peripheral arterial disease (pad) - · pdf fileauspharm cpd peripheral arterial disease (pad)...

AusPharm CPD Peripheral Arterial Disease (PAD) Published 1/05/2014

AusPharmacist.net.au – pharmacy’s home page This CPD is online at: www.auspharmacist.net.au/continuinged.php?article=194

Learning objectives: After completing this activity, pharmacists should be able to: • Describe the risk factors and epidemiology of Peripheral Arterial Disease • Identify patients presenting in the pharmacy with symptoms suggestive of Peripheral Arterial

Disease • Recognise opportunities to optimise management of Cardiovascular Disease risk factors in

Peripheral Arterial Disease.

Peripheral Arterial Disease (PAD)

Ask a health professional or a patient about cardiovascular disease (CVD) and what will usually spring to their mind? Invariably it will be coronary heart or cerebrovascular disease in some shape or form, rarely will it be peripheral arterial disease (PAD). Nonetheless, PAD is a common condition that significantly reduces the quality of life for many of those it affects and it remains one of the most common reasons that patients undergo lower limb amputation. With an underlying pathophysiology that has much in common with its coronary and cerebrovascular cousins, appropriate recognition and management of PAD can bring significant benefits in terms of morbidity and mortality.

This activity has been accredited for 1 hour of Group One CPD (1 CPD Credit) that may be converted to 2 Group Two CPD Credits upon successful completion of the corresponding assessment for inclusion on an individual pharmacist's CPD Record. Accreditation number: A1404AP1. The competency standards addressed by this activity include (but may not be limited to) 4.2.2, 4.2.3, 7.1.2, 7.1.3, 7.2.2, 7.2.3. Author: Angus Thompson. BPharm (Hons), MSc (ClinPharm), PostGradDipMRPharmS

Angus graduated from the School of Pharmacy at Bath University in the UK in 1989 and undertook pre-registration training in the South Warwickshire Hospitals. He then worked for three years as a Pharmacist at Dorset County Hospital during which time he completed his MSc in Clinical Pharmacy at Portsmouth University with a thesis looking at Antimicrobial Prescribing. In 1993 he took up a new role as Pharmacy Manager at the BMI Droitwich Private Hospital, where he became involved in oncology and was a member of the Drug Purchasing group for BMI. Six years later, saw a move back to the South-West of England and appointment as the Pharmaceutical Advisor to South Somerset Primary Care Group/Trust (PCT), with responsibilities including provision of advice on evidence-based and cost-effective prescribing to GPs; it was during this time that he completed his Prescribing Sciences diploma at Liverpool University. In 2002, he moved to develop a portfolio career which included PCT work, project management, pharmaceutical writing, community pharmacy locums; and education and training for nurses, GP trainees and pharmaceutical industry personnel. Angus’s publications have appeared in the Pharmaceutical Journal, Prescriber and Independent Nurse and include research into patient satisfaction with medication changes. He moved from the UK to Tasmania with his family and joined UMORE (Unit for Medication Outcomes Research and Education, University of Tasmania) in July 2008. Angus Thompson is Lecturer in Therapeutics and Pharmacy Practice at the School of Pharmacy, University of Tasmania, Hobart and practising Home Medicines Review and hospital pharmacist.

AusPharm gratefully acknowledges the financial support provided by the sponsors of our CE program, MIMS



Peripheral Arterial Disease (PAD) Ask a health professional or a patient about cardiovascular disease (CVD) and what will usually spring to their mind? Invariably it will be coronary heart or cerebrovascular disease in some shape or form, rarely will it be peripheral arterial disease (PAD). Nonetheless, PAD is a common condition that significantly reduces the quality of life for many of those it affects and it remains one of the most common reasons that patients undergo lower limb amputation. With an underlying pathophysiology that has much in common with its coronary and cerebrovascular cousins, appropriate recognition and management of PAD can bring significant benefits in terms of morbidity and mortality.

Prevalence, pathophysiology and risk factors

In the general population the prevalence of PAD is between 3 and 7%,1 but this increases with age, such that around 20% of those aged over 60 years have the condition.2 Around half of all people with PAD are asymptomatic, but between 5 and 10% of asymptomatic individuals will progress and develop symptoms over a 5 year period.3 Peripheral arterial disease is a manifestation of arterial atherosclerosis and it is for this reason that the term peripheral vascular disease is no longer routinely used to describe the condition. The most common vessels affected in PAD include the aorta, superficial femoral and iliac arteries. The risk factors for the development of PAD are common to those other sequelae of arterial atherosclerosis; coronary and cerebrovascular disease, and may be described as modifiable or non-modifiable, as summarised in Figure 1.

Figure 1. Risk factors for Peripheral Arterial Disease (adapted from references 4 and 5)

Modifiable risk factors Non-modifiable risk factors

Cigarette smoking

Diabetes mellitus

Hypertension

Dyslipidaemia

Hyperhomocysteinaemia

Increasing age

Male gender

Non-caucasian race

It is therefore not surprising that there is a significant overlap in the various manifestations of arterial atherosclerosis and data to support this comes from the CAPRIE trial which recruited a range of patients with atherosclerotic disease.6 Of those patients enrolled in this study, PAD symptoms alone were present in 19.2%, symptomatic PAD and coronary arterial disease co-existed in a further 11.9%, symptomatic PAD and cerebrovascular disease in 3.8%, and symptoms of all three manifestations in 3.3%.6 Although mortality may result from PAD directly, coronary artery disease accounts for around 75% of deaths in those with PAD. Consistent with this, there is also a high rate of non-fatal myocardial infarction and stroke in the PAD population, of around 20%.5



Signs and symptoms

The most common manifestation of PAD is intermittent claudication (IC), which has been defined as “leg-muscle discomfort on exertion that is relieved by rest“.7 The exact site of PAD symptoms within the lower limb varies, but may include any of the foot, calf, thigh, hip or buttock.7 The site reflects the arteries affected by the atherosclerosis, for example calf pain is invariably a consequence of superficial femoral disease. The discomfort usually involves pain, typically a cramping or aching pain, but may be otherwise described as tightness or tiredness. Symptoms occur in response to muscular oxygen demand exceeding supply as a result of the narrowed arterial lumen and consequently develop in response to exercise involving the legs, most commonly walking. Rest produces rapid relief of symptoms, as oxygen supply is once again able to meet demand. People with PAD typically know the level of exertion that they can undertake without symptoms, for example walking a certain distance, or experience pain when walking uphill, but not when making the same journey on the flat or downhill. The legs affected by PAD tend to be pale, cool to touch and pulses may be absent or weak; other signs may be poor hair growth or toenail growth. Many older people with PAD may ignore symptoms, thinking that they may reflect other causes of musculo-skeletal pain, which highlights the importance of professionals specifically asking about the signs and symptoms of PAD.1 This is particularly pertinent in those with CVD risk factors or who already have other manifestations of atherosclerotic disease.

Very occasionally people may present with PAD symptoms affecting the arms. In advanced cases, the degree of ischaemia can be severe and patients may develop critical limb ischaemia. This is characterised by significant impairment of perfusion, patients may have pain at rest and ulceration or gangrene of the toes or feet may develop. Given the prevalence of PAD amongst those with diabetes, it is important to recognise that peripheral neuropathy may compromise the person’s ability to sense the pain associated with such problems and highlights the importance of foot care in this population.

Diagnosis

The typical presenting features of someone with PAD are often sufficient for clinicians to establish a diagnosis with reasonable certainty, however confirmation may be provided by undertaking Ankle-Brachial Pressure Index (ABPI) testing.8 This non-invasive technique uses a sphygmomanometer and a Doppler probe to enable a comparison of the blood pressure in the ankle to the pressure in the arm. The proportional difference between the two readings correlates with the severity of vessel occlusion and can be used to grade PAD, as summarised in Figure 2. ABPI Testing may be undertaken in general practice, in hospital clinics or by podiatrists as part of routine care for example for those with diabetes.



Figure 2. Ankle-Brachial Pressure Index Testing and Severity of PAD7

Ankle-Brachial Pressure Index Significance

Above 0.90 Normal

0.71 – 0.90 Mild obstruction

0.41-0.70 Moderate obstruction

≤ 0.40 Severe obstruction

In some cases, where ABPI testing does not support the provisional clinical diagnosis of PAD, it may be appropriate to repeat ABPI testing after exercise, for example after repeated toe raises or a treadmill.7 Other tools which may be used in diagnosis include duplex ultrasound and angiography. There is interest in whether biomarkers may play a useful role in helping predict those at greatest risk of adverse outcomes, especially amongst those with more severe disease. One of these markers is cardiac Troponin T (cTnT) and recent research reported an association between elevated cTnT levels and amputation, as well as the risk of myocardial infarction and overall mortality.9

Management

There are three main components to the management of PAD:

• cardiovascular risk factor management • symptom management • management of severe disease

Risk Factor Management The aim of risk factor management is to reduce the progression of atherosclerotic disease, within the peripheral arteries themselves, together with the coronary and cerebral vessels. The importance of this is starkly highlighted by the fact that coronary artery disease is the major cause of death in people with PAD. In common with other forms of clinically evident atherosclerotic disease, people with PAD should be managed in line with the principles of secondary prevention. The fact that they have manifest disease is considered to place them automatically at increased risk of progression of CVD and adverse CV outcomes. For that reason, assessment of absolute cardiovascular risk, using tools such as that developed by the National Vascular Disease Prevention Alliance (NVDPA) is not appropriate for people with PAD.

Two interventions are routinely recommended, a statin and antiplatelet therapy. Statins are indicated for all patients with PAD, irrespective of lipid levels. In general, the aim should be to use a statin regimen that has been shown to deliver improved cardiovascular outcomes for patients,10 or another statin of at least equivalent potency. Examples of such regimens would include simvastatin 40mg/day, atorvastatin 20mg/day or rosuvastatin 5-10mg/day. In the event that a patient is intolerant to the initial statin



prescribed, it may be reasonable to try switching to one of the alternative statins, given the variation in tolerability between the different options. A recently published study found that as well as the established rationale of reducing overall CVD risk, statins may have specific benefits for those with PAD. Kumbhani et al found that amongst those PAD patients on a statin, there was an 18% lower rate of adverse limb outcomes, including worsening symptoms, peripheral revascularisation and ischaemic amputations.11 Given this finding, it remains a concern that use of statins in people with PAD remains sub-optimal and significant opportunities remain to improve adherence and persistence.12 The data supporting ezetimibe or fibrates remains less robust and as such these should be seen as second line options for those patients who are genuinely unable to tolerate statins; or in the case of fibrates, where there is a mixed dyslipidaemia. Antiplatelet therapy is similarly recommended as routine for those with PAD, having been found to reduce all-cause mortality and CVD mortality specifically in this population.13 Although the CAPRIE trial showed that clopidogrel was slightly more effective than aspirin in those affected by PAD,6 aspirin 100mg/day remains the standard antiplatelet agent used in those with the condition, largely based on the significantly lower cost. In common with other indications for aspirin, many patients may gravitate towards enteric coated (EC) preparations, based upon on a perception of improved gastrointestinal safety. However, research suggests that EC aspirin is no safer and that it may have a diminished antiplatelet effect.14,15,16 Standard aspirin 100mg tablets should therefore be seen as the most appropriate first line option. For those with dyspepsia, but no red flags regarding gastrointestinal bleeding, EC aspirin may be a reasonable second line option, especially if the dyspepsia threatens adherence and persistence. Where there is genuine aspirin hypersensitivity, clopidogrel would be the most appropriate option, however it should be noted that unless the patient has a history of prior acute coronary or cerebral ischaemic event, this is not a PBS indication.

Controlling elevated blood pressure (BP) and hyperglycaemia are also important for people with PAD. Although Australian national guidelines recommend a BP target of < 130/80 mmHg for many patients with end organ damage, there is a lack of evidence to specifically support this target in those with PAD and as such it may be reasonable to aim for the more general target of <140/90 mmHg.17 In the absence of other co-morbidities, the choice of drug(s) used to achieve blood pressure control in people with PAD is probably of less importance than attainment of control itself. However, based on the findings of the HOPE study, there is good evidence that an angiotensin converting enzyme inhibitor such as ramipril, can be beneficial in those with PAD.18 It should however be noted that renal artery stenosis may have a significant prevalence amongst those with peripheral arterial disease.19 Consequently caution is warranted with ACE inhibitor therapy in PAD and closer renal function monitoring may be indicated. The presence of PAD may increase the likelihood of inconsistent BP readings between the right and left arms. For that reason it is important that initial assessment involves measurement in both arms, after which the arm with the highest pressure should be the one that continues to be used for monitoring. Whilst control of hyperglycaemia amongst those with diabetes may have a particularly beneficial effect on microvascular disease, there is also a compelling need to maintain good control of glycaemia as part of peripheral arterial disease management. It is important that glycaemic control targets should be individualised, for example an HbA1c target of < 7% (53mmol/mol) may be appropriate for a younger patient, whereas a more relaxed target of < 8% (64mmol/mol) might be more desirable for an older person, especially one with multiple comorbidities.



Although elevated homocysteine levels are a risk factor for the development of PAD, drug therapy to address this e.g. with folic acid, is not recommended as it has not been shown to be beneficial.5 Lifestyle modification plays an important role in the management of CVD risk in those with PAD. A number of these interventions also have an impact on symptoms and are discussed further below.

Symptomatic management Intermittent claudication can have a significant impact on the quality of life and activities of daily living for those affected. For this reason, people with symptoms are likely to seek the opinion of a health professional. Whilst discussing symptom management, pharmacists have a good opportunity to highlight the importance of seeking medical advice for investigation and a more holistic approach to management that also addresses risk factor management, as discussed above.

The first line approaches to help with the symptoms of PAD are non-pharmacological. Evidence shows that exercise can improve walking distance by 150% compared to usual care and that supervised exercise is more effective than non-supervised exercise.20,21 Consequently, guidelines recommend that exercise should be provided as a structured supervised programme for two hours each week for three months, with encouragement to exercise to the point of maximal pain.2 Such programmes if maintained also have the advantage of promoting the maintenance of a healthier weight and so also can impact on CVD risk. Cessation of smoking may also lead to an increase in walking distance, as well as reducing overall CVD risk and should be strongly encouraged. Pharmacists are ideally placed to offer advice and support for those who are considering quitting or who have already done so and may be at risk of relapse. Peripheral vasodilators have only a limited role to improve circulation and symptoms, but may be considered as an adjunct to non-pharmacological therapy and CVD risk management. Of the drugs available, cilostazol at a dose of 100mg twice daily has the highest level of evidence to support its use in PAD, having been shown to improve walking distance by around 50% compared to placebo.22 A significant limitation on the utility of this drug is the lack of a PBS subsidy which puts it out of the financial reach of many Australians. Where cilostazol is being considered, it is important to recognise that it is contra-indicated in those with heart failure or a recent acute coronary event. In addition to which, cilostazol is a substrate for the cytochrome P-450 system and a dose reduction (to 50mg twice daily) is recommended when inhibitors of CYP3A4 (e.g. azole antifungals, clarithromycin, diltiazem, verapamil, protease inhibitors) or CYP2C19 (e.g. azole antifungals, fluvoxamine, omeprazole) have to be co-prescribed. The only other peripheral vasodilator marketed in Australia for relief of claudication symptoms is oxpentifylline. This has more modest effects on exercise tolerance and walking distance, but may be used alongside exercise therapy.5 Where it is used, the standard dose is 400mg three times a day, but again, reflecting the modest beneficial effects it is not PBS listed. Overseas, other agents such as naftidrofuryl are recommended by some guidelines as a therapeutic option in some cases,2 but this drug is not TGA approved in Australia. Preparations of Ginkgo Biloba have also been reported to have a modest effect on walking distance in those with PAD, but trial data does not support this as an effective therapy.24



Management of Severe Disease

Patients with severe PAD are the most likely to require procedural interventions. For those who remain highly symptomatic despite non-pharmacological and pharmacological therapy, revascularisation procedures such as angioplasty, stenting or bypass surgery may be undertaken electively. In the most severe cases, the degree of ischaemia can be profound, with severe pain even at rest, sensory and/or motor nerve dysfunction, ulceration and gangrene. Revascularisation procedures can play an important role in management of these, but in the most extreme cases salvage of the limb may not be possible and amputation may need to be considered as the most appropriate way to limit further complications such as infection and pain.

Conclusion

Whilst symptom management is often seen as the priority by patients, it is important to recognise that PAD may act as a sentinel for the presence of clinically sub-evident coronary or cerebrovascular disease. A diagnosis of PAD should be seen as an opportunity to address a range of cardiovascular risk factors through a combination of pharmacotherapy and lifestyle modification, as doing so can have a valuable impact on morbidity and mortality.



References 1. Leyden J, Michaels J, Birmingham S et al Diagnosis and management of lower limb peripheral arterial disease: summary of NICE guidance. BMJ 2012; 345: e4947 2. Anon. NICE Clinical Guideline 147: Lower limb peripheral arterial disease: diagnosis and management National Institute for Health and Clinical Excellence, London, UK, 2012 3. Hankey GJ, Norman PE and Eikelboom JW Medical Treatment of Peripheral Arterial Disease JAMA 2006; 295: 547-553 4. Ouriel K Peripheral arterial disease Lancet 2001; 358: 1257-1264 5. Cardiovascular Expert Groups Therapeutic guidelines: cardiovascular (Version 6) Melbourne: Therapeutic Guidelines Limited; 2012. 6. CAPRIE steering committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) Lancet 1996; 348: 1329-1339 7. White C Intermittent Claudication N Engl J med 2007; 356:1241-1250 8. Grenon SM, Gagnon J and Hsaing Y Ankle-Brachial Index for Assessment of Peripheral Arterial Disease N Engl J Med 2009; 361: e40 9. Linnemann B, Sutter T, Herrmann E et al Elevated Cardiac Troponin T is Associated with Higher Mortality and Amputation Rates in Patients with Peripheral Arterial Disease. J Am Coll Cardiol 2013; In-Press: Available online 21 June 2013 10. Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo controlled trial Lancet 2002; 360(9326): 7 – 22 11. Kumbhani DJ, Steg G, Cannon CP et al on behalf of the REACH Registry Investigators Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry European Heart Journal 2014, Advance access published on-line February 28 2014



12. Kumbhani DJ, Steg PG, Cannon CP et al Adherence to Secondary Prevention Medications and Four-year outcomes in Outpatients with Atherosclerosis The American Journal of Medicine 2013; 126: 693-700 13. Wong PF, Ching L-Y and Stansby G Antiplatelet Therapy to Prevent Cardiovascular Events and Mortality in Patients with Intermittent Claudication JAMA 2013; 309(9): 926-927 14. Kelly JP, Kaufman DW, Jurgelon JM et al Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product Lancet 1996; 348(9039): 1413-1416 15. Cox D, Maree AO, Dooley M et al Effect of Enteric Coating on Antiplatelet Activity of Low-Dose Aspirin Stroke 2006; 37: 2153-2158 16. Maree AO, Curtin RJ, Dooley M et al Platelet Response to Low-Dose Enteric-Coated Aspirin in Patients with Stable Cardiovascular Disease J Am Coll Cardiol 2005; 46(7): 1258-1263 17. National Blood Pressure and Vascular Disease Advisory Committee Guide to management of hypertension National Heart Foundation of Australia 2008 (updated 2010) 18. The Heart Outcomes Prevention Evaluation Study Investigators Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients N Engl J Med 2000, 342(3); 145-153 19. Watchell K, Ibsen H, Olsen MH et al Prevalence of renal artery stenosis in patients with peripheral vascular disease and hypertension. J Hum Hypertens. 1996 Feb;10(2):83-5. 20. Leng GC, Fowler B and Ernst E Exercise for intermittent claudication Cochrane Database Systematic Review 2000; 2: CD000990 21. Bendermacher BL, Willigendael EM, Teijink JA et al Supervised exercise therapy versus non-supervised exercise therapy for intermittent claudication. Cochrane Database Systematic Review 2006; 2: CD005263 22. Strandness DE, Dalman RL, Panian S et al Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study Vasc Endovascular Surg 2002; 36: 83-91 23. Gardner CD, Taylor-Piliae RE, Kiazand A et al Effect of Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral artery disease: a randomized clinical trial. J Cardiopulm Rehabil Prev 2008; 28(4): 258-65



MCQs Questions based on this article:

Select ONE alternative that best represents the correct answer to each of the following multiple choice questions (only one answer per question is correct)

Q1. Which ONE of the following would be regarded as a first line antiplatelet regimen for a person affected by PAD?

a) Aspirin/dipyridamole MR capsules 25/200mg twice daily b) Aspirin tablets 100mg daily a) Clopidogrel tablets 75mg daily b) Ticagrelor tablets 90mg twice daily c) Aspirin/clopidogrel tablets 100/75mg daily

Q2. Jim is a 65 year old man with diabetes and PAD. His GP has been proactive in managing his CVD risk factors and Jim has been taking atorvastatin 20mg daily for a month. For the last fortnight Jim has been complaining of non-specific muscle pain/weakness and his GP suspects this is statin related, as it has settled on cessation of the atorvastatin. Which ONE of the following would be the most appropriate response to this situation?

c) Record Jim as intolerant to statins and focus on management of other risk factors d) Commence ezetimibe 10mg daily e) Commence fish oil 4g daily f) Commence pravastatin 10mg daily g) Commence rosuvastatin 5mg daily

Q3. What is a reasonable blood pressure target for a person who has co-existing hypertension alongside PAD? a) <150/90 mmHg b) <140/90 mmHg a) <130/80 mmHg b) <125/75 mmHg c) <120/70 mmHg

Q4. The role of ankle brachial pressure index testing is… c) In the diagnosis of PAD only d) In the severity assessment of PAD only a) In both the diagnosis and severity assessment of PAD e) In determining which PAD patients require antihypertensive therapy f) In determining which PAD patients require foot amputation

Q5. Pharmacological management of which ONE of the following risk factors for PAD has NOT been shown to be beneficial?

b) Hypertension c) Dyslipidaemia d) Diabetes e) Smoking f) Hyperhomocysteinaemia

peripheral arterial disease (pad) - · pdf fileauspharm cpd peripheral arterial disease (pad)...

Documents