statins and peripheral arterial disease: effects on claudication, disease progression, and...

Archives of Medical Research 38 (2007) 479e488

REVIEW ARTICLE

Statins and Peripheral Arterial Disease: Effects on Claudication,Disease Progression, and Prevention of Cardiovascular Events

Giuseppe Coppola and Salvatore Novo

Department of Internal Medicine, Cardiovascular and Nephro-Urological Diseases, University of Palermo, Chair of Cardiovascular Disease, Palermo, Italy

Received for publication August 11, 2006; accepted December 4, 2006 (ARCMED-D-06-00349).

Peripheral arterial disease (PAD) of the lower limbs is the third most important site ofatherosclerotic disease alongside coronary heart disease (CHD) and cerebrovascular dis-ease (CVD). Best medical treatment is beneficial even in patients who eventually needinvasive treatment, as the safety, immediate success, and durability of intervention isgreatly improved in patients who adhere to best medical treatment. In recent years, a num-ber of studies have suggested that the ACE-inhibitor ramipril and different statins, to-gether with antiplatelet drugs, reduce cardiovascular morbidity and mortality in PAD.Patients with PAD are really a category of patients with a very high cardiovascular riskburden for fatal and nonfatal cerebrovascular and cardiovascular events; therefore, theyneed to be treated not only for local problems deriving from arteriopathy (intermittentclaudication, rest pain and/or ulcers) but, above all, for preventing vascular events. Statinsnot only lower the risk of vascular events, but they also improve the symptoms associatedwith PAD. Statins exert beneficial pleiotropic effects on hemostasis, vasculature and in-flammatory markers; there is also evidence that statins improve renal function consider-ing that the plasma creatinine level is considered as an emerging vascular riskfactor. � 2007 IMSS. Published by Elsevier Inc.

Key Words: Intermittent claudication, Peripheral arterial disease, Cardiovascular events, Statins.

Introduction

Peripheral arterial disease (PAD) of the lower limbs is thethird most important site of atherosclerotic disease along-side coronary heart disease (CHD) and cerebrovascular dis-ease (CVD) (1). This clinical condition has often beenneglected in the past but, in recent years, PAD has receivedgrowing attention as an important cause of disability and ofcardiovascular morbidity and mortality (1e3). The mostcommon symptom is muscle pain in the lower limbs on ex-ercise, and the clinical diagnosis of PAD may be made onthe basis of an accurate history by using the WHO/RoseQuestionnaire or the Edinburgh Questionnaire. From a clin-ical point of view, PAD may be classified into four stages,according to the Leriche and Fontaine classification (1e4).

Epidemiological data show that male gender, aging,family history, smoking, diabetes, hypertension and dyslipi-

Address reprint requests to: Giuseppe Coppola, Department of Internal

Medicine, Cardiovascular and Nephro-Urological Diseases, University

of Palermo, Chair of Cardiovascular Disease, Palermo, Italy; E-mail:

[email protected]

0188-4409/07 $esee front matter. Copyright � 2007 IMSS. Published by Elsdoi: 10.1016/j.arcmed.2006.12.012

demia are the most important risk factors; however, femaleswith diabetes mellitus, with early menopause after hyster-ectomy or age O70 years have a prevalence of the diseasesimilar to males (1e4).

Simple non-invasive tests such as measurement of ankle/brachial pressure index (ABI), the so-called Index of Win-sor, ankle and toe Doppler pressures, as well as the detec-tion of transcutaneous PO2 and PCO2 take only a fewminutes to provide sufficient information to confirm the di-agnosis of PAD and to document the severity of limb ische-mia (Figure 1) (4e6).

Diagnostic imaging studies such as ultrasound duplexscanning, magnetic resonance angiography (MRA), or tra-ditional arteriography provide detailed information to planrevascularization. In patients requiring an assessment ofthe peripheral vascular bed before distal revascularization,contrast-enhanced MRA can be the first examination andonly in the case of inadequate results selective arteriogra-phy needs to be performed (Figure 2) (4).

Balloon angioplasty and stenting work best for focalsegments of narrowing or short occlusions of the iliac ar-teries, but endovascular treatments yield progressively

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480 Coppola and Novo/ Archives of Medical Research 38 (2007) 479e488

Age 50–69 years and smoking or diabetesAge >70

Leg pain with exertionAbnormal results on vascular examination of leg

Coronary, Carotid, or renal disease

Measure ankle-brachial index

Index 0.91–1.30Index <0.90Index >1.30

Measure ankle-brachial indexafter treadmill test

Pulse-volume recoringToe-pressure

measurement Duplexultrasonography

Normal postexercise ankle-brachialindex: no peripheral

arterial disease

Decrease postexerciseankle-brachial index

Abnormal results

Normal results:no peripheral

arterial disease

Evaluate other causes of legsymptoms

Peripheral arterial disease

Figure 1. Evaluation of patients suspected of having peripheral arterial disease.

poorer results with longer and more distal lesions; long seg-ments of occlusion, especially those distal to the commonfemoral artery, are best treated with surgical bypass(Figure 2) (4).

Pharmacotherapy, topical therapies, and hyperbaric oxy-gen treatment may have a role for patients in whom revas-cularization procedures have failed or for those in whomrevascularization is not technically possible, particularlywhen amputation is the only alternative; in these cases,prostanoids are the best-studied class of drugs and arewidely used in Europe (4). Smoking cessation, treatmentof hypertension, diabetes, and hyperlipidemia are the mile-stones for the control of risk factors and reduction of therisk of cardiovascular events and mortality of these patients(Figure 2) (2e7).

Statins: Not Only Lipid-lowering Effects

By competitive inhibition of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, which is a key en-

zyme of cholesterol biosynthesis, statins reduce cellularcholesterol content, notably in liver cells. The cholesterol-lowering effect of statins is mainly mediated by the upregu-lation of LDL receptor activity, which leads to enhancedhepatic uptake of atherogenic apoB containing lipoproteins(VLDL, VLDL remnants, IDL, and LDL) and to a lesserextent, by partial inhibition of hepatic VLDL synthesis.Consequently, statin therapy positively influences the equi-librium between atherogenic and antiatherogenic lipopro-teins, favoring reverse cholesterol transport and leading tobeneficial changes in the composition, structure, and stabil-ity of atherosclerotic plaques (Figure 3) (8).

Systemic markers of inflammatory activity are signifi-cantly attenuated after statin treatment (Figure 4). Indeed,clinical trials in the context of primary and secondary pre-vention have shown that statin therapy reduces plasmalevels of C-reactive protein (CRP), which is a marker ofoverall systemic inflammation (8e11). In the Cholesteroland Recurrent Events (CARE) trial, pravastatin-treated pa-tients displayed progressive reduction of CRP levels (up to37.8%) during the 5-year follow-up period, indicating that

481Use of Statins in PAD

Peripheral arterial disease

Assess severity of claudicationTreadmill MWD and PFWD

SF-36 and WHOquestionnaires

Critical leg ischemia

Therapy for claudicationSupervised exercise

Citostazol

Symptomsimprove

Symptomsworsen

ContinueLocalize lession

• Hemodynamic localization• Duplex ultrasonography

• Magnetic resonance angiography• Conventional angiography

RevascularizationAngioplasty

Bypass surgery

Assess cardiovascularrisk factors

Figure 2. Evaluation and treatment of patients with proven peripheral arterial disease.

this anti-inflammatory effect is progressive and maintainedover a prolonged period (12). The effect of statins onsystemic inflammatory markers results potentially fromlipid-lowering dependent and independent actions (8,13).Arterial wall macrophages, stimulated by oxidized LDL,secrete proinflammatory cytokines such as interleukin-6which, in turn, stimulate hepatic production of CRP andother acute-phase reactants (13). Statins reduce the resi-dence time of LDL particles in the circulation and, conse-quently, the substrate available for generation of oxidizedLDL, thereby reducing the inflammatory stimulus.

Equally, statins can directly attenuate the inflammatoryresponse via mechanisms related to the inhibition of meval-onate synthesis but also via mechanisms independent ofHMG-CoA reductase inhibition (8). These mechanisms, in-volving lipid-lowering dependent and independent actions,are not mutually exclusive and thus operate concomitantly(Figure 4).

It is unclear whether there may be a preponderance ofone of these mechanisms in the statin-induced reductionin plasma CRP levels. Studies involving pravastatin, ceri-vastatin, lovastatin, simvastatin, and atorvastatin treatmentsin dyslipidemic patients have consistently demonstrateda decrement in plasma CRP levels in a manner unrelatedto their effects on LDL or HDL cholesterol levels

(8,10,14). However, estimation of proinflammatory oranti-inflammatory actions of lipoproteins is not fully re-flected in the determination of their cholesterol content.For example, LDL particles differ in their susceptibilityto oxidation as a function of their physicochemical proper-ties (e.g., size and chemical composition), raising the pos-sibility that LDL particle phenotype may be intimatelyrelated to the magnitude of the inflammatory stimulus(8,15). Thus, the potential association between statin-induced modifications in LDL particle phenotype andvariation in the circulating levels of acute-phase reactantsrequires further study.

Statin treatment attenuates TF expression on macro-phages, reducing activation of the coagulation cascade (Fig-ure 5). Once the cascade is activated, statins reducethrombin formation by reduction in factor VII coagulationactivity and mass, inhibition of factor V activation, and in-crease in factor Va inactivation. Last, statins inhibit factorXIII activation, reducing the formation of a stable clot; inaddition, statins attenuate platelet aggregability, thereby re-ducing thrombus formation (8). Mechanisms involved inthe anti-thrombotic action of statins may include the en-hanced production of NO from endothelial cells (16).

The effect of statins on other cells involved in thrombo-sis also appears to play a part. Human aortic smooth muscle


Liver

Endogenous Cholesterol Synthesis

LDL-Receptors

VLDL-LDL- Cholesterol

HDL

AtherogenicVLDL, IDL, LDL

HDLAtherogenic

VLDL, IDL, LDL

Influx

Cholesterol efflux Atheroma

Plaque cholesterolcontent Plaque stability Cardiovascular

events

Statin

HDL

ApoB LPs

Figure 3. Effect on lipid metabolism. (Adapted from Sposito A, Chapman J. Statin therapy in acute coronary syndromes. Mechanistic insight into clinical

benefit. Arterioscler Thromb Vasc Biol 2002;22:1524e1534).

cells in vitro were found to increase their expression ofCOX-2 and production of prostacyclin, a platelet inhibitoryagent, under the influence of mevastatin or lovastatin (17).Monocytes are also influenced in an antithrombotic direc-tion by statins, as synthesis of plasminogen activator inhib-itor (PAI)-1 is decreased, a change likely to result inenhanced fibrinolysis and thrombus dissolution (16). Thesame result may be achieved in another route in endothelialcells, as statins cause an increase in expression of tissueplasminogen activator; activation of the coagulation path-way may also be impeded, as tissue factor expression hasbeen found to be prevented by statins in human endothelialcells (16).

It seems likely that further pathways remain to be dis-covered. Remarkably, statins may have a direct influenceon the coagulation pathway itself, as patients treated withsimvastatin were seen to have decreased rates of stimulatedactivation of fibrinogen, prothrombin, factor V, and factorXIII (16).

Statins Improve Symptoms in Patientswith Claudication

Atherosclerosis is an inflammatory disease involving me-dium-size arteries, particularly the carotid, coronary, and

femoral vessels (18e20); the detection of atherosclerosisin one of these arterial areas should prompt the clinicianto intervene to protect the patient’s whole arterial tree.

Contrary to popular belief, the risk of a person with clau-dication progressing to critical limb ischemia and needingamputation is low (!1% a year) (4,5); however, the riskof death, mainly from coronary and cerebrovascular events,is high (5e10% a year), some three to four times greaterthan that of an age- and sex-matched population withoutclaudication (4).

Best medical treatment is beneficial even in patients whoeventually need invasive treatment, as the safety, immediatesuccess, and durability of intervention is greatly improvedin patients who adhere to best medical treatment (Figures1 and 2) (21,22). Lipid management is the mainstay ofrisk-factor modification for patients with cardiovasculardisease.

In the POSCH Study, 838 patients were randomized toperform an ileal by-pass or a traditional medical treatmentfor the control of hypercholesterolemia; after a 5-yearfollow-up, the risk to detect an abnormal ABI was 0.60(CI 95%, 0.40e0.90) and the risk to observe new cases ofintermittent claudication or peripheral severe ischemiawas 0.70 (CI 95%, 0.2e0.9) in patients undergoing ilealby-pass in comparison with control group (23).


Lymphocyte

LFA-1

Selectiveblock

ICAM-1

Statins

1

2

3 LDL oxLDL

NO Inactivations

NO

Monocyte

ReducedAdhesionHMG-CoA Reductase

activity

Geranylgeranyl PPFarnesyl PP

Reduced prenylationRho protein

Increase transcriptionsNOS mRNA

Decreasedactivation NF-KB Endothelial cell

NO production

Increased stability of mRNA

++

Figure 4. Anti-inflammatory effects of statins. (Adapted from Sposito A, Chapman J. Statin therapy in acute coronary syndromes. Mechanistic insight into

clinical benefit. Arterioscler Thromb Vasc Biol 2002;22:1524e1534).

Since 1994, the Scandinavian Simvastatin SurvivalStudy (4S) demonstrated that simvastatin significantly re-duced the incidence of new cases of intermittent claudica-tion by 38%, the appearance of $1 new bruits by 30%,and new carotid bruits by 48% compared with placebo, inpatients with hypercholesterolemia and CAD in a 5.4-yearmedian follow-up (24,25).

The SISOPAD Study considered the effects of chronictreatment with simvastatin in 283 patients with a meanage of 61 years and second stage Leriche-Fontaine classifi-cation PAD. After 1 year of treatment an increase of ABI atrest was shown, a mild increase of ankle systolic bloodpressure at rest, soon after the treadmill test and after 10min of recovery, a noticeable reduction of total cholesteroland of LDL-cholesterol, a mild increase of HDL-choles-terol and a significant reduction of plasma levels of fibrin-ogen and an improvement of whole blood viscosity.Differences were all significant ( p !0.01) and the authorshypothesized a regression of iliac-femoral atherosclerosisand/or an improvement of endothelial function and of thehemorheological and microcirculatory pattern induced bythe chronic treatment with simvastatin in patients withPAD (26).

Aronow et al. showed that simvastatin, compared withplacebo, significantly increased exercise time until onsetof intermittent claudication after 6 months and 1 year of

treatment in older patients (mean age 75 years) who had in-termittent claudication due to PAD and a mean ankle/bra-chial index of 0.63 (27). In this study, the authorsunderlined how simvastatin significantly increased tread-mill exercise time until onset of intermittent claudicationfrom baseline by 54 sec (a 24% increase, p !0.0001) after6 months of treatment and by 95 sec (a 42% increase,p !0.0001) after 1 year at 6 months and 1 year, treadmillexercise time until onset of intermittent claudication wasnot significantly different from baseline exercise time aftertreatment with placebo (27).

The results of these previous studies with simvastatinwere confirmed in a more recent study in which Mondilloet al. demonstrated that simvastatin improves walking per-formance, ankle-brachial index and symptoms of intermit-tent claudication in hypercholesterolemic patients withperipheral vascular disease because a direct reduction inplaque dimension seems to be unlikely. These positive out-comes may be due to functional effects such as plaque sta-bilization and a possible improvement in endothelialfunction (28).

Mohler and co-workers, using a different statin, demon-strated how atorvastatin improves pain-free walking dis-tance and community-based physical activity in patientswith intermittent claudication. When treated with atorvasta-tin, patients with PAD experienced an improvement in


Plaque rupture

Tissue Factors expression

Factor VII-TF complex

Factor Xa

Prothrombin

Cross-Linked Fibrin

Thrombusformation Platelet aggregation

Factor XIII

Fibrin Polymer Fibrinogen

Thrombin

Factor Vainactivation

Factor Vactivation

Factor VII

+

Statinstherapy

Figure 5. Modulation of thrombogenesis. (Adapted from Sposito A, Chapman J. Statin therapy in acute coronary syndromes. Mechanistic insight into clinical

benefit. Arterioscler Thromb Vasc Biol 2002;22:1524e1534).

symptoms to complement the early reduction in cardiovas-cular events reported in other studies (29).

Recently, McDermott et al. carried out a study to deter-mine whether statin use vs. nonuse was associated with su-perior lower-extremity functioning independently ofcholesterol levels and other confounding factors, in patientswith and without PAD. Participants included 392 men andwomen with an ABI !0.90 and 249 with ABI from 0.90 to1.5. Functional outcomes included 6 min walking distanceand 4 m walking velocity. Adjusting for age, sex, ABI, co-morbidities, educational level, medical insurance status, cho-lesterol and other confounders, participants taking statins hadbetter 6-min walk performance (1276 vs. 1218 feet,p !0.05), faster walking velocity (0.93 vs. 0.89 m/sec,p 5 0.006) than participants not taking statins (30).

Statins Reduce the Cardiovascular RiskBurden of PAD

In recent years a number of studies have suggested that theACE-inhibitor ramipril and different statins, together withantiplatelet drugs, reduce cardiovascular morbidity andmortality in PAD (31e34). In fact, in the Hope Study, thesubgroup of patients with PAD treated with ramipril 10

mg/day (n 5 1996) showed a significant reduction of thecomposite outcome (cardiovascular mortality, acute myo-cardial infarction, ischemic stroke) in comparison with pa-tients treated with placebo (n 5 2085) of 22% ( p !0.001)(35). These results were evident both in patients with symp-tomatic PAD as well as in asymptomatic ones with onlya reduction of ABI !0e90 (36).

The Heart Protection Study (HPS) has shown that lower-ing total cholesterol and low-density lipoprotein cholesterolby 25% with a statin reduces cardiovascular mortality andmorbidity in patients with peripheral arterial disease by ap-proximately one-quarter, irrespective of age, sex or baselinecholesterol concentration (33). The proportional reductionin the rate of major vascular events was about one-quarterin each subcategory of participants studied. In particular,there was a highly significant 25% proportional reduction( p !0.0001) among participants with PAD, with or withouthistory of coronary disease at entry (37). Therefore, the re-sults of the HPS demonstrate that lowering LDL cholesterolwith a statin produces a substantial reduction in the inci-dence of major vascular events among a much wider rangeof high-risk individuals than had previously been shown tobenefit from such treatment. In particular, it demonstratessubstantial benefit not only in those already known to havecoronary disease, but also in those without diagnosed


coronary disease who have cerebrovascular disease, periph-eral arterial disease, or diabetes, irrespective of the bloodlipid concentrations when treatment is initiated. The impli-cation is that every patient with PAD should be treated withstatins.

An interesting field of study turns around the effect ofstatin treatment on creatinine and urate levels in patientswith PAD who are, as we know, associated with a high riskfor cardiovascular events. A recent study reported that thereis also a strong association between atherosclerotic renalartery stenosis and PAD (38). The aim of the study byYoussef et al. was to investigate the effects of short-termtreatment with simvastatin on renal function in patientswith PAD. They enrolled 103 patients with PAD and allwere started on simvastatin 20 mg/day for 3e4 months.There was a significant decrease in serum creatinine (froma mean of 87 mmol/L pre-treatment to 84 mmol/L post-treatment; p !0.0001) and this difference was more markedin the tertile of patients with the highest baseline levels.There was also a significant reduction in serum urate. Boththese effects were independent of the degree of total choles-terol or low-density lipoprotein cholesterol reduction (39).The authors suggested that statins may improve renalfunction by restoring endothelium-dependent nitric oxideproduction, which could improve renal blood flow by exert-ing its vasodilator action.

Aronow and Ahn reported in 2002 data from their obser-vational study investigating the effect of statins on the inci-dence of new coronary events in older men and womenwith PAD and a serum low-density lipoprotein (LDL) cho-lesterol $125 mg/dL; 264 men and 396 women (mean age80 � 9 years, range 60e99 years) with symptomatic PADand a serum LDL cholesterol $125 mg/dL, treated witha statin or with no lipid-lowering drug, were followed pro-spectively in a long-term health care facility for the inci-dence of new coronary events. In this study, patients withPAD and a serum LDL cholesterol $125 mg/dL hada 48% incidence of new coronary events if they weretreated with statins and a 73% incidence of new coronaryevents if they were treated with no lipid-lowering drug atthe 39-month mean follow-up period (40). It is importantto underline that no prior study has shown that the use ofstatins in elderly patients with PAD reduces the risk ofnew coronary events but, as the authors suggest in theirconclusion, the major limitation of this study is that itwas an observational study, not a randomized, double-blind,placebo-controlled study.

All published randomized trials that have compareda statin to placebo in high cardiovascular risk patients havedemonstrated an important reduction, both statistically andclinically, of the fatal or nonfatal 5-year cardiovascularcomplication rate. In these studies, the reductions in relativeand absolute risk ranged, respectively, from 25e35% andfrom 2e8% (NNT 12e50) (41). In this regard, the observa-tional study by Schillinger et al. showed a lower cardiovas-

cular risk in patients with PAD using a statin. Interestingly,patients with an elevated baseline high sensitive C-reactiveprotein (hs-CRP Omedian) showed the largest reduction incardiovascular risk (42). This finding confirms the prognos-tic yield of hs-CRP in patients with symptomatic athero-sclerosis and is consistent with the results of a post hocanalysis of the CARE trial in postmyocardial infarction(MI) patients with high serum levels of inflammatorymarkers (hs-CRP and SAA) (9,12).

Therefore, it is well known how cardiovascular eventsare a major cause of morbidity and mortality in patientswith PAD. Recently, Feringa et al. evaluated the potentialbenefit of cardiac medication including statins, beta-blockers, aspirins, angiotensin-converting enzyme (ACE)inhibitors, calcium-channel blockers, diuretics, nitrates,coumarins, and digoxin on long-term mortality among pa-tients with PAD (43). On the basis of this observational lon-gitudinal study, statins, beta-blockers, aspirin, and ACEinhibitors are associated with a reduction in long-term mor-tality risk in patients with PAD. The use of cardiac medica-tions as therapeutic and preventive agents in patients withPAD seems to be promising in reducing long-term mortalityand could be incorporated among other management strat-egies, including walking exercise and risk factor modifica-tion (43).

How Low Should We Go with LDL-Cholesterolin PAD Patients?

Patients with PAD are really a category of patients witha very high cardiovascular risk burden for fatal and nonfatalcerebrovascular and cardiovascular events; therefore, theyneed to be treated not only for local problems deriving fromarteriopathy (intermittent claudication, rest pain and/or ul-cers) but, above all, for preventing vascular events. This lat-ter includes an aggressive treatment of all risk factorspresent as CHD patients in secondary prevention (3).

The beneficial effects may be related to plaque stabiliza-tion, reduction in inflammatory cell activity, platelet activa-tion, thrombus formation and improvement in endothelialfunction.

Irrespective of serum lipid and hs-CRP levels, the gen-eral practitioner and specialist should prescribe a statin toall PAD patients to reduce their risk of cardiovascular is-chemic attacks and aim at reaching the 11 other therapeutictargets to optimize the management of high cardiovascularrisk (41). Statins not only lower the risk of vascular events(Table 1), but they also improve the symptoms associatedwith PAD. There is also evidence that statins reduce surgi-cal mortality and improve graft patency, limb salvage andrenal function. Because of the high risk, a more aggressivegoal should be considered to maximally reduce the ather-oma burden and related events (44,45).


Table 1. Clinical outcome studies using statins

Study, n (% women) Intervention

Baseline

LDL

mg/dL

% LDL

reduction

On-trial

LDL *mg/dL

% Reduction

in total

mortality

% Reduction

in coronary

events

% Reduction

in CABG and

PTCA NNT

Secondary prevention trials

4S, 4444 (19) Simvastatin

20e40 mg/day

188 35 120 30 ( p 5 0.003) 34 ( p !0.0001) 37 ( p !0.0001) 15

CARE, 4159 (14) Pravastatin

40 mg/day

139 32 95 9 ( p 5 NS ) 24 ( p 5 0.003) 27 ( p !0.001) 33

LIPID, 9014 (17) Pravastatin

40 mg/day

150 25 113 22 ( p !0.0001) 24 ( p !0.0001) 22** ( p !0.001) 28

Primary prevention trials

WOSCOPS, 6595 (0) Pravastatin

40 mg/day

192 26 142 22 ( p 5 0.051) 31 ( p !0.001) 37 ( p 5 0.009) 42

AFCAPS/TexCAPS,

6605 (15)

Lovastatin

20e40 mg

150 25 113 0 ( p 5 NS ) 37 ( p !0.001) 33 ( p 5 0.001) 24

NNT, number to treat to prevent one major coronary event (100/absolute risk reduction).

(Adapted from Maron D, Fazio S, MacRae F. Current perspectives on statins. Circulation 2000;101:207e213).

*On trial LDL-C values are calculated from published data.

**Results for CABG: the need for PTCA was reduced by 19% ( p 5 0.024).

Because PAD patients often take several drugs, there isa need to carefully consider their selection so as to maxi-mize benefits and minimize adverse effects; in fact, patientswith PAD often do not receive adequate lipid-loweringtreatment (46). This situation needs to change as the newguidelines for the management of patients with peripheralarterial disease have recently suggested. In fact, in this re-port, it is recommended that patients with PAD and LDL-cholesterol of 100 mg/dl or greater be treated with a statin,but when risk is very high, an LDL cholesterol goal of !70mg/dl is a therapeutic option (47).

In the past, concern has been raised about potential dan-gers of reducing LDL to very low levels. Some epidemio-logical studies suggest that very low serum cholesterollevels are associated with an increase in total mortality;in particular, an association with cerebral hemorrhage hasbeen reported (48e50). In these studies, a causal link be-tween low cholesterol levels and morbidity or mortalityhas not been established and some investigators attributethe association to confounding factors. In recent clinical tri-als with statin therapy, no significant side effects from LDL

lowering have been identified (44) as the 8-year follow-upof the 4S trial confirmed (51).

As a class, statins are well tolerated, and there are noknown differences in safety because statins are prescribedon a long-term basis. However, possible interactions withother drugs deserve particular attention, as many patientswill typically receive pharmacological therapy for concom-itant conditions during the course of statin treatment (52).The most important adverse effects are liver and muscletoxicity; rhabdomyolysis and acute renal failure may resultif myopathy is not recognized and the drug is continued. Ifrecognized promptly and the drug is stopped, the myopathyis reversible, and acute renal failure is unlikely to ensue(53). Looking for statin safety, the American College ofCardiology/American Heart Association/National Heart,Lung, and Blood Institute has issued a clinical advisoryon statin therapy. This document addresses the issue ofmuscle toxicity with statins and provides recommendationsfor the appropriate use of statins including cautions, contra-indications, and safety monitoring for patients taking statins(54). A number of important drug interactions with statins

Table 2. Comparative efficacy and pharmacology of the six currently available statins

Drug

Reduction

in TC (%)

Reduction

in LDL-C (%)

Increase

in HDL-C%

Reduction

in TG (%)

Dosage from

tablets, mg Metabolism Protein binding (%) T½ Hydrophilic

Atorvastatin 25e45 26e60 5e13 17e53 10, 20, 40, 80 CYP3A4 98 13e30 No

Fluvastatin 16e27 22e36 12e25 12e25 20, 40, 80 CYP2C9 98 0.5e3.0 No

Lovastatin 16e34 21e42 6e27 6e27 10, 20, 40 CYP3A4 O95 2e4 No

Pravastatin 16e25 22e34 15e24 15e24 10, 20, 40, 80 Sulfation 43e67 2e3 Yes

Rosuvastatin 33e46 45e36 10e35 10e35 5, 10, 20, 40 CYP2C9 88 19 Yes

Simvastatin 19e36 26e47 12e34 12e34 5, 10, 20, 40, 80 CYP3A4 95e98 1e3 No

TC, total cholesterol; TG, triglycerides; T½, half-life.

(Adapted from Vaughan C, Gotto A. Update on statins: 2003. Circulation 2004;110:886e892).


have been described that may increase the risk of muscle-related side effects. The cytochrome P450 (CYP) isoformCYP3A4 serves as the major pathway for metabolism oflovastatin, simvastatin, atorvastatin, and cerivastatin; inhi-bition of the activity of CYP3A4 can increase serum levelsof these statins, which raises the potential for side effects.Pravastatin does not undergo metabolism through theCYP450 system but is metabolized by sulfation and conju-gation (Table 2). But a recent update on statins by Vaughanet al. underlined how although physicians should keep thesecautions in mind, they should also remember that myopathyis an extremely uncommon side effect that has long beenrecognized as a potential risk of these drugs (55).

In the Prospective Pravastatin Pooling Project, whichstudied more than 112,000 patient years of drug therapy,pravastatin was withdrawn from only three patients becauseof elevated creatine kinase levels (56). Given available U.S.data, muscle pain and weakness may affect 1% to 5% ofstatin-treated patients, and fatal rhabdomyolysis has an es-timated incidence of 0.15 deaths per 1 million prescriptions(57). However, compliance with these agents has still beenfar from ideal because they require long-term, probablylife-long therapy. Along these lines, Yilmaz et al. conducteda survey on patients who were already on statin treatmentand evaluated their level of awareness of prescribed statins.They suggest that comprehensive information at initial pre-scription, initiation of statins during hospitalization, anytype of contact during follow-up, and prescribing as fewdrugs as possible (if possible only those that are lifesaving)seem to increase the level of awareness of how long to usestatins. This, in turn, might well be expected to result inbetter compliance rates (58).

In conclusion, to avoid any misunderstanding about cho-lesterol management in general, it must be emphasized thatin patients with only PAD an LDL-C target of !100 mg%is good, whereas the optional goal of #70 mg/dL may beapplied to individuals at very high risk, such as those withassociated CHD.

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