Horizon Scanning Research July 2016 & Intelligence Centre
Ticagrelor (Brilique) for peripheral arterial disease
LAY SUMMARY
Peripheral arterial disease is a common condition in which a build-up of fatty deposit in the arteries (atherosclerosis) restricts blood supply to leg muscles. Many people with peripheral arterial disease have no symptoms. However, some people develop a painful ache in their legs when they walk, which usually disappears after a few minutes’ rest. This briefing is While peripheral arterial disease is not life-threatening, the process of based on atherosclerosis that causes it can lead to serious and potentially fatal information available at the time problems, such as heart attacks and stroke. of research and a limited literature Ticagrelor is a drug that can reduce blood clotting. It is given as a search. It is not tablet twice a day. If ticagrelor is licensed for use in the UK, it could be intended to be a a new treatment option for patients with peripheral arterial disease that definitive statement may reduce the complications of atherosclerosis. on the safety, efficacy or effectiveness of the NIHR HSRIC ID: 8065 health technology covered and should not be used for commercial purposes or commissioning without additional information.
This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.
NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre
TARGET GROUP
• Peripheral arterial disease: patients with established disease - to reduce cardiovascular death, myocardial infarction and ischaemic stroke.
TECHNOLOGY
DESCRIPTION
Ticagrelor (Brilique; AZD-6140; AR-C124910XX) is a member of the chemical class cyclopentyltriazolopyrimidines, and is an oral, direct acting, selective and reversibly binding purinoreceptor P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP) 1 mediated P2Y12 dependent platelet activation and aggregation . Ticagrelor does not prevent ADP binding but when bound to the P2Y12 receptor, prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of cardiovascular events such as death, myocardial infarction or stroke1. Ticagrelor is administered at 90mg orally twice dailya.
Ticagrelor is already marketed in the UK for the prevention of atherothrombotic events in adult patients with acute coronary syndromes and patients with a history of myocardial infarction who are at high risk of developing an atherothrombotic event1. Very common and common (≥1%) reported adverse events include blood disorder bleedings, hyperuricaemia, dyspnoea, gout, dizziness, syncope, headache, vertigo, hypotension, respiratory system bleedings, gastrointestinal haemorrhage, diarrhoea, nausea, dyspepsia, constipation, dermal bleeding, rash, pruritus, urinary tract bleeding, increased blood creatinine, post procedural haemorrhage and traumatic bleeding1.
Ticagrelor is currently in phase III trials for cerebral ischaemia. Ticagrelor is also in phase II trials for thrombosis.
INNOVATION and/or ADVANTAGES
If licensed, ticagrelor will offer an additional treatment option for patients with peripheral arterial disease that may reduce their risk of serious cardiovascular events.
DEVELOPER
AstraZeneca UK.
AVAILABILITY, LAUNCH OR MARKETING
Phase III clinical trials.
PATIENT GROUP
BACKGROUND
a Company provided information.
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Peripheral arterial disease (PAD) is usually caused by atherosclerosis that leads to stenosis and occlusion of non-cerebral and non-coronary arteries2,3. PAD can cause discomfort or pain in the lower legs when walking, known as intermittent claudication2. Although many never experience symptoms, 7-15% of people with asymptomatic PAD will develop intermittent claudication within five years. Of those who do develop claudication, 20-25% are likely to experience further clinical deterioration3. Critical limb ischaemia is a severe manifestation of PAD, and is characterised by severely diminished circulation, ischaemic pain, ulceration, tissue loss and/or gangrene4. Major amputation is rare (other than in patients with diabetes); only 1-3% of patients with intermittent claudication will require major amputation in a five year period3. While the most common cause for PAD is atherosclerosis, other possible causes include vasculitis, cystic adventitial disease and popliteal entrapment2.
The development of atherosclerotic PAD is a multifactorial process involving both modifiable and non-modifiable risk factors, such as smoking, diabetes, hypertension, hyperlipidaemia, age and an increased risk is observed in those from Black ethnic groups3. About 65% of patients of PAD also have clinically relevant cerebral or coronary artery disease, and a large prospective cohort study showed that patients with PAD have a six-fold higher risk of death from cardiovascular disease than those without PAD3.
CLINICAL NEED and BURDEN OF DISEASE
In the general population, up to 10% of people younger than 70 years and 15% to 20% of people older than 70 years have PAD2. Symptomatic and asymptomatic PAD has an estimated prevalence of 13% in the over 50 years age group2. However, asymptomatic PAD can account for up to 75% of cases and only 10% of patients will have symptoms of typical intermittent claudication2. Population studies have shown that about 20% of people aged over 60 years have some degree of PAD4.
In 2012, there were 2,307,306 people aged 60 years or over diagnosed with PAD, with 576,826 of these displaying symptoms of intermittent claudication4. In 2012, there were 115,365 patients with intermittent claudication who are at risk developing critical leg ischaemia4.
For those with established critical limb ischaemia the prognosis is poor. About 12% of such patients require amputation within three months of presentation and 20-25% die within a year3. The estimated five year survival rate for patients with critical limb ischaemia is 50- 60%, and these patients require urgent referral for specialist evaluation3. Each year, 500- 1,000 new cases of critical limb ischaemia are diagnosed per million population, with an estimated annual cost to the NHS of more than £200million3.
PATIENT PATHWAY
RELEVANT GUIDANCE
NICE Guidance
• NICE technology appraisal in development. Cardiovascular events (reducing, high risk) – ticagrelor (ID813). Expected December 2016. • NICE technology appraisal. Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease (TA223). May 2011. • NICE technology appraisal. Ticagrelor for the treatment of acute coronary syndromes (TA236). October 2011.
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• NICE guidelines. Peripheral arterial disease: diagnosis and management (CG147). August 2012. • NICE quality standard. Peripheral arterial disease (QS52). January 2014. • NICE interventional procedure guidance. Angioplasty and stenting to treat peripheral arterial disease causing refractory erectile dysfunction (IPG546). February 2016. • NICE interventional procedure guidance. Percutaneous laser atherectomy as an adjunct to balloon angioplasty (with or without stenting) for peripheral arterial disease (IPG433). November 2012. • NICE advice. Symptoms of peripheral arterial disease: Ramipril (ESUOM45). June 2015.
NHS England Policies and Guidance
• NHS England. 2013/14 NHS Standard Contract for Specialised Vascular Services (Adults). A04/S/a.
Other Guidance
• American College of Cardiology. Management of Patients with Peripheral Artery Disease. 20135. • American Family Physician. Diagnosis and Treatment of Peripheral Arterial Disease. 20136. • The British Medical Journal. Diagnosis and Management of Peripheral Arterial Disease. 20123. • European Society of Cardiology. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases. 20117. • Scottish Intercollegiate Guidelines Network. Diagnosis and management of peripheral arterial disease (SIGN89). 20068.
CURRENT TREATMENT OPTIONS
The starting point for managing PAD involves risk factor modification. Support and treatment are offered to reduce the risk of life threatening cardiovascular events and prevent progression of disease. This may include smoking cessation, controlling diabetes, improving diet, reducing body weight, increasing exercise, lipid modification and statin therapy, management of high blood pressure, and antiplatelet therapy3,4.
If the symptoms of PAD progress to intermittent claudication, treatment options include3,4: • Supervised exercise programme. • Angioplasty and stenting – if approach to modifying risk factors and exercise have not reduced symptoms. • Bypass surgery – if angioplasty has been unsuccessful or is unsuitable. • Vasoactive drugs - naftidrofuryl oxalate (NICE recommended) or cilostazol (not NICE recommended).
Management of critical limb ischaemia includes3,4: • Management of pain – paracetamol or opioids depending on severity. • Revascularisation. • Major amputation. • Non-surgical treatment options such as prostanoids, spinal cord stimulation and lumbar sympathectomy; however these have shown little long term benefit.
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EFFICACY and SAFETY
Trial NCT01732822, D5135c0001, 2011-004616-36; ticagrelor vs clopidogrel; phase III. Sponsor AstraZeneca. Status Ongoing. Source of Trial registry9. information Location EU (incl UK), USA, Canada and other countries. Design Randomised, active-controlled. Participants n=13,500 (planned); aged 50 yrs and older; symptomatic peripheral artery disease; no dual anti-platelet drug treatment before day 1; no planned revascularisation or amputation; no patients with known bleeding disorders; no history of intracranial bleed; no patients to be at risk of bradycardic events unless already treated with a permanent pacemaker. Schedule Randomised to ticagrelor 90mg oral twice daily in combination with clopidogrel placebo taken once daily; or clopidogrel 75mg oral once daily in combination with ticagrelor placebo taken twice daily. Follow-up Duration of treatment is event-driven; all patients will remain on treatment until a pre- defined number of events have been reached. Follow-up every 6 mths until end of study. Primary Time from randomisation to first occurrence of any of the following events: outcomes haemorrhagic stroke, acute lung injury, any revascularisation and all-cause mortality. Secondary Time from randomisation to first occurrence of any event in the composite of outcomes cardiovascular death, myocardial infarction and ischaemic stroke. No quality of life measurement included in trial outcomes. Expected Study completion date reported as Aug 2016. reporting date
ESTIMATED COST and IMPACT
COST
Ticagrelor is already marketed in the UK for the prevention of atherothrombotic events; a pack of 56 x 90mg tablets costs £54.6010.
IMPACT - SPECULATIVE
Impact on Patients and Carers
Reduced mortality/increased length of survival Reduced symptoms or disability
Other No impact identified
Impact on Health and Social Care Services
Increased use of existing services Decreased use of existing services
Re-organisation of existing services Need for new services
Other None identified
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Impact on Costs and Other Resource Use
Increased drug treatment costs Reduced drug treatment costs
Other increase in costs Other reduction in costs
Other None identified
Other Issues
Clinical uncertainty or other research question None identified identified
REFERENCES
1 electronic Medicines Compendium (eMC).Brilique 60 mg and 90 mg film coated tablets. www.medicines.org.uk/emc/medicine/23935 Accessed 21 July 2016. 2 Andras A and Ferket B. Screening for peripheral arterial disease. Cochrane Database of Systematic Reviews 2014; DOI:10.1002/14651858.CD010835.pub2. 3 Peah G, Griffin M, Jones KG et al. Diagnosis and management of peripheral arterial disease. The British Medical Journal 2012; 345:e5208. 4 National Institute for Health and Clinical Excellence. Peripheral arterial disease: diagnosis and management. Clinical Guideline CG147. London: NICE; August 2012. 5 Anderson J, Halperin J, Albert N et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations. Journal of the American College of Cardiology 2013; 61(14):1555-1570. 6 Hennion D and Siano K. Diagnosis and treatment of peripheral artery disease. American Family Physician 2013; 88(5):306-310. 7 Tendera M, Aboyans V, Bertelink ML et al. ESC guidelines on the diagnosis and treatment of peripheral artery disease. European Heart Journal 2011; 32:2851-2906. 8 Scottish Intercollegiate Guidelines Network. Diagnosis and management of peripheral arterial disease. National clinical guideline 89. Edinburgh: SIGN; October 2006. 9 ClinicalTrials.gov. A study comparing cardiovascular effects of ticagrelor and clopidogrel in patients with peripheral artery disease (EUCLID). www.clinicaltrials.gov/ct2/show/NCT01732822 Accessed 21 July 2016. 10 Joint Formulary Committee. British National Formulary. BNF July 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com
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