Chapter iii: management of cardiovascular risk factors and medical therapy

European Journal of Vascular and Endovascular Surgery (2011) 42(S2), S33–S42 Chapter III: Management of CardiovascularRisk Factors and Medical Therapy N. Diehma,*,‡, J. Schmidlib,‡, C. Setaccic, J.-B. Riccod, G. de Donatoe,F. Beckerf, H. Robert-Ebadif, P. Caog, H.H. Ecksteinh, P. De Rangoi,M. Teraab,j, F.L. Mollj, F. Dickb, A.H. Daviesk, M. Lep¨ a Clinical and Interventional Angiology, Swiss Cardiovascular Centre, University Hospital Berne, Switzerlandb Department of Cardiovascular Surgery, Swiss Cardiovascular Centre, University Hospital Berne, Switzerlandc Department of Surgery, Unit of Vascular and Endovascular Surgery, University of Siena, Italyd Department of Vascular Surgery, University Hospital of Poitiers, Poitiers, Francee Department of Vascular Surgery, University Medical Center Utrecht, The Netherlandsf Division of Angiology and Hemostasis, Geneva University Hospitals, Geneva, Switzerlandg Unit of Vascular Surgery, Department of Cardiosciences, Hospital S. Camillo-Forlanini, Rome, Italyh Clinic for Vascular Surgery, Klinikum rechts der Isar, Technische Universit¨ i Unit of Vascular and Endovascular Surgery, Hospital S. M. Misericordia, Loc. S. Andrea delle Fratte, Perugia, Italyj Department of Nephrology & Hypertension, University Medical Center Utrecht, The Netherlandsk Academic Section of Vascular Surgery, Imperial College School of Medicine, Charing Cross Hospital, London, United l Department of Vascular Surgery, Helsinki University Central Hospital, Helsinki, Finlandm Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki, Helsinki, Finlandn The Diabetic Foot Center at the Department of Endocrinology, Sk˚ o Division for Clinical Sciences, University of Lund, Sweden Critical limb ischaemia (CLI) is a particularly severe manifestation of lower limb atherosclerosis posing a major threat to both limb and life of affected patients. Besides arterial revascularisation, risk-factor modification and administration of antiplatelet therapy is a major goal in the treatment of CLI patients.
Key elements of cardiovascular risk management are smoking cessation and treatment of hyperlipidaemia with dietary modification or statins. Moreover, arterial hypertension anddiabetes mellitus should be adequately treated.
In CLI patients not suitable for arterial revascularisation or subsequent to unsuccessful revascularisation, parenteral prostanoids may be considered. CLI patients undergoingsurgical revascularisation should be treated with beta blockers. At present, neither gene norstem-cell therapy can be recommended outside clinical trials. Of note, walking exerciseis contraindicated in CLI patients due to the risk of worsening pre-existing or causing newischaemic wounds.
* Corresponding author. Nicolas Diehm, MD, Attending Physician and Director of Vascular Research, Swiss Cardiovascular Center, Clinicaland Interventional Angiology, Inselspital, University Hospital Bern, Switzerland. E-mail address: [email protected] (N. Diehm).
‡These authors contributed equally to this chapter. 1078-5884/$36 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.
CLI patients are oftentimes medically frail and exhibit significant comorbidities.
Co-existing coronary heart and carotid as well as renal artery disease should be managedaccording to current guidelines.
Considering the above-mentioned treatment goals, interdisciplinary treatment ap- proaches for CLI patients are warranted.
Aim of the present manuscript is to discuss currently existing evidence for both the management of cardiovascular risk factors and treatment of co-existing disease and todeduct specific treatment recommendations.
2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.
Most of the outlined recommendations apply to peripheral arterial disease (PAD) patients in general. Thus, it has CLI patients should be strongly and repeatedly advised to to be kept in mind that recommendations are frequently extrapolated to the subgroup of PAD with critical limb Smoking cessation rates can be improved by offering medical advice, group counseling session, nicotine re-placement, nicotine receptor partial agonists (varenicline)or antidepressant drug therapy (bupropion). (Level 1a; Smoking is the most important risk factor in PAD patients.
The extent of smoking exposure correlates with PAD diseaseseverity, rates of lower limb amputation, bypass re-occlusion Increased cholesterol, low-density lipoprotein (LDL), triglyc- as well as with mortality.1––3 Thus, CLI patients should be eride and lipoprotein (a) concentrations are independent advised to quit smoking with the aim to reduce the risk of major PAD risk factors. Moreover, PAD is considered a adverse cardiovascular events and amputation.
Physician smoking cessation advice coupled with a formal The Heart Protection Study assessed the impact of smoking cessation programme and nicotine replacement statin intake on mortality and fatal and non-fatal vascular was shown to be associated with a 22% cigarette smoking events.10 For that purpose, a total of 20,536 patients cessation rate out to 5 years.1 In this randomised controlled with coronary artery disease (CAD), other arterial occlusive trial (RCT), cessation rate was only 5% in the group of disease or diabetes mellitus were randomly assigned patients not undergoing this programme. Fourteen years to 40 mg simvastatin daily vs. placebo. In that study, post randomisation, the group of patients on this programme all-cause mortality and cardiac death were significantly still exhibited a significant survival benefit as compared to reduced by statins irrespective of the patients’ cholesterol concentration. Importantly, simvastatin reduced major The clinical utility of nicotine replacement therapy was vascular events by 22% in the subgroup of PAD patients.
assessed in a Cochrane review4 for which a total of 132 RCTs Remarkably, there was no threshold cholesterol value below were summarised. All of the commercially available forms which statin therapy was not associated with clinical of nicotine replacement therapy (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) were In the 4S study (Scandinavian Simvastatin Survival Study), shown to increase the odds of successfully stopping cigarette a total of 4444 coronary heart disease patients wererandomised to simvastatin vs. placebo.11 In the statin group, the risks for mortality, stroke and intermittent claudication A number of RCTs supported the use of bupropion, an were significantly reduced. The authors concluded that antidepressive agent, in cigarette smokers with cardiovascu- long-term treatment with simvastatin is safe and improves lar disease. Abstinence rates were reported to be 34%, 27% survival in coronary heart disease patients.
and 22% at 3-, 6- and 12-month follow-up as compared with In the PREVENT III study a total of 1404 CLI patients un- 15%, 11% and 9%, respectively, with placebo treatment.5 dergoing lower extremity bypass grafting were randomised Finally, the efficacy of nicotine receptor partial agonists to edifoligide vs. placebo aimed at preventing neointimal was assessed in a recently published systematic Cochrane hyperplasia and vein graft failure.12 In that trial, statin review summarising 11 RCTs with more than 10,300 use was associated with a significant reduction of 1-year patients.6 In this analysis, the pooled risk ratio for mortality in a propensity-score adjusted model.
continuous smoking abstinence at 6 months or longer In a Cochrane review including 18 RCTs with 10,049 for varenicline vs. placebo was 2.31 (95% CI 2.01––2.66).
participants the clinical utility of statins in PAD patients Moreover, varenicline was shown to be superior to bupropion was scrutinised.13 Lipid-lowering medication was shown to [pooled RR for varenicline vs. bupropion at 1 year: 1.52 be associated with a beneficial effect on the incidence of total cardiovascular events, primarily due to an overall Of note, smoking cessation may be associated with reduction in coronary events (OR: 0.8; 95% CI 0.7––0.9).
important benefits such as improvement of respiratory Statins were identified as the only type of drug for which symptoms7 and vascular tone already during short-term consistent, clear evidence of a beneficial effect on total cardiovascular events, total coronary events and stroke was Chapter III: Management of Cardiovascular Risk Factors and Medical Therapy available. The greatest evidence was with simvastatin in stabilisation and prevention of atherosclerosis progression people with a blood cholesterol level of at least 3.5 mmol/L beyond those of lowering arterial blood pressure. However, it has to be kept in mind that this study was not carried At present, there is no study indicating that diet out exclusively in CLI patients. Thus, as for other risk factor alone impacts on cardiovascular events in patients with interventions, data are largely extrapolated from a general atherosclerosis. It is recommended, however, that therapy PAD but not specifically CLI population.
for increased cholesterol concentrations begins with lifestyle Based on results from initial studies with non-selective modifications aimed at lowering elevated cholesterol.14 beta blockers such as propanolol, beta-adrenergic blocking Thus, dietary modification and pharmacologic intervention drugs have previously been discouraged in PAD due to their for dyslipidaemia should be tailored to meet the current potential to reduce cardiac output and to prevent beta- 2-receptor-mediated skeletal muscle vasodilation.21 Two In addition to the above-described benefits, statins may meta-analyses of studies published in patients with mild and prevent plaque instability and thrombosis due to their moderate lower limb ischaemia did not confirm the intake pleiotropic effects such as improvement of endothelial of beta blockers to be associated with exacerbation of PAD function, reduction of inflammation, and stabilisation of symptoms.22,23 Thus, the above-mentioned concern might have been overstated, especially in patients treated with Current recommendations for the management of lipid a beta-1 selective drug, especially since PAD patients with disorders in PAD are to achieve an LDL cholesterol level of coronary disease may have additional cardiac protection <100 mg/dL and to treat the pattern of increased triglyceride with beta blockers. Therefore, beta-adrenergic-blocking and low high-density lipoprotein (HDL).16,17 agents may be considered for the treatment of arterialhypertension in PAD patients.
The clinical utility of peri-operative administration of In CLI patients, statins should be the primary agents beta blockers is controversial. Use of beta blockers was to lower LDL cholesterol levels to reduce the risk of shown to be associated with significant reductions of peri- cardiovascular events. (Level 1a; Grade B) operative myocardial ischaemia and infarction in varioussurgical settings.24 In the POISE (peri-operative ischaemic For CLI patients, LDL cholesterol should be <100 mg/dL.
evaluation) study, a total of 8351 patients with, or at risk of, atherosclerotic disease who were undergoing Dietary modification is aimed at controlling body weight non-cardiac surgery were randomised to extended-release metoprolol succinate (n = 4174) vs. placebo (n = 4177).25 Study treatment had been started 2––4 hours before surgery cardiovascular events in patients with CLI. (Level 1a; and continued for 30 days. The primary endpoint, a composite of cardiovascular death, non-fatal myocardialinfarction, and non-fatal cardiac arrest, was more frequentlyobserved in the beta-blocker cohort (5.8%) as compared to the placebo group (6.9%) (HR: 0.84, 95% CI 0.70––0.99; p = 0.0399). Fewer patients in the metoprolol group Arterial hypertension is a major independent risk factor for experienced myocardial infarction (4.2% vs. 5.7%, HR: 0.73, PAD. Current hypertension guidelines advocate aggressive 95% CI 0.60––0.89; p = 0.0017). However, both mortality treatment of elevated bood pressure in patients with (3.1% vs. 2.3%, HR: 1.33, 95% CI 1.03––1.74; p = 0.0317) and atherosclerosis. Current treatment goals of antihypertensive stroke (1.0% vs. 0.5%, HR: 2.17, 95% CI 1.26––3.74; p = 0.0053) therapy are arterial blood pressures of <140/90 mmHg.
rates were higher in the metoprolol compared to the placebo Moreover, blood pressure should be <130/80 mmHg if the group. Of note, the dose of beta blockers administered in the patient also has diabetes or renal insufficiency.18,19 To POISE trial was higher as compared to that used in earlier achieve these results, all drugs capable of lowering arterial blood pressures can be considered for the prevention ofvascular events. Many patients may require agents of various classes to achieve the above-mentioned blood pressure CLI patients with arterial hypertension should be treated goals. Evidence for specific blood-pressure lowering drugs with antihypertensive medical therapy aimed at lowering in PAD patients is only available for angiotensin-converting- cardiovascular mortality. (Level 1a; Grade B) enzyme (ACE) inhibitors and beta blockers. It has to be keptin mind, however, that an acute reduction of blood pressure Treatment goals for CLI patients with arterial hyperten- may result in a further impairment of lower limb perfusion sion: arterial blood pressure should be <140/90 mmHg and in CLI patients not undergoing revascularisation.
<130/80 mmHg in case of concomitant diabetes mellitus The specific benefit of ramipril, an ACE inhibitor, in PAD or renal insufficiency. (Level 1a; Grade B) patients was documented by results from the HOPE (Heart Outcomes Prevention Evaluation) study in 4046 patients.20 In the subgroup of PAD patients, there was a 22% risk reduction Beta-adrenergic blocking drugs are not contraindicated in in the composite endpoints of myocardial infarction, stroke or cardiovascular death in patients randomised to ramipril Beta-adrenergic blocking drugs may be administered to as compared to placebo. Interestingly, this clinical benefit patients undergoing surgical lower limb revascularisation.
was independent of lowering of blood pressure. Thus, ACE inhibitors may exert beneficial effects such as plaque without controversy, there are currently no convincing datashowing a delay or reduction of the progression of lower Diabetes mellitus is independently associated with PAD limb atherothrombotic lesions by antiplatelet therapy. In and its progression to CLI. Limb salvage rates in diabetic contrast, studies assessing antiplatelet therapy for primary CLI patients have been reported to be lower as compared to prevention or peripheral vascular events are scarce and those of non-diabetic patients, and diabetes was shown to be an independent risk factor for amputation and complications The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial demonstrated that the In the STENO-2 study, 160 diabetics were randomly combined risk of death from vascular causes, myocardial assigned to either intensified or conventional therapy infarction, and stroke was significantly, albeit moderately (control of blood glucose, statins, antithrombotic therapy, (number-needed-to-treat with clopidogrel in comparison blood pressure control). After 13.3 years, intensive therapy with aspirin: 87 patients) lower with clopidogrel (75 mg/day) was associated with a significant reduction of risks of all- compared with aspirin (325 mg/day).32 Of note, the benefits cause death (HR: 0.54, 95% CI 0.32––0.89; p = 0.02, risk of clopidogrel were most pronounced in the subgroup of reduction: 20%) and cardiovascular death (HR: 0.43, 95% CI 0.19––0.94; p = 0.04, risk reduction: 13%).27 The Antithrombotic Trialists’ Collaboration meta-analysis In the UKPDS study (United Kingdom Prospective Diabetes found a 23% reduction in serious vascular events in 9214 study), a total of 5000 patients with newly diagnosed PAD patients within 42 trials.33 In the primary meta- diabetes mellitus were randomised to conventional therapy analysis, however, no significant reduction of cardiovascular (dietary restrictions as primary treatment approach) vs.
events could be demonstrated for PAD patients without further atherothrombotic lesions in other arterial terri- metformin).28 Although between-group differences in HbA1c tories. In a subsequent summary including study data levels perished after the first year, intensified therapy was on various antiplatelet drugs such as acetylsalicylic acid, associated with risk reductions for microvascular disease, myocardial infarction and death from any cause as well as a 23% risk reduction of ischaemic results could be shown for all PAD patients.34 Moreover, since clinically In contrast to these findings, it has recently been called inapparent concomitant coronary heart disease is present into doubt if intensive glucose lowering is truly beneficial: in many PAD patients,35 it might be logical to extend the In the ADVANCE (Action in Diabetes and Vascular Disease: administration of antiplatelet therapy to asymptomatic PAD Preterax and Diamicron MR Controlled Evaluation) trial, patients, although various questions related to this issue are a total of 11,140 patients with type 2 diabetes were randomised to undergo either standard glucose control or The precise daily dose for aspirin remains to be intensive glucose control to achieve a glycated haemoglobin determined. Low-dose aspirin (75––325 mg) is as effective as value of 6.5% or less.29 In that study, rates of microvascular higher doses.36 However, higher doses of aspirin result in complications, but not macrovascular complications or increased bleeding rates37 and very low doses (<75 mg) are cardiovascular deaths were improved by intensive diabetes therapy during a follow-up of 5 years.
The daily dose of clopidogrel for secondary prevention of Moreover, the ACCORD (Action to Control Cardiovascular PAD patients is 75 mg. Ticlopidin was assessed within various Risk in Diabetes) study randomised participants with PAD studies and reduces the risk for myocardial infraction, type 2 diabetes and cardiovascular disease or additional stroke and vascular death.38 However, its clinical utility is cardiovascular risk factors to receive intensive therapy limited by potential side effects such as neutropenia and (targeting a HbA1c <6.0%) or standard therapy (targeting a level of 7––7.9%).30 The study was prematurely stopped after In the absence of other indications for oral anticoagula- 3.4 years due to an increased mortality in the intensively tion, the latter is not indicated in PAD patients. Even more treated group, although the rates of non-fatal myocardial so, it was shown to be associated with higher bleeding rates infarction and stroke were lower in the intensively treated if added to aspirin, without lowering rates of cardiovascular group by that time. At 5 years, the use of intensive therapy for 3.7 years reduced 5-year non-fatal myocardial infarctions Two RCTs analysed whether or not antiplatelet therapy may improve patency rates subsequent to lower limb Whether the above-mentioned benefits of thorough endovascular therapy. In the first study,40 a total of diabetes control yield improvements in functional lower limb 199 patients undergoing femoropopliteal angioplasty were outcomes such as limb salvage or freedom from repeated randomised to dipyridamole (225 mg) combined with 900 mg revascularisation in CLI patients has yet to be determined.
of aspirin vs. dipyridamole (225 mg) with 300 mg of aspirinvs. placebo. Patients from both dipyridamole arms showed higher patency rates as compared to those on placebo.
Blood glucose levels should be monitored in CLI patients In the second study,41 a total of 223 patients after with a haemoglobin A1c (HbA1c) goal of <7.0%. (Level 5; iliac or femoropopliteal angioplasty were randomised to placebo vs. 50 mg of aspirin plus 400 mg of dipyridamole.
Primary patency was comparable in both groups. However, a substantial limitation of that study was that a significantlyhigher number of iliac angioplasties had been included in the While the clinical utility of antiplatelet therapy for placebo arm, which was shown to be associated with lower secondary prevention of patients with atherothrombosis is Chapter III: Management of Cardiovascular Risk Factors and Medical Therapy Moreover, the CASPAR study randomised a total of 425 stage III or IV PGE1 therapy not only has significant beneficial patients undergoing below-the-knee bypass grafting to effects over placebo on ulcer healing and pain relief, but either aspirin 75––100 mg per day alone or aspirin 75––100 mg also increases the rate of patients surviving with both legs per day plus clopidogrel 75 mg per day.42 In that trial a combination of clopidogrel plus aspirin did not improve A further meta-analysis has shown that a 2- to 4-week lower limb or systemic outcomes. However, dual antiplatelet treatment with iloprost reduces rest pain and ulcer size.51 therapy was associated with a lower rate of a composite Moreover, iloprost was associated with a higher rate of of index-graft occlusion or revascularisation, above-ankle amputation-free survival at 6 months. It has to be kept in amputation of the affected limb, or death as compared to mind, however, that the use of iloprost is not approved in aspirin alone without increasing bleeding risks.
Four studies analysed whether a high dose (90––1000 mg) Further vasoactive drugs such as naftidrofuryl, buflomedil or pentoxifylline did not show additional benefit with regard subsequent to endovascular therapy.43––45 Six months post- to reduction of amputations and wound healing.2,52 interventionally, there was no benefit of high-dose aspirin,whereas the rates of gastrointestinal side effects increased Parenteral prostanoids can be used in patients with critical In line with current standards in coronary endovascular limb ischaemia not suitable for arterial revascularisation revascularisation,46 a combination of aspirin with clopidogrel is used subsequent to peripheral arterial stent implantation.
However, at present there are no dedicated study datafor the peripheral arteries. The CAMPER (Clopidogrel and Aspirin in the Management of Peripheral Endovascular Revas- cularisation) study had been started in the USA to evaluatethe combined administration of aspirin and clopidogrel in The clinical utility of gene and stem-cell therapy is not patients undergoing endovascular revascularisation of the yet fully understood. While it has been shown that both femoropopliteal arteries. Due to insufficient numbers of treatment approaches are well tolerated, a significant patients randomised, this study was stopped prematurely.
clinical benefit has yet to be shown for either method.
Gene therapy has been clinically evaluated since 1994 within at least 6 placebo-controlled randomised clinicalphase II studies and within one placebo-controlled phase III Antiplatelet (aspirin or clopidogrel) therapy is indicated study. The four studies assessing gene therapy in CLI patients in patients with symptomatic peripheral arterial disease.
were positive for various endpoints.53––56 However, only amputation and mortality should be considered clinically Both aspirin and clopidogrel reduce rates of cardiovascular relevant endpoints in this regard. Only the application events in patients with symptomatic peripheral arterial of riferminogen pecaplasmid [non-viral gene construct for the fibroblast growth factor 1 (NV1FGF)] was shown to be In line with recommendations for patients with coronary associated with a reduction of the rate for major amputa- heart disease, an intermittent administration of dual tions and improved amputation-free survival as compared to antiplatelet therapy (aspirin plus clopidogrel) may be placebo within the TALISMAN 201 study.54 Further positive considered for patients undergoing stent implantation or endpoints of other studies included angiographically verified drug-eluting balloon angioplasty of femoropopliteal or improvements of arterial vascularisation during follow-up, infrapopliteal arteries. (Level 5; Grade D) improvements in transcutaneously measured oxygen partial A combination of clopidogrel and aspirin may be consid- pressure and further haemodynamic parameters.
ered as antithrombotic regimen in patients undergoing Based on positive results from the above-mentioned below-the-knee prosthetic bypass grafting. (Level 1b; TALISMAN 201 study,54 the currently largest gene therapy trial was initiated including 525 CLI patients without anyoption for endovascular or surgical revascularisation from30 countries and 171 hospitals. With 2-week intervals eight injections of a gene construct vs. placebo were applied intothigh and calf of the affected limb. After 12 months, there In patients with CLI not eligible for arterial reconstruction, was no significant difference in amputation-free survival and prostanoids are the only vasoactive drugs with proven time to major amputation comparing the NV1FGF with the efficacy. The currently available data support the use of prostanoids in patients unsuitable for lower limb Since progenitor cells have been identified as a participant revascularisation or in patients in whom revascularisation in angiogenesis, their role in therapeutic clinical applications has been assessed. The first clinical trial investigating the Two randomised double-blind studies with prostaglandin E-1 use of progenitor cells in CLI patients was published in have shown a clinical benefit with regard to the reduction 2002.58 Use of bone-marrow-derived mononuclear cells was of ulcer size.47,48 A further RCT with iloprost showed higher associated with improvements in ABI, TcPO2 and pain-free limb salvage and survival rates in the prostanoid group.49 walking time out to 6 months. Subsequent to this trial Creutzig recently concluded, in a meta-analysis of with a small sample size, this concept was investigated in randomised placebo-controlled trials50 including data from various non-randomised studies with small sample sizes.59 7 studies totalling 643 patients, that for patients with PAD To date, there are no double-blind RCTs assessing the use of bone-marrow-derived or mobilised mononuclear cells in considered high risk for peri-operative complications and PAD patients. The scientific community is currently waiting had significant CAD, coronary revascularisation did not for results of at least 10 randomised controlled cell therapy reduce peri-operative myocardial infarction or overall trials.59,60 Until data from these studies are availabe, the application of stem cells cannot be recommended outside Delay to vascular surgery was significantly longer in patients who underwent coronary revascularisation com-pared to patients who did not, which in CLI patients is often counterproductive. Therefore, the strategy of Neither gene nor stem cell therapy can be recommended a pre-emptive coronary revascularisation prior to urgent as a treatment for CLI outside clinical trials. (Level 5; peripheral vascular surgery should not normally be pursued.
In most patients, peri-operative use of beta-adrenergic-blocking agents is associated with reduced cardiovascularrisks of surgery. Recent studies have shown that beta- 8. Exercise and lower limb rehabilitation adrenergic blockade with bisoprolol significantly decreasesthe risk for cardiovascular events during vascular surgery and In contrast to patients with intermittent claudication, no afterwards.67,68 Besides controlling symptoms of myocardial data assessing the efficacy of walking exercise in CLI are ischaemia, treatment with beta-blocking agents also has available. Considering the risk of causing or worsening the benefit of favourably influencing prognosis in these already present ischaemic wounds, walking exercise is shortly before surgery (POISE), however, was not proven to be beneficial in terms of mortality and stroke as outlinedabove.25 Due to the risk of worsening pre-existing or causing new ischaemic wounds in the affected lower limb, walking Routine treatment with beta blockers before vascular exercise may be contraindicated in CLI patients not surgery is recommended. (Level 1b; Grade B) undergoing revascularisation. (Level 5; Grade D) Routine coronary revascularisation before vascular surgeryis not recommended. (Level 1b; Grade B) This section covers the management of typical co-existingdiseases in patients presenting with CLI and with important The prevalence of carotid artery disease in patients with PAD is 10––30%, and there are no specific data for CLI.
Since PAD patients are at an increased risk of strokeit might be reasonable to screen those patients for 9.1. Coronary artery disease (CAD) carotid artery disease routinely. Further evaluation andconsideration for revascularisation should be based on current guidelines.70 One must keep in mind that CLI patients which strongly increases the risk for cardiac mortality with limited life expectancy will hardly benefit from and morbidity.61,62 Therefore, all PAD patients should be carotid endarterectomy or stenting for asymptomatic carotid considered at high risk for clinically significant ischaemic heart disease, for which guidelines exist.63,64 Cardiac riskis related to urgency, extent, type and duration ofthe intervention planned. Patients should be evaluated for evidence of CAD. Treatment decisions for coexisting PAD patients are at an increased risk for renovascular hyper- CAD should be based on current practice guidelines and tension. The management of patients with atherosclerotic the intended treatment modality. Patients with unstable renal artery disease and PAD is focused on preservation of symptoms (acute coronary syndrome, congestive heart renal function and control of hypertension. Patients with failure) should be referred to a cardiovascular physician hypertension should be assessed by renovascular ultrasound for appropriate diagnosis and treatment. Most patients with imaging. In the presence of significant renal artery stenosis severe cardiac symptoms will require coronary angiography treatment should be based on current guidelines.2,71––74 These to determine the appropriate means for revascularisation.
patients should be referred to an appropriate vascular For patients with stable CAD, management should be physician. Again, one must keep in mind that CLI patients guided by the severity of the symptoms and comorbid will hardly benefit from treatment of renal artery stenosis.
conditions. All patients should be given appropriate medicaltherapy to treat symptoms and atherosclerotic risk factors.
Cardiac assessment scores may be useful in the context of patients being considered for peripheral revascularisation.65 In patients with a high cardiac risk assessment score, currentguidelines recommend further evaluation of the patient Unlike in PAD patients,2 no literature is available on for possible coronary revascularisation.24 However, in the health economics of risk-factor intervention specifically recent Coronary Artery Revascularization Prophylaxis (CARP) in CLI patients. CLI patients differ importantly from trial of patients with peripheral vascular disease who were claudicants. CLI patients are suffering from ischaemic lower Chapter III: Management of Cardiovascular Risk Factors and Medical Therapy limb pain, depression, social isolation and fear of losing their 2 Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, limb. They tend to adhere more to their habits and changing Fowkes FG, et al. Inter-Society Consensus for the Management any life style issue can be an important task.
of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg Measuring compliance of chronic patients to risk-factor interventions is difficult since these patients are treated by 3 Willigendael EM, Teijink JA, Bartelink ML, Peters RJ, Buller HR, numerous health professionals at the same time. Health and Prins MH. Smoking and the patency of lower extremity bypass economic benefits are obviously worse in CLI patients than grafts: a meta-analysis. J Vasc Surg 2005;42(1):67––74.
4 Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine in primary preventions since life expectancy in CLI patients replacement therapy for smoking cessation. Cochrane Database is significantly reduced. An additional difficulty is that health and economic benefits are delayed while resources for 5 Tonstad S, Farsang C, Klaene G, Lewis K, Manolis A, Perruchoud AP, treatment have to be expended at once. Moreover, given et al. Bupropion SR for smoking cessation in smokers with that numerous interventions are performed by means of a cardiovascular disease: a multicentre, randomised study. Eur variety of drugs, costs differ importantly between health- Heart J 2003;24(10):946––55.
economic systems in different countries. Costs in health 6 Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists economics can be expressed as average costs for 1 year of for smoking cessation. Cochrane Database Syst Rev 2:CD006103.
7 Etter JF. Short-term change in self-reported COPD symptoms after smoking cessation in an internet sample. Eur Respir J 2010;35(6):1249––55.
10.1. Cost-effectiveness of smoking cessation 8 Roux A, Motreff P, Perriot J, Pereira B, Lusson JR, Duale C, et al. Early improvement in peripheral vascular tone following No publications are available for CLI patients. Although there smoking cessation using nicotine replacement therapy: aorticwave reflection analysis. Cardiology 2010;117(1):37––43.
is good evidence for smoking cessation in peripheral artery 9 Expert Panel on Detection, Evaluation and Treatment of High disease, cessation programmes might not be successful in Blood Cholesterol in Adults. Executive summary of the third CLI patients. Training and group counseling sessions may report of the national cholesterol education program (NCEP) not be followed in normal range. Antidepressant therapy expert panel on detection, evaluation, and treatment of high (bupropion) and nicotine replacement could therefore still blood cholesterol in adults (Adult Treatment Panel III). JAMA be considered by the treating physician.5 10 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 10.2. Cost-effectiveness of pharmacologic interventions 20,536 high-risk individuals: a randomised placebo-controlled Studies on diabetes, dyslipidaemia and hypertension have trial. Lancet 2002;360(9326):7––22.
shown for primary intervention that compliance with 11 Randomised trial of cholesterol lowering in 4444 patients with guidelines is usually cost effective with a range of $20,000 coronary heart disease: the Scandinavian Simvastatin Survival to $30,000 per year of life gained.75,76 Statin drug costs Study (4S). Lancet 1994;344(8934):1383––9.
represented between 45% and 68% of the overall primary 12 Conte MS, Bandyk DF, Clowes AW, Moneta GL, Namini H, Seely L.
Risk factors, medical therapies and perioperative events in limb preventive cost of coronary heart disease.77 The specific salvage surgery: observations from the PREVENT III multicenter costs differ depending on the guidelines used. Studies on trial. J Vasc Surg 2005;42(3):456––64; discussion 464––55.
cost-effectiveness in CLI patients are currently lacking.
13 Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-lowering Considering that CLI patients would benefit from the same for peripheral arterial disease of the lower limb. Cochrane medication as claudicants, i.e. treatment by a combination Database Syst Rev 2007(4):CD000123.
of aspirin, a statin, a beta blocker and a diuretic,78 the costs 14 National Cholesterol Education Program (NCEP) Expert Panel on per additional quality-adjusted life year (QALY) would be Detection, Evaluation, and Treatment of High Blood Cholesterol £20,000 to £40,000. On top of that in CLI patients pain-relief in Adults (Adult Treatment Panel III). Third Report of the National medication, antibiotics, ACE inhibitors and more should be Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Recently the term “cost per major event averted” has (Adult Treatment Panel III) final report. Circulation 2002;106(25): been created since studies have failed to show a benefit on mortality. For example, the cost effectiveness of 40 mg/day 15 Sadowitz B, Maier KG, Gahtan V. Basic science review: simvastatin in high-risk patients is £4500 (95% CI £2300–– Statin therapy –– Part I: The pleiotropic effects of statins 7400) per major vascular event averted, but the result is in cardiovascular disease. Vasc Endovascular Surg 2010;44(4):241––51.
highly dependent on the cost of statin.79 16 Grundy SM, Cleeman JI, Merz CN, Brewer Jr HB, Clark LT, trials for the National Cholesterol Education Program AdultTreatment Panel III guidelines. Arterioscler Thromb Vasc Biol 17 De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Forceof European and other Societies on Cardiovascular Disease 1 Hirsch AT, Treat-Jacobson D, Lando HA, Hatsukami DK. The role Prevention in Clinical Practice (constituted by representatives of tobacco cessation, antiplatelet and lipid-lowering therapies of eight societies and by invited experts). Atherosclerosis in the treatment of peripheral arterial disease. Vasc Med 1997; 18 Chaturvedi S. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High 35 Diehm C, Schuster A, Allenberg JR, Darius H, Haberl R, Lange S, Blood Pressure (JNC 7): is it really practical? Natl Med J India et al. High prevalence of peripheral arterial disease and co- morbidity in 6880 primary care patients: cross-sectional study.
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