs. placebo: (HR 0.86, 95% CI 0.75-0.98; p = 0.02)
• Total vascular events, rivaroxaban vs. placebo: (HR 0.86, 95% CI 0.79-0.95; p = 0.003)

Treatment effects in older patients (participants >75 years [20%]):

• Efficacy of rivaroxaban vs. placebo (p for interaction = 0.83)
• Safety of rivaroxaban vs. placebo (p for interaction = 0.38)

Interpretation:

Among patients with lower extremity PAD undergoing revascularization, rivaroxaban/aspirin was associated with a reduction in major adverse limb and cardiovascular events compared with placebo/aspirin. Rivaroxaban/aspirin was associated with a 2.6% absolute risk reduction in cardiovascular death, acute limb ischemia, major amputation, myocardial infarction, or stroke compared with placebo/aspirin at 3 years. Although the benefit of rivaroxaban/aspirin was consistent regardless of CAD status, the absolute benefit of this regimen appeared to be greater among those with both PAD and CAD. Benefit of rivaroxaban/aspirin was observed regardless of baseline clopidogrel use. Benefit for rivaroxaban/aspirin versus placebo/aspirin was similar for endovascular and surgical lower extremity revascularization, and for revascularization of critical limb ischemia and noncritical limb ischemia. Rivaroxaban/aspirin was associated with a similar frequency of TIMI major bleeding; however, there was an increased incidence of ISTH major bleeding compared with placebo/aspirin. Intracranial hemorrhage was similar between treatment groups. Rivaroxaban/aspirin was beneficial without excess harm among participants >75 years.

Drug-coated devices were not associated with an increase (or decrease) in mortality compared with non-drug-coated devices. Rivaroxaban was beneficial at reducing major adverse cardiac and limb events, irrespective of drug-coated device use.

References:

Rymer J, Anand SS, Debus ES, et al. Rivaroxaban Plus Aspirin Versus Aspirin Alone After Endovascular Revascularization for Symptomatic PAD: Insights From VOYAGER PAD. Circulation 2023;Oct 18:[Epub ahead of print] .

Krantz MJ, Debus SE, Hsia J, et al. Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial. Eur Heart J 2021;42:4040-8 .

Debus ES, Nehler MR, Govsyeyev N, et al. Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial. Circulation 2021;144:1104-16 .

Bauersachs RM, Szarek M, Brodmann M, et al. Total Ischemic Event Reduction With Rivaroxaban After Peripheral Arterial Revascularization in the VOYAGER PAD Trial. J Am Coll Cardiol 2021;78:317-26 .

Presented by Dr. Rupert Bauersachs at the American College of Cardiology Virtual Annual Scientific Session (ACC 2021), May 16, 2021.

Presented by Dr. Marc P. Bonaca at the American Heart Association Virtual Scientific Sessions, November 14, 2020.

Presented by Dr. Manesh R. Patel at the American Heart Association Virtual Scientific Sessions, November 14, 2020.

Presented by Dr. Connie N. Hess at the Transcatheter Cardiovascular Therapeutics Virtual Meeting (TCT Connect), October 18, 2020.

Presented by Dr. William Hiatt at the European Society of Cardiology Virtual Congress, August 30, 2020.

Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in Peripheral Artery Disease After Revascularization. N Engl J Med 2020;382:1994-2004 .

Editorial: Creager MA. A Bon VOYAGER for Peripheral Artery Disease. N Engl J Med 2020;382:2047-8 .

Presented by Dr. William R. Hiatt at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 29, 2020.

Presented by Marc P. Bonaca at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 28, 2020.

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Geriatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Arrhythmias, Interventions and Vascular Medicine

Keywords: ACC21, ACC Annual Scientific Session, AHA20, AHA Annual Scientific Sessions, acc20, Anticoagulants, Amputation, Ankle Brachial Index, Aspirin, Cardiac Surgical Procedures, Endovascular Procedures, ESC20, ESC Congress, Geriatrics, Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Peripheral Arterial Disease, Secondary Prevention, Stroke, Thrombosis, Vascular Diseases, TCT20, Transcatheter Cardiovascular Therapeutics

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Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities (VOYAGER PAD)

• Study Details
• Tabular View
• Study Results

Inclusion Criteria:

• Age ≥50
• Documented moderate to severe symptomatic lower extremity atherosclerotic peripheral artery disease
• Technically successful peripheral revascularization distal to the external iliac artery for symptomatic PAD (Peripheral artery disease) within the last 10 days prior to randomization

Exclusion Criteria:

• Patients undergoing revascularization for asymptomatic PAD or mild claudication without functional limitation of the index leg.
• Patients undergoing revascularization of the index leg to treat an asymptomatic or minimally symptomatic restenosis of a bypass graft or target lesion restenosis.
• Prior revascularization on the index leg within 10 days of the qualifying revascularization.
• Planned dual antiplatelet therapy (DAPT) use for the qualifying revascularization procedure of clopidogrel in addition to Acetylic salicylic acid (ASA) for >6 months after the qualifying revascularization procedure; it is strongly recommended that any course of clopidogrel is kept to the minimum necessary in accordance with local standard of care and international practice guidelines (typically 30 days, or up to 60 days for some drug-coated products or devices) and is only allowed for up to 6 months for complex procedures or devices in the investigator's opinion that require longer use.
• Planned use of any additional antiplatelet agent other than clopidogrel and ASA after the qualifying revascularization procedure.

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• v.2021; 2021

Efficacy and Safety of Rivaroxaban Compared with Other Therapies Used in Patients with Peripheral Artery Disease Undergoing Peripheral Revascularization: A Systematic Literature Review and Network Meta-Analysis

Rupert bauersachs.

1 Klinikum Darmstadt GmbH, Darmstadt, Germany

2 Health Economics and Health Technology Assessment, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK

Neil Hawkins

Kevin bowrin.

3 Bayer Plc, Reading, UK

Piotr Wojciechowski

4 Creativ-Ceutical, Krakow, Poland

Emilie Clay

5 Creativ-Ceutical, Paris, France

Maria Huelsebeck

6 Bayer AG, Berlin, Germany

Associated Data

The input data for NMAs used to support the findings of this study are included within the supplementary information file.

The guidelines on antithrombotic treatment in patients with symptomatic peripheral artery disease (PAD) undergoing peripheral revascularization of the lower extremities were developed based on heterogeneous trials, assessing various dose regimens and recruiting patients who were subjected to different revascularization procedures.

To compare efficacy and safety of treatments used in patients with PAD undergoing peripheral revascularization accounting for between-trial heterogeneity and large dispersion of the quality of evidence.

A systematic literature review of randomised controlled trials (RCTs) recruiting adult patients with PAD receiving antithrombotics was conducted until January 2020. Hazard ratios (HR) were pooled using Bayesian network meta-analysis. The estimated between-treatment effects were presented as HR together with 95% credible intervals. The base case analysis included studies recruiting patients following recent peripheral revascularization, who received treatment regimens administered within the recommended therapeutic window, while a sensitivity scenario included all identified trials.

Thirteen RCTs were identified (8 RCTs enrolled patients following peripheral revascularization and 5 RCTs regardless of the previous revascularization). Five trials, recruiting an overall of 8349 patients, were considered for the base case analysis. Of those, 6564 patients were recruited in the VOYAGER PAD trial comparing rivaroxaban plus aspirin (RIV plus ASA) versus ASA. RIV plus ASA was associated with a lower risk of repeated peripheral revascularization versus ASA monotherapy (HR = 0.88 [0.79, 0.99]), however having a trend towards an increased rate of major bleeding (HR = 1.43 [0.98, 2.11]). There was no evidence for differences between RIV plus ASA and dual antiplatelet therapy and vitamin K antagonists plus ASA. Similar results were observed in sensitivity analyses.

Conclusions

RIV plus ASA is associated with reduced risk of revascularization compared with ASA monotherapy, but the evidence for other comparators, in particular antiplatelet regimens, was insufficient to guide treatment decisions and highlights the challenge in establishing the magnitude of comparative efficacy using existing RCTs.

1. Introduction

Peripheral artery disease (PAD) is a common cardiovascular (CV) system disease with the global prevalence exceeding 200 million people and incidence of about 11 million in 2017 [ 1 , 2 ]. Progressive atherosclerosis causes stenosis or occlusion of peripheral arteries. Depending on the location and severity of the stenosis, the disease is asymptomatic or symptomatic with intermittent claudication (IC) or atypical leg pain, critical limb ischemia (CLI), and acute limb ischemia (ALI) as typical signs [ 3 – 6 ]. CLI leads to chronic hypoperfusion resulting in a substantial increase in the risk of limb loss [ 7 – 9 ]. For this reason, patients with CLI or the occurrence of lifestyle-limiting symptoms classified as being grade IIb according to the Fontaine classification may require revascularization of the lower extremity arteries [ 10 , 11 ]. Revascularization immediately improves quality of life in PAD patients and improves long-term survival [ 12 ], although it is associated with a postprocedural increase of vascular risk [ 13 ].

The clinical trials on the antithrombotic medication differ noticeably in terms of quality and sample size, with limited evidence for the efficacy and safety of antiplatelet medication used in patients who have undergone revascularization, in particular for those after recent endovascular procedures [ 4 ]. Due to this reason, the recommendations of practice guidelines were often developed based on low-quality evidence [ 4 ]. A single antiplatelet therapy (SAPT) with acetylsalicylic acid (ASA) or clopidogrel (CLO) alone is recommended for all patients with symptomatic PAD who have undergone revascularization to reduce the risk of atherothrombotic events (Class I with level of evidence C). Dual antiplatelet therapy (DAPT), consisting of low doses of ASA in combination with a P2Y12 receptor antagonist, is recommended for at least one month for patients following endovascular procedures (Class IIa with level of evidence C). DAPT with ASA plus CLO for at least 1 month can be considered in patients undergoing bypass surgery with a prosthetic graft (Class IIb with level of evidence B) [ 4 ]. Despite existing guidelines, a comparison of treatments for PAD patients after peripheral revascularization encounters difficulties mainly due to small population of PAD patients enrolled in the studies and cooccurrence of PAD and coronary artery disease. Additionally, different revascularization procedures, including surgical and endovascular, were used in respective trials. Of note, the available endovascular procedures evolved over the years which additionally increase heterogeneity. Rivaroxaban (RIV), a selective direct inhibitor of factor Xa, plus ASA is the most recent treatment option studied for PAD patients. Based on the COMPASS trial in patients suffering from chronic coronary artery disease and/or PAD, RIV plus ASA was included in the guidelines as an antithrombotic therapy in lower extremity artery disease [ 4 ]. RIV plus ASA was also recently assessed in another large clinical trial (VOYAGER PAD) in patients with symptomatic PAD undergoing surgical or endovascular revascularization [ 14 ]. In both studies, RIV plus ASA was compared to ASA alone; there are no data comparing efficacy and safety of RIV plus ASA with other therapies (e.g., clopidogrel and VKA). Therefore, the objective of this analysis was to review available evidence for treatments used in patients with PAD undergoing peripheral revascularization procedures of the lower extremities and conduct a network meta-analysis (NMA) to estimate relative efficacy and safety.

2. Material and Methods

2.1. systematic literature review.

A systematic literature review (SLR) was conducted to identify randomised controlled trials (RCTs) on adult patients with acute symptomatic PAD, presenting the clinical evidence for the following therapeutic options: RIV plus ASA, CLO plus ASA, ASA monotherapy, CLO monotherapy, vitamin K antagonists (VKAs) with or without ASA or CLO, and a placebo. The search was conducted in January 2020 in MEDLINE, MEDLINE In-Process, EMBASE, and CENTRAL. No timeframe and geographical scope restrictions were imposed; however, for conferences/congresses searches, only records issued from 2015 on were considered. Inclusion criteria are summarised in Table 1 .

Inclusion criteria for the systematic literature review according to PICOS methodology.

AE: adverse event; ALI: acute limb ischemia; ASA: aspirin; CLO: clopidogrel; CV: cardiovascular; IS: ischemic stroke; MI: myocardial infarction; PAD: peripheral artery disease; RCT: randomised controlled trial; VKA: vitamin K antagonists.

The selection of RCTs was conducted by 2 analysts working independently, and any disagreements between the 2 analysts were resolved by a third analyst. Data from studies meeting all inclusion criteria were extracted by one analyst; its quality was thoroughly checked by the second analyst. The risk of bias was assessed for each study using the tool developed by the Cochrane Collaboration [ 15 ].

2.2. Additional Criteria for Inclusion in the Network Meta-Analysis

The intention of this analysis was to compare the RIV plus ASA regimen with treatments recommended by the current clinical practice guidelines to treat patients with PAD after revascularization. We considered all RCTs assessing antiplatelet therapies or anticoagulant treatment enrolling patients with PAD of lower extremity with and without a history of recent revascularization to increase the power of this NMA [ 4 – 6 ]. Based on clinical practice guidelines, the following therapies were considered as comparators for RIV plus ASA: ASA monotherapy, CLO monotherapy, CLO in combination with ASA, VKA monotherapy, and VKA plus ASA [ 4 ].

Treatments were compared regarding clinically relevant outcomes reported across analysed studies [ 14 ]. Efficacy outcomes included IS, any stroke, MI, CV death, coronary heart death, all-cause death, major amputations (between-trial heterogeneity of definition), revascularization, venous thromboembolism (VTE), and hospitalization. Major bleeding (MB) was considered as a safety outcome; however, the definitions of this event varied across studies (Supplementary Table 7 ). Therefore, the comparison regarding major bleeding needs to be interpreted with caution.

2.3. Data Synthesis

Two trials assessing RIV plus ASA in patients with PAD were identified through the SLR [ 14 , 16 ]. Both compared a combination of RIV plus ASA versus ASA alone. There are no studies comparing efficacy and safety of RIV-based treatment to other therapies mentioned in the clinical guidelines. In 11 RCTs (BOA [ 17 ], CAPRIE [ 18 ], CASPAR [ 19 ], Cassar 2005 [ 20 ], CHARISMA [ 21 ], COMPASS [ 16 ], Eikelboom 2005 [ 22 ], Johnson 2002&2004 [ 23 ], MIRROR [ 24 ], VOYAGER PAD [ 14 ], and WAVE [ 25 ]), patients allocated to reference arms received ASA monotherapy, and in 9 of those 11 trials, ASA was also administered as a combination therapy in the second arm. ASA monotherapy serves as a common reference treatment in the majority of studies, thus forming a network of evidence and allowing an indirect-treatment comparison using an NMA.

An NMA in Bayesian framework was used to compare RIV plus ASA versus other treatments [ 26 ]. The NMA is an extension of traditional pairwise meta-analysis which uses Markov chain Monte Carlo sampling to compare different treatments assessed in different studies, if they form a connected network of evidence.

The model inputs are natural logarithms of hazard ratio (log(HR)) for between-treatment comparison and the corresponding SE(log(HR)). When respective trials reported estimates calculated after several interim analyses, only final estimates corresponding to the longest available follow-up were included for the NMA. Neither of the included trials reported information suggesting violation of proportionality of hazards. For studies not reporting HRs, they were estimated by fitting the exponential survival curve to the reported number of events.

Three chains were initiated with noninformative priors and run in parallel for each analysis. The convergence between chains was checked using the Brooks-Gelman-Rubin diagnostic and trace plots. There were no closed loops in the evidence networks; thus, there was no reason for the analysis of consistency.

The NMA was conducted using fixed- and random-effect models with deviance information criterion (DIC) as the indicator of model fit to clinical data. The fixed-effect model was preferred; however, the random-effect model was considered relevant when associated with DIC value lower by ≥5 points [ 27 ]. The results are presented as HR together with corresponding 95% credible intervals (95% CI). Ranking probabilities of all treatments used the surface under the cumulative ranking area (SUCRA).

3.1. SLR Results

Overall, 14 RCTs were identified, including a small, phase II study (RIVAL PAD [ 28 ]), which did not report any events relevant for this analysis and thus was finally excluded from the NMA. Therefore, a total of 13 RCTs were considered relevant for inclusion in the NMA (Supplementary Table 1 ). Of those, 8 RCTs (VOYAGER PAD [ 14 ], BOA [ 17 ], CASPAR [ 19 ], Johnson 2002&2004 [ 23 ], Cassar 2005 [ 20 ], Li 2013 [ 29 ], MIRROR [ 24 ], and Liang 2012 [ 30 ]) recruited patients following peripheral revascularization procedures of the lower extremities. Three studies (BOA [ 17 ], CASPAR [ 19 ], and Johnson 2002&2004 [ 23 ]) assessed patients after recent surgical procedures, four (Cassar 2005 [ 20 ], Li 2013 [ 29 ], MIRROR [ 24 ], and Liang 2012 [ 30 ]) recruited participants who have undergone endovascular procedures, and one (VOYAGER PAD) recruited a large sample representative for patients who have undergone either surgical or endovascular procedures. The remaining 5 studies (CAPRIE [ 18 ], COMPASS [ 16 ], CHARISMA [ 21 ], Eikelboom 2005 [ 22 ], and WAVE [ 25 ]) enrolled patients with a diagnosis of PAD regardless of previous revascularization ( Table 2 ). Figure 1 shows a distribution of clinical trials according to the history and type of revascularization.

Distribution of clinical trials according to the history and type of revascularization.

Characteristics of eligible studies on PAD patients meeting inclusion criteria for NMA.

AE: adverse event; ALI: acute limb ischemia; ASA: aspirin; bid: twice a day; CLO: clopidogrel; CV: cardiovascular; INR: international normalised ratio; IS: ischemic stroke; MI: myocardial infarction; NMA: network meta-analysis; PAD: peripheral artery disease; pt-yrs: patient-years; RCT: randomised controlled trial; VKA: vitamin K antagonists; ∗ treatment was initiated soon after revascularization, not later than 10 days following the procedure.

Input data for the NMA is presented in Supplementary Tables 1–8 . Identified studies differed in terms of methodological quality, of population characteristics, of procedure types, of follow-up duration, of ASA doses, of history of previous revascularization procedure, and of concomitant CAD and differed regarding major bleeding definition (Supplementary Table 7 ) and additional treatments contributing to between-trial heterogeneity ( Table 2 ). Moreover, in the light of the rapid development of technologies for endovascular revascularization, all the identified studies assessing P2Y12 receptor antagonist in this group of patients, which were published between 2005 and 2013, may not be representative for the contemporary procedures.

3.1.1. Risk of Bias

The risk of bias was evaluated for all included trials and summarised in Supplementary Table 1 . There was no evidence for the risk of bias arising from the randomisation, although Li 2013 did not disclose all necessary details of the randomisation process. All trials comparing different antiplatelet regimens were conducted in a double-blinded fashion, while studies assessing anticoagulation were open label, which is justified given the need for close monitoring of INR in patients receiving VKA. Baseline characteristics were generally well balanced between the study groups; in some studies, there were differences however with no statistically significant interaction with the reported results. There was a higher proportion of patients with a history of coronary artery disease and/or cerebrovascular disease in the CLO treatment arm in the CASPAR trial and a higher proportion of patients with coronary artery disease in the antiplatelet arm in the WAVE trial.

3.1.2. Population

Eleven out of 13 clinical trials enrolled just patients with lower extremity PAD; however, the protocols of 2 RCTs (COMPASS [ 16 ]; WAVE [ 25 ]) allowed also the inclusion of patients with carotid artery disease.

As mentioned before, the included trials differed regarding a history of the previous revascularization, type of procedures, etc. Eight out of the 13 RCTs were designed to assess therapeutic effects following recent peripheral revascularization. They recruited patients who recently underwent revascularization using either surgical (4 RCTs: VOYAGER PAD [ 14 ], BOA, CASPAR [ 19 ], and Johnson 2002&2004 [ 23 ]) or endovascular procedures (5 RCTs: VOYAGER PAD [ 14 ], CASSAR, Li 2013 [ 29 ], MIRROR [ 24 ], and Liang 2012 [ 30 ]) or hybrid procedure (VOYAGER). Studies just including PAD patients after a recent endovascular revascularization were small, with the number of recruited patients ranging from 56 to 132. The VOYAGER PAD trial [ 14 ] assessed RIV plus ASA in patients after surgical and/or endovascular procedures. The randomisation in this trial was stratified by procedure type and CLO use into surgical revascularization and endovascular procedures with or without concomitant CLO; hybrid procedure was considered as endovascular procedure.

Six trials (VOYAGER PAD [ 14 ], BOA [ 17 ], CASPAR [ 19 ], Cassar 2005 [ 20 ], MIRROR [ 24 ], and Li 2013 [ 29 ]) provided the number of days, within which the treatment was initiated after the revascularization. In general, the first dose of the investigated treatment was administered within 10 days after the procedure. In one RCT (Johnson 2002&2004 [ 23 ]), the treatment with warfarin was administered as soon as patients tolerated oral fluids. The remaining trial (Li 2012) stated that the treatment was initiated following angioplasty.

The 5 remaining trials (WAVE [ 25 ], CAPRIE [ 18 ], COMPASS [ 16 ], CHARISMA [ 21 ], and Eikelboom 2005 [ 22 ]) recruited patients with chronic PAD. These trials allowed to include patients with or without a history of peripheral revascularization. Prior procedure was not required for enrolment, and the time since revascularization was quite inconsistent. Three (COMPASS [ 16 ], CHARISMA [ 16 ], and Eikelboom 2005 [ 22 ]) out of these 5 RCTs recruiting patients with chronic PAD reported history of peripheral revascularization with a range of 27% to 58% ( Table 2 ).

3.1.3. Interventions and Comparators

Out of the 5 RCTs (BOA [ 17 ], Johnson 2002&2004 [ 23 ], Li 2013 [ 29 ], and Liang 2012 [ 30 ]) assessing VKA-based regimens in 2 RCTs (BOA [ 17 ]; WAVE [ 25 ]), the target INR was 2.0-3.0 and 3.0 to 4.5, respectively. In 11 RCTs (BOA [ 17 ], CAPRIE [ 18 ], CASPAR [ 19 ], Cassar 2005 [ 20 ], CHARISMA [ 21 ], COMPASS [ 16 ], Eikelboom 2005 [ 22 ], Johnson 2002&2004 [ 23 ], MIRROR [ 24 ], VOYAGER PAD [ 14 ], and WAVE [ 25 ]), patients allocated to the reference arm received either ASA monotherapy and/or ASA combined with other treatments. There was between-trial heterogeneity regarding ASA doses. A high ASA daily dose (325 mg) was administered in 2 trials (CAPRIE [ 18 ], Johnson 2002&2004 [ 23 ]); a broad range of ASA daily doses (81-325 mg) was allowed in the WAVE trial [ 25 ]; and low ASA dose (≤100 mg) was administered in the remaining trials.

In the WAVE trial [ 25 ], around 7% of participants received concomitant thienopyridines in either group, which further increased the level of heterogeneity associated with the assessed treatments. There was no analysis stratified by clopidogrel use in the WAVE trial that could assess the potential impact of thienopyridine use on the efficacy and safety results. Similarly, patients assigned to endovascular procedures of the VOYAGER PAD trial were stratified according to clopidogrel use (endovascular procedure with or without clopidogrel), but finally, no significant interaction between clopidogrel use and the outcomes was observed, between-trial heterogeneity.

The analysis of heterogeneity revealed noticeable between-trial differences, which could potentially interact with the estimates of the treatment effects and bias the inference based on the results of the NMA. The most important sources of heterogeneity were rooted in population differences, in procedure differences, e.g., different ASA doses and different treatment strategies. Due to the between-trial heterogeneity, two variants of the analysis were chosen.

(1) Base Case . The aim of this analysis was to assess between-treatment differences in efficacy and safety based on RCTs with a high level of homogeneity regarding the target population and assessing treatment regimens administered in accordance with clinical practice guidelines [ 4 ]. Therefore, this analysis was conducted only on studies recruiting patients following recent revascularization, who received treatment regimens administered within the recommended therapeutic doses.

There was limited number of studies meeting the inclusion criteria for the base case analysis; thus, the comparison with some of the predefined comparators including VKA monotherapy, CLO monotherapy, and the combination treatment including CLO plus ASA was not feasible.

(2) Sensitivity Analysis . The aim of this analysis was to allow for the comparison versus comparators not assessed in the base case and analyse the robustness of the comparative results based on relaxed inclusion/exclusion criteria while acknowledging the heterogeneity introduced with that. This analysis was conducted based on the 13 studies included in the NMA.

3.2. Results of the NMA

3.2.1. base case analysis.

Fixed-effect models were considered for each comparison based on DIC criterion and considering that in most cases only one study was available for each comparison; therefore, the heterogeneity parameter could not be estimated. A consistency analysis was not conducted as all the networks had star-like shape without closed loops allowing to compare between direct and indirect evidence.

The trials eligible for the base case analysis allowed to form a network of evidence linking RIV plus ASA (VOYAGER PAD) with CLO plus ASA (CASPAR, Cassar 2005, MIRROR) and VKA plus ASA (Johnson 2002&2004) through ASA monotherapy. RIV plus ASA and CLO plus ASA could formally be compared regarding all outcomes of interest except for ALI, which was assessed only in the VOYAGER PAD trial [ 14 ]. On the contrary, the Johnson et al.'s trial (Johnson 2002&2004) [ 23 ] which compared VKA plus ASA and ASA reported only all-cause death, any stroke, MI, and major bleeding; therefore, the comparison was limited to reported outcomes.

Consistent with the results of the VOYAGER PAD trial [ 14 ], this analysis showed that RIV plus ASA compared with ASA monotherapy is associated with a significantly lower risk of unplanned index-limb revascularization for recurrent ischemia. The comparison between RIV plus ASA with DAPT (CLO plus ASA) and warfarin-based regimen did not reveal any significant differences between treatments regarding safety and efficacy outcomes. However, a trend in favour of RIV plus ASA was observed for comparison with VKA plus ASA regarding all-cause deaths (HR = 0.77 [0.57, 1.04]) ( Table 3 ).

The results of the base case scenario and sensitivity analysis.

ASA: aspirin; CLO: clopidogrel; DIC: deviance information criterion; FE: fixed effect; RE: random effect; VKA: vitamin K antagonists. Note: the risk of ALI was not reported in the comparator trials; therefore, the comparison regarding this outcome was not feasible.

3.2.2. Sensitivity Analysis

Additional trials included in the sensitivity analysis allowed for the assessment of relative treatment effects also versus CLO monotherapy and VKA monotherapy, although the former option was only the comparison for CV deaths, IS, any stroke, and the risk of MI.

Consistent with the base case analysis, RIV plus ASA was associated with a lower risk of peripheral revascularization compared with ASA monotherapy (HR = 0.89 [0.81, 0.98]). For the majority of the remaining outcomes, there was no significant difference between RIV plus ASA and ASA except for the risk of major bleeding, which was significantly higher in the RIV plus ASA group (HR = 1.52 [1.17, 1.98]) compared to ASA alone.

The NMA did not reveal significant treatment differences, with the exception for the comparison with VKA plus ASA regarding major bleeding; there was a lower risk associated with RIV plus ASA (HR = 0.54 [0.33, 0.89]).

The inclusion of additional studies enrolling stable population leads to a nonsignificant modification of the relative effects. The results of the CHARISMA trial [ 21 ] favoured CLO plus ASA over ASA regarding all-cause death, CV death, and major bleeding; thus, the point estimates for comparison between RIV plus ASA versus CLO plus ASA favoured the latter treatment regarding these outcomes, although all estimates were not significant.

There were no other major differences in the direction and significance of the effect estimates between the base case scenario and the sensitivity analysis, which could modify the inference.

Input data on amputations for the NMAs are presented in Table 4 . Input data on other outcomes for the NMAs (Supplementary Tables 1–8 ), figures presenting networks of evidence for all outcomes (Supplementary Figures 1 , 3 , 5 , 7 , 9 , 11 , 13 , and 15 ), and forest plots (Supplementary Figures 2 , 4 , 6 , 8 , 10 , 12 , 14 , and 16 ) are presented in Supplementary Materials. The results of the base case scenario and sensitivity analysis are shown in Table 3 .

Input data for the NMA of the risk of amputation.

✔: study eligible for the analysis; ❌: study ineligible for the analysis. ASA: acetylsalicylic acid; CLO: clopidogrel; RIV: rivaroxaban; VKA: vitamin K antagonist.

4. Discussion

With this NMA, we attempted to summarise existing evidence on efficacy and safety profiles of treatments used in patients with PAD undergoing peripheral revascularization and accounting for the between-trial heterogeneity and large dispersion of the quality of evidence.

The SLR conducted to collect data for the NMA revealed scarcity and serious limitations of available clinical data. We identified only 5 RCTs reporting adequate results that were eligible for the base case analysis and allowed to compare RIV plus ASA only with 2 regimens: CLO plus ASA and VKA plus ASA. Of those, the VOYAGER PAD study was the largest trial enrolling 6564 out of 8449 patients recruited in all studies included for the base case scenario. The study was designed and powered to compare RIV plus ASA versus ASA in a double-blinded fashion regarding clinically relevant outcomes and showed a significant reduction of the primary efficacy endpoint defined as a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. All participants underwent a recent peripheral revascularization prior to a random allocation to treatment groups, which was stratified according to the type of revascularization procedure (endovascular (including hybrid) vs. surgical) and according to clopidogrel use among those who underwent an endovascular procedure [ 14 ]. The primary ITT analysis was based on the primary efficacy composite endpoint, and several secondary outcomes were tested in a hierarchical order. The principal safety outcome was major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) classification. The results of the VOYAGER PAD trial showed that RIV plus ASA reduced the risk of the primary efficacy outcome by 15% compared with ASA monotherapy (HR = 0.85 [0.76, 0.96]; p = 0.009) with no significant increase of the rate of TIMI major bleeding (HR = 1.43 [0.97, 2.10]; p = 0.07) and a significant increase in ISTH major bleeding events (HR = 1.42 [1.10, 1.84]; p = 0.007).

While the large VOYAGER study provided high-quality results for assessing the clinical effectiveness of RIV plus ASA, the evidence for other therapeutic options in a postrevascularization setting is limited. ASA and ASA plus CLO were compared in patients after endovascular procedures in only 2 RCTs (Cassar 2005 [ 20 ]; MIRROR [ 24 ]) recruiting 103 and 68 patients, respectively. Both RCTs were designed to assess platelet functions and had inadequate power for the evaluating clinically relevant outcomes. Moreover, both studies were conducted before 2012 and thus may not represent the contemporary endovascular procedures, which evolved in the recent years.

One trial (CASPAR [ 19 ]) compared CLO plus ASA versus ASA monotherapy in 851 patients following surgical revascularization. This study did not demonstrate a benefit of CLO plus ASA over ASA regarding the primary endpoint, defined as a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death (HR = 0.98 [0.78-1.23]). A post hoc analysis in the subset of patients with prosthetic grafts showed a difference in favour of the CLO plus ASA regimen (HR = 0.65 [0.45-0.95]). Finally, the remaining trial included in the base case compared VKA plus ASA versus ASA in 831 PAD patients after a surgical revascularization. The study was designed to assess graft patency and mortality. The results indicated that a combination of VKA plus ASA is associated with increased mortality (HR = 1.41 [1.09, 1.84]) and elevated risk of major bleeding ( p = 0.02) including intracranial bleed, hospitalization for bleeding, an operation for control of bleeding, or a blood transfusion. Neither of the trials identified through an SLR provided clinical evidence for the efficacy of CLO monotherapy in patients following revascularization; thus, the evidence supporting the use in that population is questionable.

This NMA suggests that RIV in combination with ASA is associated with reduced risk of peripheral revascularization compared with ASA monotherapy, but there seems to be no differences between RIV plus ASA and other treatment options. However, such an indirect comparison has major limitation due to the high heterogeneity of the included trials. The sensitivity analysis with broader inclusion criteria, but with an even more increased heterogeneity, came to the same result. With one exception, the inclusion of additional trials led to an increased estimate of the risk of major bleeding in the VKA plus ASA group compared with RIV plus ASA. The results of this NMA were still imprecise since not all studies included in the network were of sufficient quality and power to draw reliable conclusions based on indirect treatment comparison. Included trials were not powered for the assessment of the individual clinical outcomes but were designed to assess either composite outcomes or surrogates. The results of the sensitivity analysis were associated with high uncertainty due to associated between-trial heterogeneity. Therefore, although this NMA was conducted in accordance with the highest methodological principles, the available clinical evidence is insufficient to draw reliable conclusions regarding the relative effectiveness and safety of the therapies used in patients after revascularization of peripheral arteries.

The main limitations of the identified scientific evidence are the inadequate samples of included trials and the related insufficient statistical power to assess respective clinically relevant outcomes. In addition, this NMA with a star-like evidence network inherited the limitations from the individual pairwise comparisons, which means that the quality of the comparison between RIV plus ASA and comparators is limited by the quality of evidence for comparators. Thus, small trials on comparators, not always designed to assess clinically relevant outcomes, are insufficient to draw reliable conclusions regarding relative efficacy and safety between the treatments used in clinical practice in this target population. The low power of this analysis and the between-trial heterogeneity with high probability explains the lack of significant differences between treatments assessed within this NMA. The definition of major bleeding was heterogeneous across included studies (Supplementary Table 7 ), although there was no evidence that the definition of major bleeding events could affect the relative difference between groups expressed with hazard ratios. Moreover, the risk of bleeding is expected to increase with the dose/number of antiplatelet therapies and the intensity of anticoagulation treatments. Since the daily dose of ASA ranged from 75 mg to 325 mg and the target INR also differed across studies assessing anticoagulation, the between-treatment differences regarding the risk of major bleeding should be interpreted with adequate caution. Despite including additional studies, the sensitivity analysis also did not allow a reliable and unequivocal conclusion regarding treatment differences and did not noticeably change the results of the primary analysis.

In summary, the results of this NMA are considered imprecise due to the low power of some of the included trials to assess relevant clinical outcomes and due to the high between-trial heterogeneity. Therefore, although this NMA was conducted in accordance with high methodological principles, no reliable conclusions regarding efficacy and safety of therapies in symptomatic PAD patients after a recent revascularization can be drawn. To assess clinical efficacy and safety of, for example, clopidogrel or other anticoagulant therapies in such a population, well-powered, randomised double-blind clinical studies like the VOYAGER trial are required.

5. Conclusions

There was limited clinical evidence for the therapies used in the treatment of patients with PAD undergoing peripheral revascularization procedures of the lower extremities. Of these, RIV plus ASA was assessed in the largest clinical program on over 11,500 patients with PAD, of which 6564 were enrolled following recent peripheral revascularization. This analysis suggests that RIV in combination with ASA is associated with reduced risk of revascularization compared with ASA monotherapy, but the evidence for comparators was insufficient to improve treatment decisions and highlights the challenge in establishing the magnitude of comparative treatment effects using existing RCT data. Robust evaluation of clinical outcomes may therefore require extending the scope of the evaluation beyond RCT data.

Acknowledgments

The authors wish to thank the employees of Creativ-Ceutical: Małgorzata Biernikiewicz for medical writing support, Justyna Chorąży and Beata Smela for the management and conduction of the SLR, and Katarzyna Jabłońska for the conduction of statistical analyses. This project was initiated and financed by Bayer AG Pharmaceuticals, which commissioned Creativ-Ceutical to design and conduct the analysis.

Data Availability

Conflicts of interest.

RB, OW, and NH are external experts invited by Bayer AG to participate in the design of this analysis, consult for study selection and interpretation of the outcomes, and review the manuscript. KB and MH are the employees of Bayer Plc and Bayer AG, respectively, who participated in the design, interpretation of the results, and manuscript preparation. PW and EC are the employees of Creativ-Ceutical, who designed the analysis, managed the conduction of simulations and outcome reporting, interpreted the results, and actively participated in the preparation of the manuscript.

Supplementary Materials

Supplementary Table 1: credibility assessment of trials included in the NMA [ 1 ]. Supplementary Table 2: input data for the NMA of the risk of myocardial infarction. Supplementary Table 3: input data for the NMA of the risk of ischemic stroke. Supplementary Table 4: input data for the NMA of the risk of cardiovascular death. Supplementary Table 5: input data for the NMA of the risk of all-cause mortality. Supplementary Table 6: input data for the NMA of the risk of any stroke. Supplementary Table 7: input data for the NMA of the risk of major bleeding. Supplementary Table 8: input data for the NMA of the risk of revascularization. Supplementary Figure 1: networks of evidence for the risk of amputations. Supplementary Figure 2: forest plots comparing RIV plus ASA versus comparators regarding amputation. Supplementary Figure 3: networks of evidence for the risk of myocardial infarction. Supplementary Figure 4: forest plots comparing RIV plus ASA versus comparators regarding myocardial infarction. Supplementary Figure 5: networks of evidence for the risk of ischemic stroke. Supplementary Figure 6: forest plots comparing RIV plus ASA versus comparators regarding ischemic stroke. Supplementary Figure 7: networks of evidence for the risk of cardiovascular death. Supplementary Figure 8: forest plots comparing RIV plus ASA versus comparators regarding cardiovascular death. Supplementary Figure 9: networks of evidence for the risk of all-cause mortality. Supplementary Figure 10: forest plots comparing RIV plus ASA versus comparators regarding all-cause mortality. Supplementary Figure 11: networks of evidence for the risk of any stroke. Supplementary Figure 12: forest plots comparing RIV plus ASA versus comparators regarding any stroke. Supplementary Figure 13: networks of evidence for the risk of major bleeding. Supplementary Figure 14: forest plots comparing RIV plus ASA versus comparators regarding major bleeding. Supplementary Figure 15: networks of evidence for the risk of revascularization. Supplementary Figure 16: forest plots comparing RIV plus ASA versus comparators regarding revascularization.

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Landmark Phase 3 VOYAGER PAD Study of XARELTO ® (rivaroxaban) Plus Aspirin Shows Significant Benefit in Patients with Symptomatic Peripheral Artery Disease (PAD) after Lower-Extremity Revascularization

Xarelto ® has the potential to be the first anticoagulant in 20 years [i] to show a benefit in these high-risk patients two major phase 3 trials have evaluated xarelto ® vascular dose plus aspirin in treating patients with atherosclerotic disease.

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RARITAN, NJ, March 28, 2020 – The Janssen Pharmaceutical Companies of Johnson & Johnson today announced the VOYAGER PAD study met its primary efficacy and principal safety endpoints, demonstrating the XARELTO ® (rivaroxaban) vascular dose (2.5 mg twice daily) plus aspirin (100 mg once daily) was superior to aspirin alone in reducing the risk of major adverse limb and cardiovascular (CV) events by 15 percent in patients with symptomatic peripheral artery disease (PAD) after lower-extremity revascularization, with similar rates of TIMI [1] major bleeding. VOYAGER PAD is the only study to show a significant benefit using dual pathway inhibition, an anticoagulant plus aspirin, in this patient population. Findings from this global, randomized, double-blind, Phase 3 study were presented as a late-breaking presentation during the virtual American College of Cardiology’s 69 th Annual Scientific Session, together with the World Congress of Cardiology (ACC.20/WCC), and simultaneously published in The New England Journal of Medicine .

PAD is a common circulatory condition that occurs when narrowed blood vessels reduce blood flow to the limbs, most often the legs. PAD affects more than 200 million people globally, [i] including eight million in the U.S. [ii PAD is the leading cause of amputation [iii] and results in high rates of fatal and non-fatal CV events. Often starting as asymptomatic, PAD typically progresses to a more symptomatic, chronic form, with revascularization needed when symptoms become severe. Current PAD guidelines recommend antiplatelet therapy alone, such as aspirin or clopidogrel, to help prevent CV events [iv] , [v] following revascularization; however, no medicines are specifically indicated to prevent amputation or acute limb ischemia in these patients.

“While the COMPASS trial established the efficacy of rivaroxaban plus aspirin in stable patients with PAD and coronary artery disease (CAD), there were important unanswered questions on the optimal strategy for patients with symptomatic PAD after lower-extremity revascularization, including those without CAD. This is a particularly high-risk period for severe limb outcomes as well as bleeding,” said Marc P. Bonaca, M.D., Department of Medicine, Division of Cardiovascular Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. “The VOYAGER PAD study shows us the potential clinical utility of rivaroxaban 2.5 mg twice daily plus aspirin in preventing the most critical thrombotic complications, adverse limb and cardiovascular outcomes, during the post-revascularization period when PAD patients are most vulnerable to these serious events.”

CLICK TO TWEET: Now available: New Phase 3 results show significant benefit of @JanssenUS medicine plus aspirin in patients with symptomatic #PAD after lower-extremity revascularization. Full press release here: http://bit.ly/3ddwFNr

The VOYAGER PAD results complement findings from the landmark Phase 3 COMPASS study , which also examined the dual pathway approach of XARELTO ® (2.5 mg twice daily) plus aspirin (100 mg once daily). COMPASS found XARELTO ® plus aspirin significantly reduced the risk of major CV and limb events in patients with chronic PAD and/or coronary artery disease (CAD) compared to aspirin alone.

“Our EXPLORER clinical research program continues to produce evidence of the critical role XARELTO ® plays in helping to shape clinical practice and transform cardiovascular care,” said James List, M.D., Ph.D., Global Therapeutic Area Head, Cardiovascular & Metabolism, Janssen Research & Development, LLC. “Based on the findings from the COMPASS and VOYAGER PAD studies, we believe a dual pathway approach of XARELTO ® 2.5 mg twice daily dose plus aspirin can potentially change how PAD is managed. We look forward to discussing these data with the U.S. Food & Drug Administration (FDA).”

“Janssen continues to live up to our long-standing commitment of working tirelessly to bring transformational therapies to patients in need,” said Mathai Mammen, M.D., Ph.D., Global Head of Janssen Research & Development, LLC, Johnson & Johnson. “XARELTO ® has the potential to be the first anticoagulant in 20 years to show a benefit in patients with PAD after lower-extremity revascularization and is a strong example of that commitment.”

VOYAGER PAD Results For the primary efficacy endpoint, XARELTO ® plus aspirin significantly reduced the risk of major adverse limb and CV events compared to aspirin alone. Specifically, researchers observed that nearly one in five patients taking aspirin alone suffered a major adverse limb or CV event, but this risk was significantly reduced by 15 percent when XARELTO ® was added. The Kaplan-Meier (KM) estimates of the incidence at three years for XARELTO ® /aspirin compared to aspirin alone were 17.3% vs. 19.9%, respectively (Hazard Ratio [HR]=0.85; 95% confidence interval [CI], 0.76-0.96; p=0.009). The benefit of adding XARELTO ® to aspirin was apparent early, was consistent among major subgroups and continued to accrue over time.

The principal safety endpoint was met, with no significant increase in TIMI major bleeding in patients treated with XARELTO ® plus aspirin compared to aspirin alone. The KM estimates of the incidence at three years for XARELTO ® /aspirin compared to aspirin alone were 2.65% vs. 1.87%, respectively (HR=1.43; 95% CI, 0.97–2.10; p=0.07). Of note, there were numerically fewer intracranial bleeding events in the XARELTO ® /aspirin group (0.60% vs. 0.90%; HR=0.78; 95% CI, 0.38–1.61) and no increase in fatal bleeding (0.21% vs. 0.21%; HR=1.02; 95% CI, 0.33–3.15) across both groups.

About VOYAGER PAD The Phase 3 VOYAGER PAD study included 6,564 patients from 542 sites across 34 countries worldwide. Patients were randomized in a 1:1 ratio and received either XARELTO ® (2.5 mg twice daily) plus aspirin (100 mg once daily) (n=3,286) or aspirin alone (100 mg once daily) (n=3,278). Patients were stratified by revascularization procedure type (endovascular vs. surgical) and use of clopidogrel, which was administered at the treating physician’s discretion. Patients were followed for a median of 28 months.

The primary efficacy endpoint was a composite of major adverse limb and CV events, including acute limb ischemia, major amputation for vascular causes, heart attack (myocardial infarction), ischemic stroke, or death from CV causes. The principal safety endpoint was major bleeding according to the TIMI classification.

Eligible patients were at least 50 years old and had documented symptomatic lower extremity PAD. Patients were eligible after a successful revascularization for symptomatic PAD within the last 10 days. Approximately two-thirds were treated with an endovascular procedure (65%) and one-third treated surgically (35%). Patients were excluded if they were clinically unstable, at heightened bleeding risk, or needed prohibited concomitant medications, including long-term clopidogrel. The median age was 67 years and 26% were women. Common risk factors included diabetes, an estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 (indicating mild-to-moderate kidney disease) and current smokers.

More on COMPASS COMPASS, the largest clinical study of XARELTO ® to date, enrolled a total of 27,395 patients with chronic CAD and/or PAD. Patients were randomized in a 1:1:1 ratio, with one group receiving XARELTO ® (2.5 mg twice daily) plus aspirin (100 mg once daily), another group receiving XARELTO ® 5 mg twice daily, and the final group receiving aspirin 100 mg once daily. COMPASS was stopped approximately one year ahead of schedule due to efficacy.

COMPASS met its primary efficacy endpoint, with XARELTO ® /aspirin shown to be superior to aspirin alone, reducing major CV events by 24%. This finding was driven by a robust 42% reduction in any stroke and 22% reduction in CV death. While the risk of major bleeding was significantly higher in patients taking XARELTO ® /aspirin compared to aspirin alone, there was no significant difference in fatal bleeds, intracranial bleeds, symptomatic bleeding into a critical organ, or bleeding into the surgical site requiring reoperation between the treatment groups.

WHAT IS XARELTO ® (rivaroxaban)?

XARELTO ® is a prescription medicine used to:

· reduce the risk of stroke and blood clots in people who have a medical condition called atrial fibrillation that is not caused by a heart valve problem. With atrial fibrillation, part of the heart does not beat the way it should. This can lead to the formation of blood clots, which can travel to the brain, causing a stroke, or to other parts of the body

· treat blood clots in the veins of your legs (deep vein thrombosis or DVT) or lungs (pulmonary embolism or PE)

· reduce the risk of blood clots happening again in people who continue to be at risk for DVT or PE after receiving treatment for blood clots for at least 6 months

· help prevent a blood clot in the legs and lungs of people who have just had hip or knee replacement surgery

· help prevent blood clots in certain people hospitalized for an acute illness and after discharge, who are at risk of getting blood clots because of the loss of or decreased ability to move around (mobility) and other risks for getting blood clots, and who do not have a high risk of bleeding

XARELTO ® is used with low dose aspirin to:

· reduce the risk of serious heart problems, heart attack and stroke in people with coronary artery disease (a condition where the blood supply to the heart is reduced or blocked) or peripheral artery disease (a condition where the blood flow to the legs is reduced)

It is not known if XARELTO ® is safe and effective in children.

IMPORTANT SAFETY INFORMATION

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT XARELTO ® ?

XARELTO ® may cause serious side effects, including:

· Increased risk of blood clots if you stop taking XARELTO ® . People with atrial fibrillation (an irregular heart beat) that is not caused by a heart valve problem (nonvalvular) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO ® lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO ® , you may have increased risk of forming a clot in your blood.

Do not stop taking XARELTO ® without talking to the doctor who prescribes it for you. Stopping XARELTO ® increases your risk of having a stroke. If you have to stop taking XARELTO ® , your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.

· Increased risk of bleeding. XARELTO ® can cause bleeding which can be serious, and may lead to death. This is because XARELTO ® is a blood thinner medicine (anticoagulant) that lowers blood clotting. During treatment with XARELTO ® you are likely to bruise more easily, and it may take longer for bleeding to stop. You may be at higher risk of bleeding if you take XARELTO ® and have certain other medical problems.

You may have a higher risk of bleeding if you take XARELTO ® and take other medicines that increase your risk of bleeding, including:

o Aspirin or aspirin-containing products

o Long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)

o Warfarin sodium (Coumadin ® , Jantoven ® )

o Any medicine that contains heparin

o Clopidogrel (Plavix ® )

o Selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)

o Other medicines to prevent or treat blood clots

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

o Unexpected bleeding or bleeding that lasts a long time, such as:

§ Nosebleeds that happen often

§ Unusual bleeding from gums

§ Menstrual bleeding that is heavier than normal, or vaginal bleeding

o Bleeding that is severe or you cannot control

o Red, pink, or brown urine

o Bright red or black stools (looks like tar)

o Cough up blood or blood clots

o Vomit blood or your vomit looks like “coffee grounds”

o Headaches, feeling dizzy or weak

o Pain, swelling, or new drainage at wound sites

· Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like XARELTO ® , and have medicine injected into their spinal and epidural area, or have a spinal puncture, have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

o A thin tube called an epidural catheter is placed in your back to give you certain medicine

o You take NSAIDs or a medicine to prevent blood from clotting

o You have a history of difficult or repeated epidural or spinal punctures

o You have a history of problems with your spine or have had surgery on your spine

If you take XARELTO ® and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have back pain, tingling, numbness, muscle weakness (especially in your legs and feet), or loss of control of the bowels or bladder (incontinence).

XARELTO ® is not for use in people with artificial heart valves.

XARELTO ® is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing.

Do not take XARELTO ® if you:

· Currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO ® if you currently have unusual bleeding.

· Are allergic to rivaroxaban or any of the ingredients of XARELTO ® .

Before taking XARELTO ® , tell your doctor about all your medical conditions, including if you:

· Have ever had bleeding problems

· Have liver or kidney problems

· Have antiphospholipid syndrome (APS)

· Are pregnant or plan to become pregnant. It is not known if XARELTO ® will harm your unborn baby.

o Tell your doctor right away if you become pregnant during treatment with XARELTO ® . Taking XARELTO ® while you are pregnant may increase the risk of bleeding in you or in your unborn baby.

o If you take XARELTO ® during pregnancy, tell your doctor right away if you have any signs or symptoms of bleeding or blood loss. See “What is the most important information I should know about XARELTO ® ?” for signs and symptoms of bleeding.

· Are breastfeeding or plan to breastfeed. XARELTO ® may pass into your breast milk. Talk to your doctor about the best way to feed your baby during treatment with XARELTO ® .

Tell all of your doctors and dentists that you are taking XARELTO ® . They should talk to the doctor who prescribed XARELTO ® for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some of your other medicines may affect the way XARELTO ® works, causing side effects. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO ® ?”

HOW SHOULD I TAKE XARELTO ® ?

· Take XARELTO ® exactly as prescribed by your doctor.

· Do not change your dose or stop taking XARELTO ® unless your doctor tells you to. Your doctor may change your dose if needed.

· Your doctor will decide how long you should take XARELTO ® .

· XARELTO ® may need to be stopped for one or more days before any surgery or medical or dental procedure. Your doctor will tell you when to stop taking XARELTO ® and when to start taking XARELTO ® again after your surgery or procedure.

· If you need to stop taking XARELTO ® for any reason, talk to the doctor who prescribed XARELTO ® to you to find out when you should stop taking it. Do not stop taking XARELTO ® without first talking to the doctor who prescribes it to you.

· If you have difficulty swallowing XARELTO ® tablets whole, talk to your doctor about other ways to take XARELTO ® .

· Do not run out of XARELTO ® . Refill your prescription of XARELTO ® before you run out. When leaving the hospital following a hip or knee replacement, be sure that you will have XARELTO ® available to avoid missing any doses.

· If you take too much XARELTO ® , go to the nearest hospital emergency room or call your doctor right away.

If you take XARELTO ® for:

o Atrial Fibrillation that is not caused by a heart valve problem:

§ Take XARELTO ® 1 time a day with your evening meal.

§ If you miss a dose of XARELTO ® , take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.

o Blood clots in the veins of your legs or lungs:

§ Take XARELTO ® 1 or 2 times a day as prescribed by your doctor.

§ For the 10-mg dose , XARELTO ® may be taken with or without food.

§ For the 15-mg and 20-mg doses , take XARELTO ® with food at the same time each day.

§ If you miss a dose:

Ø If you take the 15-mg dose of XARELTO ® 2 times a day (a total of 30 mg of XARELTO ® in 1 day): Take XARELTO ® as soon as you remember on the same day. You may take 2 doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.

Ø If you take XARELTO ® 1 time a day: Take XARELTO ® as soon as you remember on the same day. Take your next dose at your regularly scheduled time.

o Hip or knee replacement surgery:

§ Take XARELTO ® 1 time a day with or without food.

o Blood clots in people hospitalized for an acute illness:

§ Take XARELTO ® 1 time a day, with or without food, while you are in the hospital and after you are discharged as prescribed by your doctor.

o Reducing the risk of serious heart problems, heart attack and stroke in coronary artery disease or peripheral artery disease:

§ Take XARELTO ® 2.5 mg 2 times a day with or without food.

§ If you miss a dose of XARELTO ® , take your next dose at your regularly scheduled time.

§ Take aspirin 75 to 100 mg once daily as instructed by your doctor.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF XARELTO ® ?

XARELTO ® may cause serious side effects:

· See “What is the most important information I should know about XARELTO ® ?”

The most common side effect of XARELTO ® was bleeding.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc., at 1-800-JANSSEN (1-800-526-7736).

Please read full Prescribing Information , including Boxed Warnings, and Medication Guide for XARELTO ® .

Trademarks are those of their respective owners.

About Janssen Cardiovascular & Metabolism

In Cardiovascular & Metabolism (CVM), we take on the most pervasive diseases that burden hundreds of millions of people and healthcare systems around the world. As part of this long-standing commitment and propelled by our successes in treating type 2 diabetes (T2D) and thrombosis, we advance highly differentiated therapies that prevent and treat life-threatening cardiovascular and metabolic diseases. Uncovering new therapies that can improve the quality of life for this large segment of the population is an important endeavor – one which Janssen CVM will continue to lead in the years to come. Our mission is global, local and personal. Together, we can reshape the future of cardiovascular and metabolic prevention and treatment. Please visit www.janssen.com/cardiovascular-and-metabolism .

About the Janssen Pharmaceutical Companies of Johnson & Johnson

At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Learn more at www.janssen.com . Follow us at www.twitter.com/JanssenUS . Janssen Research & Development, LLC, is one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Cautions Concerning Forward-Looking Statements

This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding rivaroxaban. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended December 29, 2019, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q, and the company’s subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov , www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

[1] Thrombolysis In Myocardial Infarction

[i] Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329-40. [ii] Centers for Disease Control and Prevention. Peripheral Arterial Disease Fact Sheet/Data & Statistics. Retrieved 20 March 2020 from https://www.cdc.gov/heartdisease/pad.htm . [iii] Norgren L, Hiatt WR, Dormandy JA, Hirsch, et al. The next 10 years in the management of peripheral artery disease: perspectives from the ‘PAD 2009’ Conference. European Journal of Vascular and Endovascular Surgery 2010;40(3):375-380. [iv] Aboyans V, Ricco JB, Bartelink MEL, et al. 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 Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J 2018;39:763-816. [v] Gerhard-Herman MD, Gornik HL, Barrett C 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. Circulation 2017;135:e726-e779.

Media contacts: Joy-Lee Pasqualoni Mobile: (917) 547-8078 [email protected]

Sarah Freeman Mobile: (215) 510-4758 [email protected]

Investor contacts: Johnson & Johnson Christopher DelOrefice Office: (732) 524-2955

Lesley Fishman Office: (732) 524-3922

Voyager Therapeutics Announces Selection of Development Candidate for GBA1 Program in Collaboration with Neurocrine Biosciences, Triggering Milestone Payment

Selection of the development candidate triggered a $3 million milestone payment to Voyager, which the Company expects to receive in the second quarter of 2024. Voyager is eligible to receive additional future development and commercialization milestone payments based on the further advancement of this program.

“The nomination of this development candidate in the GBA1 program, following the recent nomination of a development candidate in the Friedreich’s ataxia program, demonstrates the productivity of the collaboration between Voyager and Neurocrine to advance gene therapies for neurological diseases,” said Alfred W. Sandrock, Jr., M.D., Ph.D., Chief Executive Officer of Voyager. “We now see the potential for three gene therapies leveraging our novel TRACER capsids to enter the clinic in 2025: the Neurocrine-partnered GBA1 and FA programs, and our wholly-owned SOD1 ALS program.”

The GBA1 program is being developed under the 2023 strategic collaboration agreement between Voyager and Neurocrine Biosciences for research, development, manufacture, and commercialization of certain AAV gene therapy products for programs targeting Parkinson’s disease and other GBA1-mediated diseases and three other undisclosed programs to address central nervous system diseases or conditions associated with rare genetic targets. Under the terms of the 2023 collaboration agreement, Voyager is eligible to receive up to $1.5 billion in potential development milestone payments, as well as additional commercial milestone payments, tiered royalties on net sales, and program funding. Voyager maintains an option to elect 50/50 cost- and profit-sharing in the U.S. for the GBA1 program following topline data from the first Parkinson’s disease clinical trial.

About the TRACER™ Capsid Discovery Platform

Voyager’s TRACER™ (Tropism Redirection of AAV by Cell-type-specific Expression of RNA) capsid discovery platform is a broadly applicable, RNA-based screening platform that enables rapid discovery of AAV capsids with robust penetration of the blood-brain barrier and enhanced central nervous system (CNS) tropism in multiple species, including non-human primates (NHPs). TRACER™ generated capsids have demonstrated superior and widespread gene expression in the CNS compared to conventional AAV capsids as well as cell- and tissue-specific transduction, including to areas of the brain that have been traditionally difficult to reach, while de-targeting the liver and dorsal root ganglia. As part of its external partnership strategy, Voyager has established multiple collaboration agreements providing access to its next-generation TRACER™ capsids to potentially enable its partners’ gene therapy programs to treat a variety of diseases.

About Voyager Therapeutics

Voyager Therapeutics ® is a registered trademark, and TRACER™ is a trademark, of Voyager Therapeutics, Inc. 

Forward-Looking Statements

This press release contains forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as “expect,” “future,” or “potential,” and other similar expressions are intended to identify forward-looking statements.

For example, all statements Voyager makes regarding filing an IND on the GBA1 program and the potential to advance Voyager’s AAV-based gene therapy programs into the clinic in 2025, and Voyager’s eligibility to receive development and commercial milestone payments, tiered royalties on net sales, and program funding under the 2023 Neurocrine collaboration agreement are forward-looking.

All forward-looking statements are based on estimates and assumptions by Voyager’s management that, although Voyager believes such forward-looking statements to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that Voyager expected. Such risks and uncertainties include, among others, the continued development of Voyager’s technology platforms, including Voyager’s TRACER™ platform and its antibody screening technology; the ability to initiate and conduct preclinical studies in animal models; the development by third parties of capsid identification platforms that may be competitive to Voyager’s TRACER™ capsid discovery platform; Voyager’s ability to create and protect intellectual property rights associated with the TRACER™ capsid discovery platform, the capsids identified by the platform, and development candidates for Voyager’s pipeline programs; the initiation, timing, conduct and outcomes of Voyager’s preclinical studies; the possibility or the timing of Voyager’s receipt of program reimbursement, development or commercialization milestones, option exercise, and other payments under Voyager’s current licensing or collaboration agreements; the ability of Voyager to negotiate and complete licensing or collaboration agreements with other parties on terms acceptable to Voyager and the third parties; the ability to attract and retain talented directors, employees, and contractors; and the sufficiency of cash resources to fund its operations and pursue its corporate objectives.

These statements are also subject to a number of material risks and uncertainties that are described in Voyager’s most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission. All information in the press release is as of the date of this press release, and any forward-looking statement speaks only as of the date on which it was made. Voyager undertakes no obligation to publicly update or revise this information or any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

Trista Morrison, NACD.DC, [email protected]

Investors: Adam Bero, Ph.D., [email protected]

Media: Brooke Shenkin, [email protected]

Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial

Affiliations.

• 1 Department of Vascular Medicine, Vascular Surgery-Angiology-Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg, Germany (E.S.D.).
• 2 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.).
• 3 Division of Vascular Surgery, Department of Surgery (M.R.N., N.G.), Department of Medicine, University of Colorado School of Medicine, Aurora.
• 4 Department of Vascular Medicine, Klinikum Darmstadt, Darmstadt, and Center for Thrombosis and Hemostasis, University of Mainz, Germany (R.M.B.).
• 5 Population Health Research Institute, Hamilton Health Sciences and McMaster University, Ontario, Canada (S.S.A.).
• 6 Duke Clinical Research Institute, Division of Cardiology, Duke University, Durham, NC (M.R.P.).
• 7 Vascular and Interventional Radiology Department, Careggi University Hospital, University of Florence, Italy (F.F.).
• 8 Division of Endocrinology (W.H.C.), Department of Medicine, University of Colorado School of Medicine, Aurora.
• 9 Department for Vascular Surgery Krankenhaus Barmherzige Brüder Linz, Austria (F.H.).
• 10 Pauls Stradins University Hospital, University of Latvia, Riga (D.K.).
• 11 Vascular and Endovascular Surgery, McGill University Montreal, Quebec, Canada (P.N.).
• 12 Vascular Surgery, Department of Medicine and Surgery, University of Insubria School of Medicine, Varese, Italy (G.P.).
• 13 The I.I. Mechnikov North-Western State Medical University, Department of Cardiovascular Surgery, St. Petersburg, Russia (A.S.).
• 14 Division of Cardiology (C.N.H., W.R.H., M.P.B.), Department of Medicine, University of Colorado School of Medicine, Aurora.
• 15 Department of Vascular Surgery, Rigshospitalet, Institute of Clinical Medicine, University of Copenhagen, Denmark (H.H.S.).
• 16 Division of Vascular and Endovascular Surgery, University of California, San Francisco (M.C.).
• 17 Division of Vascular Surgery and Endovascular Therapy, Baylor College of Medicine, Houston, TX (J.M.).
• 18 Bayer, Wuppertal, Germany (E.M.).
• 19 Janssen Research and Development, Raritan, NJ (L.P.H.).
• 20 Thrombosis Group Head, Clinical Development, Bayer US, Whippany, NJ (S.D.B.).
• PMID: 34380322
• DOI: 10.1161/CIRCULATIONAHA.121.054835

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

Keywords: lower extremity revascularization; major adverse cardiovascular events (MACE); major adverse limb events (MALE); peripheral artery disease; revascularization; rivaroxaban.

Publication types

• Randomized Controlled Trial
• Research Support, Non-U.S. Gov't
• Aspirin / pharmacology
• Aspirin / therapeutic use*
• Middle Aged
• Peripheral Arterial Disease / drug therapy*
• Peripheral Arterial Disease / surgery*
• Rivaroxaban / pharmacology
• Rivaroxaban / therapeutic use*
• Rivaroxaban

Associated data

• ClinicalTrials.gov/NCT02504216