Currently, worldwide, there is an impending epidemic of symptomatic peripheral artery disease (PAD). This is largely due to the increasing prevalence of risk factors such as: smoking, diabetes, high blood pressure (BP), cholesterol, and end-stage renal disease (ESRD). In the developed world this is largely due to an epidemic of diabetes and obesity. There is a wide spectrum of PAD that ranges from asymptomatic disease through to chronic limb-threatening ischaemia (CLTI). Depending upon income and region, the number of sufferers with PAD has increased by 13–25% during the last decade, accounting for 202 million people worldwide in 2010.1 The majority of those affected are represented by people older than 60 years, of whom 10–20% are thought to be affected by PAD.2 PAD is believed to double the risk of cardiovascular morbidity and mortality, even without major limb ischaemia.3
Awareness of PAD is low among patients and the public, despite PAD having five-year mortality rates higher than common cancers and acute myocardial infarction (MI) in both symptomatic and asymptomatic groups (figure 1).4–6 Despite this clear clinical need, the evidence underpinning treatment in PAD, and CLTI in particular, is poor. Heterogeneity in the literature and poor levels of evidence make any conclusions difficult to generalise to the PAD population. In 2012, the National Institute for Health and Care Excellence (NICE) suggested areas of focus for future research in patients with symptomatic PAD (table 1).7 These call for focus on: assessment, patients with PAD and diabetes, infra-geniculate disease and improving patient awareness. Below, we discuss the challenges of improving life and limb, including unmet needs for the whole spectrum of patients with PAD.
Table 1. National Institute for Health and Care Excellence recommendations for research in peripheral artery disease7
|The recommendations for reasearch in peripheral artery disease|
|Effectiveness of tools for diagnosing peripheral artery disease in people with diabetes|
|Effectiveness of tools for establishing the severity of peripheral artery disease in people with diabetes|
|Inter- and intra-rate reliability of assessment tools in the diagnosis of peripheral artery disease in people with diabetes|
|Angioplasty versus bypass surgery for treating people with critical limb ischaemia caused by disease of the infra-geniculate arteries|
|Supervised exercise programmes for treating people with intermittent claudication|
|Patient attitudes and beliefs about peripheral artery disease|
|Primary versus secondary stenting for treating people with critical limb ischaemia caused by disease of the infra-geniculate arteries|
|Chemical sympathectomy for managing critical limb ischaemic pain|
Asymptomatic PAD and primary prevention
Screening by measurement of the ankle-brachial pressure index (ABPI) is formally required to assess PAD, with an index of <0.9 being diagnostic. The prevalence of asymptomatic PAD is of interest due to its implications for cardiac and stroke risk.3 Studies have suggested that approximately 35% of women aged over 65 years have ABPI-detected PAD,8 compared with 29% in men over the age of 68.9
The randomised Aspirin for Asymptomatic Atherosclerosis trial failed to show any benefit of aspirin on reducing future vascular events,10 despite asymptomatic PAD being associated with functional decline, and a five-fold higher baseline mortality from cardiovascular events than a non-PAD population.11 A recent systematic review into the effectiveness of screening using ABPI and its effect on outcome, proved inconclusive.12 Fowkes et al. estimated the odds ratios for all-cause mortality in individuals with asymptomatic and symptomatic PAD (1.53 and 1.98, respectively) compared with matched, disease-free individuals in a pooled analysis of known population studies to date.13 This was supported by long-term findings from Sartipy et al., who demonstrated all-cause, 10-year mortality of 56% for patients with asymptomatic PAD (APAD) and a doubling of the age-adjusted hazard ratio for cardiovascular death.14 At present, the European Society of Cardiology (ESC) recommends screening for APAD only in patients with previously diagnosed heart failure or coronary artery disease, based on level IIb evidence.15
Due to a lack of evidence, it is difficult to estimate the proportion of patients with APAD that go on to develop symptoms; a meta-analysis estimated that those developing intermittent claudication having been previously diagnosed with APAD is somewhere between 4–11%.6 Without a large, worldwide public health effort, it is unlikely that the true incidence of APAD can be identified, as current data are available only from selected interventional studies. The outcomes from treating APAD with best medical therapy (BMT; antiplatelet and statin) or otherwise are largely unknown.
Best medical therapy – secondary prevention
In patients diagnosed with symptomatic PAD, a regime of BMT is recommended in national guidelines worldwide. This constitutes lifestyle modification and control of known risk factors. In the UK, NICE recommend an antiplatelet agent (clopidogrel 75 mg once daily) and lipid-lowering therapy (high-dose statin such as 80 mg atorvastatin daily as first line), as widely used in patients with coronary artery disease. Research into the use of direct oral anticoagulants (DOACs), dual antiplatelet agents and combinations of the two continue, with the ultimate goal of a tailor-made, individual approach to addressing individual risk factors. Ongoing genomic testing is investigating targeted alleles expressed in some patients who cannot metabolise antiplatelet therapies. This may have screening implications in the future. There are wider issues around compliance, adherence and patient and public education; even in large, prospective clinical trials the uptake of BMT is poor at around 70%.
Direct oral anticoagulants
The recent publication of the COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) trial has raised hope that adjunctive, low-dose rivaroxaban (2.5 mg twice daily) with aspirin will improve long-term cardiovascular outcomes, particularly in patients with PAD16 (the COMPASS trial outcomes and results are discussed in detail elsewhere in this supplement).
Encouraging results from the PLATO (Platelet Inhibition and Patient Outcomes) study demonstrated a reduction in secondary cardiac events when ticagrelor was given with aspirin (as opposed to clopidogrel and aspirin) in patients with acute coronary syndrome.17 There were no reductions in cardiovascular morbidity in patients with symptomatic PAD, however, when ticagrelor was given as a monotherapy, compared with clopidogrel alone.18 Some evidence from the American Vascular Quality Initiative suggests a survival benefit in those patients undergoing lower limb revascularisation when using dual antiplatelet therapy, particularly in high-risk patients.19 More evidence is required to define the dosage and combination of therapies of most benefit.
The evidence underpinning the use of statins and other lipid-lowering therapies is primarily extrapolated from the coronary literature. Most guidelines in the US, UK and rest of Europe recommend the use of high-intensity statin treatment to reduce secondary cardiovascular events. There is limited evidence in the literature pertaining to the use of lipid-lowering therapy and its specific benefits for patients with PAD. One recent study reported that patients with CLTI, the most severe form of PAD, had reduced mortality and improved freedom from major adverse limb events when lipid therapy guidelines were followed in patients undergoing revascularisation.20
Intermittent claudication, a clinical syndrome of exertional pain in the muscles of the lower limbs that terminates with rest, is the commonest manifestation of symptomatic PAD. The long-term risks of cardiovascular mortality in patients with intermittent claudication are well documented, and 20% of individuals will have a cardiovascular event in a 10-year period.11,21,22 Symptomatic PAD, in general, is a stronger predictor of mortality than CAD or cerebrovascular disease alone.23–25 Although intermittent claudication is generally considered as a ‘benign’ condition, one patient in five will progress to CLTI in a five-year period,6 and those with diabetes and persistent smokers are most at risk. The lifetime amputation risk for all patients with claudication is thought to be around 1%. Despite these clear risks, uptake and delivery of recommended, evidence-based treatment strategies remain problematic.
In the UK, intervention in patients with intermittent claudication is discouraged by NICE unless a patient is thought by local multidisciplinary teams to be symptomatic enough that health-related quality of life (HRQoL) is significantly impacted.7 They must also have made a concerted effort to control any identified risk factors such as smoking and attended a 12-week programme of supervised exercise therapy (if available, see below). Intervention for intermittent claudication is on the increase in other parts of the developed world, particularly as most countries are now practising an endovascular first revascularisation strategy.
Supervised exercise therapy
The aforementioned NICE guidance (Clinical Guideline 147) stipulates that all patients should have any risk factors for PAD addressed as part of secondary prevention (smoking, obesity, hypertension, dyslipidaemia, diabetes) and also be enrolled in a programme of supervised exercise therapy (SET).7 Despite good quality evidence that SET is beneficial26 and cost effective at current willingness to pay thresholds in the UK,27 provision and uptake is low. This may be due to a variety of issues, including lack of funding from healthcare providers, poor patient compliance and an upturning worldwide trend towards increasing use of endovascular treatment, such as angioplasty, drug-eluting technology, atherectomy and stenting.28
The benefits of SET on overall health, even in those undergoing intervention, are clear; a recent systematic review and meta-analyses of seven randomised trials reported improved outcomes in terms of reduced numbers of amputation, increased walking distance and ABPI in patients receiving adjunctive SET with endovascular treatment versus those receiving endovascular treatment alone.29 Despite high quality evidence, only around 30–40% of vascular centres in the UK currently offer SET.30 Regardless of intervention, a regime that improves overall health and treats risk factors to reduce secondary events seems logical and the evidence to support this approach is growing.31
Drug-eluting endovascular technology
Many industry-funded studies have assessed anatomically-based outcomes of patients with intermittent claudication receiving drug-eluting endovascular technology with paclitaxel coated balloons and stents in small, selected groups of claudicants with primarily femoropopliteal disease initially demonstrating promising results.32-35 However, the recent meta-analysis by Katsanos et al.36 has resulted in considerable controversy, demonstrating an increase in mid-term mortality for patients undergoing drug-eluting endovascular treatment when compared with those undergoing plain balloon angioplasty. The impact of this on clinical practice and translation to patients with chronic limb-threatening ischaemia is currently a topic of debate.
Chronic limb-threatening ischaemia
CLTI represents the most severe form of PAD and also carries by far the worst outcomes. The average five-year survival is known to be around 50%. By definition, patients usually present with challenging, multilevel disease that is often above and below the inguinal ligament. Tibial involvement is increasingly common. Despite this, there is still, to date, only one randomised controlled trial comparing revascularisation outcomes in people with CLTI.
The BASIL (Bypass vs. Angioplasty in Severe Ischaemia of the Leg) trial demonstrated that those with a predicted survival of two years or greater fared better in terms of amputation-free survival with open surgical bypass, rather than best endovascular treatment.37 About 75% of patients in BASIL had primarily femoro-popliteal disease. A recent post-hoc, subgroup analysis from the trial of patients with primarily infra-popliteal disease demonstrated a reduction in rest pain but similar clinical outcomes in other domains, when comparing the same two revascularisation options. The trial, however, was not powered to demonstrate significant differences in this subgroup.38
The longstanding debate regarding which revascularisation modality should be used as a first treatment strategy remains – ‘endo-enthusiasts’ claim that if the BASIL trial were to be repeated using modern endovascular technology, the outcomes may be different. Ongoing trials in the US and UK aim to resolve this debate.39–41 A recent, large meta-analysis of around 8,000 patients undergoing infra-inguinal revascularisation demonstrated higher patency rates for patients undergoing vein bypass. The authors commented, however, that a severe lack of high-quality data and heterogeneity made any comparisons difficult.42 There have been recent attempts to improve reporting, assessment and classification of CLTI, and recently, the Global Vascular Guidelines have been published which focus on a new ‘Global Limb Anatomical Staging System’ (GLASS) that aims to improve reporting standards in future trials as well as predicting endovascular treatment failure in patients with CLTI.43–44
The lack of patient and public awareness, high quality randomised data and disparity in treatment algorithms worldwide is concerning, given that PAD is common and has relatively poor outcomes. A significant effort is required on a worldwide scale from clinicians, researchers, health care providers and public health to address these highlighted shortcomings. In particular, more work is needed to clarify the role of therapies in APAD to prevent deterioration, defining best medical treatment for those with symptomatic disease and revascularisation options for those with end-stage PAD, with the hope of improving long-term outcomes both in terms of limb and life.
- There is an impending global epidemic in peripheral artery disease (PAD) due to increasing levels of diabetes, hypertension, smoking and end-stage renal disease
- Such patients have poorer health outcomes than aged-matched populations with other cardiovascular disease
- There is a lack of robust evidence to guide treatment in all forms of PAD that urgently needs addressing
- A global, public health effort is required to boost patient and public awareness and improve health outcomes in patients with PAD
Conflicts of interest
AG has received honoraria from Bayer. MAP, RB and OF: none declared.
Matthew A Popplewell
Academic Clinical Lecturer in Vascular Surgery
Ruth A Benson
Academic Clinical Lecturer in Vascular Surgery
Institute of Translational Medicine,
University of Birmingham, Edgbaston, Birmingham, B15 2TH
ST5 in Vascular Surgery
University Hospital of Coventry and Warwick, Clifford Bridge Road, Coventry, CV2 2DX
Black Country Vascular Service, New Cross Hospital, Wolverhampton, WV10 0QP
Articles in this supplement
Atherosclerotic peripheral artery disease: the growing challenge to improve life and limb
Peripheral artery disease: current diagnosis and management
Combining rivaroxaban with aspirin in stable atherosclerotic vascular disease: clinical evidence from the COMPASS study
1. Fowkes FGR, 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. https://dx.doi.org/10.1016/S0140-6736(13)61249-0
2. Sigvant B, Wiberg-Hedman K, Bergqvist D, et al. A population-based study of peripheral arterial disease prevalence with special focus on critical limb ischemia and sex differences. J Vasc Surg 2007;45:1185–91. https://dx.doi.org/10.1016/j.jvs.2007.02.004
3. Fowkes FGR, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300:197–208. https://dx.doi.org/10.1001/jama.300.2.197
4. Cancer Research UK Cancer Survival Group. Cancer Research UK Survival Statistics. http://www.cancerresearchuk.org/health-professionals/cancer-statistics. Published 2014 (last accessed 29 October 2018).
5. Tang EW, Wong C-K, Herbison P. Global Registry of Acute Coronary Events (GRACE) hospital discharge risk score accurately predicts long-term mortality post acute coronary syndrome. Am Heart J 2007;153:29–35. https://dx.doi.org/10.1016/j.ahj.2006.10.004
6. Sigvant B, Lundin F, Wahlberg E. The risk of disease progression in peripheral arterial disease is higher than expected: a meta-analysis of mortality and disease progression in peripheral arterial disease. Eur J Vasc Endovasc Surg 2016;51:395–403. https://dx.doi.org/10.1016/j.ejvs.2015.10.022
7. National Institute for Health and Care Excellence. Lower limb peripheral arterial disease: diagnosis and management (Clinical Guideline 147). London: NICE, 2012. http://www.nice.org.uk/guidance/CG147
8. McDermott MM, Fried L, Simonsick E, Ling S, Guralnik JM. Asymptomatic peripheral arterial disease is independently associated with impaired lower extremity functioning: the women’s health and aging study. Circulation 2000;101:1007–12.
9. Ogren M, Hedblad B, Engstrom G, Janzon L. Prevalence and prognostic significance of asymptomatic peripheral arterial disease in 68-year-old men with diabetes. Results from the population study “Men born in 1914” from Malmo, Sweden. Eur J Vasc Endovasc Surg 2005;29:182–9. https://doi.org/10.1016/j.ejvs.2004.11.013
10. Fowkes FGR, Price JF, Stewart MCW, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010;303:841–8. https://dx.doi.org/10.1001/jama.2010.221
11. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res 2015;116:1509-1526. https://dx.doi.org/10.1161/CIRCRESAHA.116.303849
12. Guirguis-Blake JM, Evans C V, Redmond N, Lin JS. Screening for peripheral artery disease using the ankle-brachial index: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2018;320:184–96. https://dx.doi.org/10.1001/jama.2018.4250
13. Fowkes FGR, Aboyans V, Fowkes FJI, McDermott MM, Sampson UKA, Criqui MH. Peripheral artery disease: epidemiology and global perspectives. Nat Rev Cardiol 2017;14:156–70. https://dx.doi.org/10.1038/nrcardio.2016.179
14. Sartipy F, Sigvant B, Lundin F, Wahlberg E. Ten year mortality in different peripheral arterial disease stages: a population based observational study on outcome. Eur J Vasc Endovasc Surg 2018;55:529–36. https://dx.doi.org/10.1016/j.ejvs.2018.01.019
15. Sansone R, Busch L, Langhoff R. [Update ESC-Guideline 2017: Focus on PAD]. Dtsch Med Wochenschr 2018;143:1455–9. https://dx.doi.org/10.1055/a-0588-7317
16. 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 2018;391:219–29. https://dx.doi.org/10.1016/S0140-6736(17)32409-1
17. Wallentin L, Becker RC, Budaj A, et al. for the PLATO investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. https://dx.doi.org/10.1056/NEJMoa0904327
18. Hiatt WR, Fowkes FGR, Heizer G, et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med 2017;376:32–40. https://dx.doi.org/10.1056/NEJMoa1611688
19. Soden PA, Zettervall SL, Ultee KHJ, et al. Dual antiplatelet therapy is associated with prolonged survival after lower extremity revascularization. J Vasc Surg 2016;64:1633–44.e1. https://dx.doi.org/10.1016/j.jvs.2016.05.098
20. O’Donnell TFX, Deery SE, Darling JD, et al. Adherence to lipid management guidelines is associated with lower mortality and major adverse limb events in patients undergoing revascularization for chronic limb-threatening ischemia. J Vasc Surg 2017;66:572–8. https://dx.doi.org/10.1016/j.jvs.2017.03.416
21. Diehm C, Allenberg JR, Pittrow D, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009;120:2053–61. https://dx.doi.org/10.1161/CIRCULATIONAHA.109.865600
22. Smith GD, Shipley MJ, Rose G. Intermittent claudication, heart disease risk factors, and mortality. The Whitehall Study. Circulation 1990;82:1925–31.
23. Steg PG, Bhatt DL, Wilson PWF, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197–206. https://dx.doi.org/10.1001/jama.297.11.1197
24. Subherwal S, Patel MR, Kober L, et al. Peripheral artery disease is a coronary heart disease risk equivalent among both men and women: results from a nationwide study. Eur J Prev Cardiol 2015;22:317–25. https://dx.doi.org/10.1177/2047487313519344
25. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304:1350–7. https://dx.doi.org/10.1001/jama.2010.1322
26. Fokkenrood HJP, Bendermacher BLW, Lauret GJ, Willigendael EM, Prins MH, Teijink JAW. Supervised exercise therapy versus non-supervised exercise therapy for intermittent claudication. Cochrane database Syst Rev 2013:CD005263. https://dx.doi.org/10.1002/14651858.CD005263.pub3
27. Bermingham SL, Sparrow K, Mullis R, et al. The cost-effectiveness of supervised exercise for the treatment of intermittent claudication. Eur J Vasc Endovasc Surg 2013;46:707–14. https://dx.doi.org/10.1016/j.ejvs.2013.09.005
28. Popplewell MA, Bradbury AW. Why do health systems not fund supervised exercise programmes for intermittent claudication? Eur J Vasc Endovasc Surg 2014;48:608–10. https://dx.doi.org/10.1016/j.ejvs.2014.07.008
29. Pandey A, Banerjee S, Ngo C, et al. Comparative efficacy of endovascular revascularization versus supervised exercise training in patients with intermittent claudication: Meta-analysis of randomized controlled trials. JACC Cardiovasc Interv 2017;10:712–24. https://dx.doi.org/10.1016/j.jcin.2017.01.027
30. Harwood AE, Smith GE, Broadbent E, Cayton T, Carradice DCI. Access to supervised exercise services for peripheral vascular disease patients: which factors determine the current provision of supervised exercise in the UK. R Coll Surg Bull 2017:207–11. https://dx.doi.org/10.1308/rcsbull.2017.207
31. Hussain MA, Al-Omran M, Mamdani M, et al. Efficacy of a guideline-recommended risk-reduction program to improve cardiovascular and limb outcomes in patients with peripheral arterial disease. JAMA Surg 2016;151:742–50. https://dx.doi.org/10.1001/jamasurg.2016.0415
32. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med 2015;373:145–53. https://dx.doi.org/10.1056/NEJMoa1406235
33. Scheinert D, Duda S, Zeller T, et al. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv 2014;7:10–9. https://dx.doi.org/10.1016/j.jcin.2013.05.022
34. Schneider PA, Laird JR, Tepe G, et al. Treatment effect of drug-coated balloons is durable to 3 years in the femoropopliteal arteries: long-term results of the IN.PACT SFA randomized trial. Circ Cardiovasc Interv 2018;11:e005891. https://dx.doi.org/10.1161/CIRCINTERVENTIONS.117.005891
35. Dake MD, Ansel GM, Jaff MR, et al. Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial. Circulation 2016;133:1472–83; discussion 1483. https://dx.doi.org/10.1161/CIRCULATIONAHA.115.016900
36. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2018;7(24):e011245. https://dx.doi.org/10.1161/JAHA.118.011245
37. Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005;366:1925–34. https://dx.doi.org/10.1016/S0140-6736(05)67704-5
38. Popplewell MA, Davies HOB, Narayanswami J, et al. A comparison of outcomes in patients with infrapopliteal disease randomised to vein bypass or plain balloon angioplasty in the bypass vs. angioplasty in severe ischaemia of the leg (BASIL) trial. Eur J Vasc Endovasc Surg 2017;54:195–201. https://dx.doi.org/10.1016/j.ejvs.2017.04.020
39. Popplewell MA, Davies H, Jarrett H, et al. Bypass versus angioplasty in severe ischaemia of the leg – 2 (BASIL-2) trial: study protocol for a randomised controlled trial. Trials 2016;17:11. https://dx.doi.org/10.1186/s13063-015-1114-2
40. Hunt BD, Popplewell MA, Davies H, et al. Balloon versus stenting in severe ischaemia of the leg-3 (BASIL-3): study protocol for a randomised controlled trial. Trials 2017;18:224. https://dx.doi.org/10.1186/s13063-017-1968-6
41. Menard MT, Farber A, Assmann SF, et al. Design and rationale of the best endovascular versus best surgical therapy for patients with critical limb ischemia (BEST-CLI) trial. JAMA 2016;5:pii: e003219. https://dx.doi.org/10.1161/JAHA.116.003219
42. Almasri J, Adusumalli J, Asi N, et al. A systematic review and meta-analysis of revascularization outcomes of infrainguinal chronic limb-threatening ischemia. J Vasc Surg 2018;68:624–33. https://dx.doi.org/10.1016/j.jvs.2018.01.066
43. Conte MS, Bradbury AW, Kolh P, et al. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. Eur J Vasc Endovasc Surg 2019;58(1S):S1-S109.e33. https://dx.doi.org/10.1016/j.ejvs.2019.05.006
44. Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg 2019;69(6):3S-125S.e40. https://dx.doi.org/10.1016/j.jvs.2019.02.016
Notes on dosing recommendations from Xarelto® ▼ (rivaroxaban) SmPC (Summary of Product Characteristics)
Xarelto 2.5 mg twice daily, coadministered with a daily dose of 75–100 mg aspirin, is indicated for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events.
The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial discussed in this supplement compared both Xarelto 2.5 mg twice-daily plus aspirin and also Xarelto 5 mg twice-daily without aspirin, versus aspirin alone. Results for both comparisons are provided reflecting the original study publication.
Please note, however, that Xarelto 5 mg twice-daily is not a licensed dosage regimen for the above, nor for any other therapeutic indication.