NIHR Signal Rivaroxaban plus aspirin may reduce heart attack and strokes in people with peripheral arterial disease, but with an added risk of bleeding

Published on 14 February 2018

People with peripheral arterial disease who took rivaroxaban plus aspirin daily over an average of 21 months reduced their risk of cardiovascular death, heart attack or stroke from seven to five in every 100 people treated compared with those given aspirin alone. The rivaroxaban plus aspirin group also reduced their risk of major limb problems or amputation but increased their risk of bleeding from one to two for every hundred people treated.

Peripheral arterial disease is a condition in which the arteries in the legs and feet are narrowed by a build-up of fatty deposits. If it becomes severe, this can lead to limb damage or amputation. The blockages can also affect other arteries such as those supplying the heart and brain. This puts people with arterial disease at increased risk of other cardiovascular diseases.

Current practice is to treat people daily with aspirin. This study suggests that adding a low dose of rivaroxaban to aspirin is an option that provides some additional benefits and some additional risks. The additional costs of prescribing rivaroxaban will need to be taken into account when assessing the population benefits.

The trial was sponsored by Bayer AG.

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Why was this study needed?

Population studies show that about 20% of people aged over 60 years have peripheral arterial disease. About 10-15% of people who report symptoms, such as restrictions in the distance they can walk, will probably die of related cardiovascular causes over five years. This is three times as many as a comparable group of age and sex-matched controls. 

Treatment involves lifestyle changes, drugs and surgery to reduce this risk. A daily dose of aspirin (an antiplatelet drug) is often prescribed. Newer antiplatelet and other types of drugs have been developed to prevent cardiovascular problems, but none has been shown to be more effective than aspirin for people with peripheral arterial disease. Rivaroxaban is effective in people with different types of cardiovascular diseases.

This study aimed to show whether a low dose of rivaroxaban, given with or without aspirin, was more effective than aspirin alone for people with peripheral arterial disease.

What did this study do?

This trial recruited 7,470 patients with peripheral arterial disease from 558 centres in 33 countries. They were randomly assigned to one of three groups. One group received 2.5mg of rivaroxaban twice a day, plus 100mg of aspirin once a day. The second group had 5mg of rivaroxaban twice a day. The third group received 100mg of aspirin once a day. The second and third groups also received dummy pills, so that everyone took the same number of tablets each day, without knowing which group they were in.

Participants were followed up in clinics at one and six months, and then every six months. The median duration of treatment was 21 months.

Patients with a high risk of bleeding, recent stroke or severe heart failure were excluded from the trial.

What did it find?

  • The primary outcome was a combination of cardiovascular death, heart attack or stroke. This occurred in 126 out of 2,492 patients (5%) who received rivaroxaban plus aspirin, 149 of 2,474 patients (6%) in the rivaroxaban alone group, and in 174 of 2,504 patients (7%) who received just aspirin. The rivaroxaban plus aspirin combination reduced the risk compared to aspirin alone (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.57 to 0.90). But rivaroxaban alone compared to aspirin alone did not reduce this risk (HR 0.86, 95% CI 0.69 to 1.08).
  • Major adverse limb events including major amputation occurred in 32 of 2,492 patients (1.3%) who received rivaroxaban plus aspirin, 40 of 2,474 patients (1.6%) in the rivaroxaban alone group, and in 60 of 2,504 patients (2.3%) who received aspirin alone. Rivaroxaban plus aspirin reduced the risk of this outcome compared to aspirin alone (HR 0.54, 95% CI 0.35 to 0.82).
  • Rivaroxaban plus aspirin increased major bleeding compared to aspirin alone (77 of 2,492 [3%] versus 48 of 2,504 [2%], HR 1.61, 95% CI 1.12 to 2.31).

What does current guidance say on this issue?

The NICE guideline on diagnosing and managing peripheral arterial disease makes recommendations about the secondary prevention of cardiovascular disease in people with peripheral arterial disease. These include offering advice on diet and exercise, lipid modification and statin therapy, and antiplatelet therapy. No specific antiplatelet drug is recommended.

Rivaroxaban is not currently licensed in the UK for treating this condition, but it is licensed at this dose for use with aspirin after acute heart attacks.

What are the implications?

The combination of low dose rivaroxaban plus aspirin seems like an option for people with stable peripheral arterial disease who are not at high risk of bleeding, instead of aspirin alone.

This could reduce their risk of cardiovascular death, heart attack and stroke at the expense of a small increase in major bleeding. A cost-effectiveness analysis would be helpful to see if the net benefit here is worth any increase in cost for this drug compared to alternatives.

Citation and Funding

Anand SS, Bosch J, Eikelboom, JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017. [Epub ahead of print].

This study was funded by Bayer AG.

Bibliography

BNF. Rivaroxaban. London: BMJ Group and Pharmaceutical Press; accessed 2018.

NICE. Peripheral arterial disease. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2016.

NHS Choices. Peripheral arterial disease. London: Department of Health; 2016.

NICE. Peripheral arterial disease: diagnosis and management. CG147. London: National Institute for Health and Care Excellence; 2012.

Why was this study needed?

Population studies show that about 20% of people aged over 60 years have peripheral arterial disease. About 10-15% of people who report symptoms, such as restrictions in the distance they can walk, will probably die of related cardiovascular causes over five years. This is three times as many as a comparable group of age and sex-matched controls. 

Treatment involves lifestyle changes, drugs and surgery to reduce this risk. A daily dose of aspirin (an antiplatelet drug) is often prescribed. Newer antiplatelet and other types of drugs have been developed to prevent cardiovascular problems, but none has been shown to be more effective than aspirin for people with peripheral arterial disease. Rivaroxaban is effective in people with different types of cardiovascular diseases.

This study aimed to show whether a low dose of rivaroxaban, given with or without aspirin, was more effective than aspirin alone for people with peripheral arterial disease.

What did this study do?

This trial recruited 7,470 patients with peripheral arterial disease from 558 centres in 33 countries. They were randomly assigned to one of three groups. One group received 2.5mg of rivaroxaban twice a day, plus 100mg of aspirin once a day. The second group had 5mg of rivaroxaban twice a day. The third group received 100mg of aspirin once a day. The second and third groups also received dummy pills, so that everyone took the same number of tablets each day, without knowing which group they were in.

Participants were followed up in clinics at one and six months, and then every six months. The median duration of treatment was 21 months.

Patients with a high risk of bleeding, recent stroke or severe heart failure were excluded from the trial.

What did it find?

  • The primary outcome was a combination of cardiovascular death, heart attack or stroke. This occurred in 126 out of 2,492 patients (5%) who received rivaroxaban plus aspirin, 149 of 2,474 patients (6%) in the rivaroxaban alone group, and in 174 of 2,504 patients (7%) who received just aspirin. The rivaroxaban plus aspirin combination reduced the risk compared to aspirin alone (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.57 to 0.90). But rivaroxaban alone compared to aspirin alone did not reduce this risk (HR 0.86, 95% CI 0.69 to 1.08).
  • Major adverse limb events including major amputation occurred in 32 of 2,492 patients (1.3%) who received rivaroxaban plus aspirin, 40 of 2,474 patients (1.6%) in the rivaroxaban alone group, and in 60 of 2,504 patients (2.3%) who received aspirin alone. Rivaroxaban plus aspirin reduced the risk of this outcome compared to aspirin alone (HR 0.54, 95% CI 0.35 to 0.82).
  • Rivaroxaban plus aspirin increased major bleeding compared to aspirin alone (77 of 2,492 [3%] versus 48 of 2,504 [2%], HR 1.61, 95% CI 1.12 to 2.31).

What does current guidance say on this issue?

The NICE guideline on diagnosing and managing peripheral arterial disease makes recommendations about the secondary prevention of cardiovascular disease in people with peripheral arterial disease. These include offering advice on diet and exercise, lipid modification and statin therapy, and antiplatelet therapy. No specific antiplatelet drug is recommended.

Rivaroxaban is not currently licensed in the UK for treating this condition, but it is licensed at this dose for use with aspirin after acute heart attacks.

What are the implications?

The combination of low dose rivaroxaban plus aspirin seems like an option for people with stable peripheral arterial disease who are not at high risk of bleeding, instead of aspirin alone.

This could reduce their risk of cardiovascular death, heart attack and stroke at the expense of a small increase in major bleeding. A cost-effectiveness analysis would be helpful to see if the net benefit here is worth any increase in cost for this drug compared to alternatives.

Citation and Funding

Anand SS, Bosch J, Eikelboom, JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017. [Epub ahead of print].

This study was funded by Bayer AG.

Bibliography

BNF. Rivaroxaban. London: BMJ Group and Pharmaceutical Press; accessed 2018.

NICE. Peripheral arterial disease. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; 2016.

NHS Choices. Peripheral arterial disease. London: Department of Health; 2016.

NICE. Peripheral arterial disease: diagnosis and management. CG147. London: National Institute for Health and Care Excellence; 2012.

Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Published on 15 November 2017

Anand, S. S.,Bosch, J.,Eikelboom, J. W.,Connolly, S. J.,Diaz, R.,Widimsky, P.,Aboyans, V.,Alings, M.,Kakkar, A. K.,Keltai, K.,Maggioni, A. P.,Lewis, B. S.,Stork, S.,Zhu, J.,Lopez-Jaramillo, P.,O'Donnell, M.,Commerford, P. J.,Vinereanu, D.,Pogosova, N.,Ryden, L.,Fox, K. A. A.,Bhatt, D. L.,Misselwitz, F.,Varigos, J. D.,Vanassche, T.,Avezum, A. A.,Chen, E.,Branch, K.,Leong, D. P.,Bangdiwala, S. I.,Hart, R. G.,Yusuf, S.

Lancet , 2017

IncludedBACKGROUND: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. METHODS: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0.90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0.72, 95% CI 0.57-0.90, p=0.0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0.54 95% CI 0.35-0.82, p=0.0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0.86, 95% CI 0.69-1.08, p=0.19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0.67, 95% CI 0.45-1.00, p=0.05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1.61, 95% CI 1.12-2.31, p=0.0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1.68, 95% CI 1.17-2.40; p=0.0043). INTERPRETATION: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding. FUNDING: Bayer AG.

Expert commentary

Atherosclerosis is a systemic disease, in which peripheral arterial disease predicts increased risk of more severe consequences of coronary and cerebrovascular disease. Best medical treatment rarely improves symptoms of limb ischaemia but reduces risk of myocardial infarction and stroke.

Treatment with rivaroxaban, in combination with aspirin, significantly reduces risk of major cardiovascular events and need for revascularisation or amputation, compared to treatment with aspirin alone.

This benefit has to be offset against doubled risk of bleeding, although this is more likely to occur in the gut, than to result in fatal or critical organ bleeds, and may be preventable with proton pump inhibitors, drugs that reduce stomach acid.

Frank CT Smith, Professor of Vascular Surgery & Surgical Education, University of Bristol, Faculty of Health Sciences; North Bristol NHS Healthcare Trust, Southmead Hospital