Statins in patients with peripheral arterial disease

I - PAD of the lower limbs

a) Definition and risk factors

Peripheral arterial disease (PAD) of the lower limbs is the third topographic location of atherosclerosis (ATS) for frequency and severity of disability. Risk Factors (RF) are similar to those of coronary heart disease, but PAD is strongly related to cigarette smoking, diabetes, as well as with impaired glucose tolerance.

Other important risk factors are hypertension, hypercholesterolemia and low levels of HDL-cholesterol, high levels of triglycerides, apolipoprotein B, lipoprotein (a), hyperhomocysteinemia, hyperfibrinogenemia and blood hyperviscosity (1).

b) Incidence and prevalence

The incidence is approximately 2 to 1 for men over women. Women in most cases are affected by an almost asymptomatic form -  if you exclude women with diabetes (1). The prevalence increases with age: 1% of men between ages 45 and 50, 3-3,5% of those over 50, more than 5% of men and 2.5% of women over 60 years are symptomatic for claudication intermittens (1).

The prevalence of PAD is higher if we consider asymptomatic patients with ABI < 0.90 as demonstrated by Hirsh et al. in the PARTNERS study, reaching 29% in those aged > 70 years or in adults aged 50-59 with important risk factors such as smoking or diabetes (2).

c) Symptamatology

Functionally the disease is characterised by hypoperfusion of the lower limbs caused by arterial steno-occlusion in the iliac-femoral-popliteal district and, consequently, it will result in an altered relationship between oxygen demand and supply and metabolites in tissues (1).

This hypoperfusion induces a variety of clinical situations, ranging from asymptomatic disease, to the appearance of pain and ischemic muscle strain in claudication intermittens and critical lower limbs ischemia (CLI) with the presence of pain at rest, necrosis and gangrene (1). The appearance of symptoms is conditioned not only by the vascular steno-occlusion, but also by the development of collateral circles and the lifestyle of the patient. The progression of symptoms of PAD is relatively slow over time.

d) Prognosis

After 5 years of follow-up,

• more than 70% of patients who stop smoking and control other risk factors refer a stabilisation or even an improvement of their symptoms, while
• 20-30% have a progression of symptoms that requires revascularisation (PTA or vascular surgery according to the kinds of lesions and the clinical condition of the patient) and
• fewer than 10% of cases resulting in a distal amputation of the leg (1).

However, despite the fact that PAD prognosis is relatively benign for the affected limb, claudication intermittens must be always considered as a possible marker of multifocal atherosclerosis. It is very important to stress that patients suffering from PAD have an increased risk of developing coronary heart disease and cerebrovascular disease (1).

II - Treatment of symptoms and prevention of future vascular events

a) The ABI index

Because of the high risk of fatal and non-fatal cardiovascular events, patients with PAD should be subjected to a careful examination of the cardiovascular system in its entirety and to an aggressive correction of risk factors. An independent and significant indicator of mortality is the ankle-brachial index (ABI).

Generally, the lower the value of ABI, the higher the incidence of ischemic coronary and cerebral events and the lower survival is, as evidenced by the group of Diehm et al. (3) in the getABI Study, in which were followed for 5 years 6880 elderly subjects, aged > 65 years, with average age of 72.5 years, without PAD (79.2%), or with asymptomatic PAD and ABI < 0.90 (12.1%) and with symptomatic PAD (8.7% of the population). The mortality at 5 years was respectively 9,5%, 19.2% and 24.1% in the three groups. These results confirm the importance of symptomatic or asymptomatic PAD in increasing the cardiovascular risk in 10 years above 20% and therefore placing these subjects in a very high risk category (3).  

b) Medical treatment and therapy

The goal of the treatment of PAD is to

• slow down the progression of atherosclerotic lesions,
• improve the macro- and microcirculation,
• prevent or reduce the pain,
• prevent or treat trophic lesions,
• reduce the risk of fatal and non-fatal cardio- and cerebrovascular events (1).

Therapy is based on changes in lifestyle (cessation of smoking, regular physical exercise, a mediterranean diet) and on the control of RF;

Pharmacological treatment can offer

• symptom relief (1)

Antiplatelet drugs and statins

• may reduce non fatal and fatal cardiac and cerebrovascular events.

There are well-defined potential benefits of cardiovascular drugs in patients with PAD as recently demonstrated in a cohort, prospective, observational study involving 2420 patients with median age of 64 years (72% males) with PAD  and ABI = or < 0.9 (4). 18% of the patients also suffered from diabetes, 24% had hypercholesterolemia, 35% were smokers, 48% suffered from  hypertension, 44% from coronary heart disease and 9% had a history of heart failure. The average ABI was 0.58 (4). During an average follow-up of 8 years, 44% of patients died. After adjustment for RF, certain classes of drugs were associated with a reduced risk of mortality: statins, hazard ratio (HR) = 0.46; beta-blockers, HR = 0, 68; Aspirin, HR = 0.72; ACE-I, HR = 0.80 (4).

• Statins have been shown to reduce claudication intermittens and atherosclerosis while improving endothelial function and walking time

The 4S study (Scandinavian Simvastatin Survival Study) showed, for the first time, that in patients with coronary artery disease and hypercholesterolemia, followed with a follow-up of 5.4 years,  treatment with simvastatin vs placebo, reduced 38% of the incidence of new cases of claudication intermittens and about 48% of cases of carotid atherosclerosis (7).

The SISOPAD study evaluated the effects of treatment with simvastatin in 283 patients of average age of 61 years at the second stage Leriche-Fontaine. After 1 year of treatment, the patients treated with simvastatin showed an improvement of ABI values versus the baseline values, a reduction in blood total cholesterol, an increase in HDL cholesterol, a significant reduction in blood plasma fibrinogen and a significant improvement in plasma viscosity (p < 0.01). The authors thought that treatment with simvastatin probably reduced the femoral-popliteal atherosclerosis with improving of the endothelial function (8).

A recent study published by Mondillo et al. (9) showed that treatment with simvastatin improves the performance of patients with PAD thanks to its effect on plaque stabilisation and on the improvement of the endothelial function.
Eighty-six patients with intermittent claudication, and total cholesterol levels > 220 mg/dL were enrolled in a randomised, placebo-controlled, double-blind study. Forty-three patients were assigned to simvastatin (40 mg/d); the remaining 43 patients were assigned to placebo treatment. All patients underwent an exercise test and clinical examination, and completed a self-assessment questionnaire at 0, 3, and 6 months. At 6 months, the mean pain-free walking distance increased by 90 meters (95% confidence interval [CI]: 64 to 116 meters; P <0.005), in the simvastatin group versus the placebo group.

Aronow and coworkers, (10) in elderly patients (mean age 75 years) with PAD and ABI of 0.63 has shown that simvastatin, in comparison with placebo, increased walking time after 6 months of treatment. Specifically, in this study the authors have shown an increase of walking time at the treadmill of 54 sec. (+ 24%, p <. 0001) after 6 months and 95 sec. (+ 42%, p <. 0001) after one year.

Another study, conducted at Northwestern University Feinberg School of Medicine in Chicago, examined if the use of statins was associated with a smaller decline in the functioning of the lower limbs in patients with and without PAD, during a three year follow-up.

The study involved 332 men and women with ABI < 0.90 and 212 subjects with ABI between 0.90 and 1.50. After adjusting for various factors, patients with PAD who used statins had a lower annual decline in walking speed to normal step, in speed walking at fast pace, and in the process of testing than 6 minutes those who did not use statins. Data from the study showed that patients with PAD taking a statin may present a minor decline in the performance of the lower extremities (11). 

• Non fatal and fatal events in patients with PAD are reduced when treated with statins

The HPS study, which included 20,536 patients at high risk, has demonstrated the protective effect of chronic administration of simvastatin (40 mg/day) for 5 years in the subgroup of patients with PAD (n = 6748), with (n = 4042 ) or without (n = 2706) concomitant coronary artery disease, with a reduction major cardiovascular events of 22.3% (p < 0.00001) (12).

Researchers from the Vienna General Hospital have assessed the relationship between the use of statins, inflammation and outcome in patients with atherosclerosis at an advanced stage. 
515 patients with severe PAD were studied in a prospective study. Patients were 70 years old on average, and 57% were male. The observation period was on average 21 months. There were 19 reported cases of myocardial infarction and 65 patients died. Patients (n=269, 52%) treated with statins had a lower level of inflammation, and improved survival compared with patients who have not taken drugs.
However, patients with reduced inflammatory activity do not have any benefit from statin therapy, while patients with high levels of CPR (C-reactive protein) experienced a significant reduction in the risk of mortality (adjusted hazard ratio, HR: 0,58) and the composite risk of myocardial infarction and death (adjusted HR: 0.46). According to this study, treatment with statins is associated with a substantial improvement in medium-term survival in patients with severe PAD and high inflammatory activity (13).

Aronow & Ahn studied the frequency of new coronary events in 660 elderly patients with PAD (mean age 80 ± 9)  and serum levels of LDL-C > 125 mg%, treated or not treated with lipid lowering drugs and followed for a period of 39 months. Within the two groups, the following events were recorded: sudden death 19% vs 31%, IMA fatal 16% vs. 25%, IMA non-fatal 13% vs 18%, all new coronary events 48% vs. 73% (p < 0.0001) (14). Consequently, long-term administration of statins in patients with PAD is extremely useful in reducing the incidence of fatal and non-fatal cardiovascular and cerebrovascular events during follow-up.

c) Recommendations of different guidelines in the use of statins in patients with PAD

The National Cholesterol Education Programme-Adult Treatment Panel III (NCEP-ATP III) Guidelines consider patients with PAD as a high-risk group. The report identifies

- an optimal level of LDL-cholesterol <100 mg / dl and lays down a level of HDL-cholesterol <40 mg / dl in men and < 50 mg / dl in women.
- beyond the level of LDL-C, a treatment for all those subjects with a triglyceride level > 200 mg / dl (15) is recommended.

The guidelines on the prevention of cardiovascular diseases of the European Society of Cardiology (ESC) recommend

- in patients with a manifest ATS a target level of LDL-C < 100 mg%
- in those patients with multifocal ATS with previous CAD, PAD and diabetes or multiple risk factor : a desirable target of 80 mg% s (16).

The Recommendation n. 2 of the TASC II document on the control of lipids patients with PAD suggests that patients with PAD and an LDL-C > 125 mg/dl, because of the risk of having another concomitant location of atherosclerosis and a risk of mortality like the patients with known ischemic heart disease, should do

- secondary prevention, in first instance
- diet changes lifestyle followed by
- administration of statins in order to reduce LDL-C <100 mg% in both asymptomatic or symptomatic patients and < 70 mg in patients with previous AMI or diabetes or multiple RF because considered at very high risk (1)  

III - Despite all this evidence, PAD receives little attention

Despite the fact that several studies have shown that patients with PAD present a high risk of cardiovascular mortality, the disease still receives little attention. In fact, the correction of cardiovascular risk factors and secondary prevention measures are implemented effectively and less widespread than currently ago against ischemic heart disease, as shown by the data of the PARTNERS study (2).

The study demonstrated the lack of awareness of the disease both in patients and in medical care physicians. 83% of subjects diagnosed with PAD were aware of their condition and only 49% of their doctors were aware of the diagnosis of PAD. Moreover, in patients with PAD, the major cardiovascular risk factors were corrected less effectively compared with ischemic heart: high blood pressure was treated in 88% vs 95%, dyslipidemia in 56% vs. 73% and platelet antiplatelet therapy was prescribed in 54 % vs 71% of cases. This study shows that PAD is underestimated by the physician in general medicine can be a barrier to effective prevention of cardiovascular complications (2).

PAD is independently associated with an increase in the rate of mortality; it is not a rare clinical condition and simple questionnaires are able to facilitate its identification (WHO/or Questionnaire of Rose-Edinburgh), although probably the most sensitive test remains ABI (2, 3).

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Conclusion:

PAD should be properly included in the assessment of cardiovascular risk and in screening program of patients at risk. Patients with PAD actually represent a very high-risk category of fatal and non-fatal cerebrovascular and cardiovascular events. Novo S, Pitruzzella V, Novo GChair of Cardiovascular Disease, post-graduate School of Cardiology, Master of Vascular Diseases, Center for the Diagnosis of Preclinical Atherosclerosis and Secondary Prevention, Division of Cardiology, University Hospital “P. Giaccone” of the University of Palermo, Italy