Lipid-lowering therapy in patients with peripheral artery disease

Introduction

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and is therefore associated with an increased cardiovascular risk [1]. Patients with PAD often have simultaneous coronary artery and cerebrovascular disease, with high cardiovascular morbidity and mortality. Although coronary artery disease and peripheral artery disease share the same risk factors, there are considerably fewer studies concerning risk factor modification in peripheral artery disease than in coronary artery disease. However, risk factor modification is of the outmost importance if we consider the fact that the mortality risk is also increased in patients with PAD without co-existing coronary artery disease and in asymptomatic patients with PAD diagnosed through routine screening [2,3]. These observations should raise awareness about the high prevalence of PAD, the large number of undiagnosed cases of PAD and its importance as an indicator of systemic atherosclerosis. Therefore, routine ankle-brachial index (ABI) measurements should be used in order to identify patients with high cardiovascular risk and risk factor reduction should be implemented early after the diagnosis has been established.

Another major concern regarding patients with PAD is impaired quality of life due to symptoms of claudication, rest pain or risk of limb loss. Although the symptoms in patients with PAD worsen in time, with a decline of functional capacity, severe peripheral complications in these patients are relatively infrequent compared to cardiac complications. Long time symptomatic patients are more likely to receive intense medical treatment and are candidates to lower-extremity peripheral revascularization, which makes critical limb ischemia and amputations rare events. The number of these complications seems to be higher, though, in patients who associate chronic kidney disease or diabetes.

For patients with PAD, aggressive risk factor modification is the first approach to be considered, followed by early intensive medical therapy.

In clinical practice, the major questions to be addressed regarding lipid-lowering therapy in patients with PAD are:

• Which are the strategies to be used for lowering the cardiovascular risk?
• What are the clinical benefits of lipid-lowering treatment in PAD?
• Which lipid fractions should be targeted?
• What is the target low-density lipoprotein (LDL) value in patients with PAD?
• How low is low enough?
• What should be monitored during statin therapy?

Reduction of cardiovascular risk

Among cardiovascular risk factors, dyslipidemia (especially high LDL cholesterol) predicts the risk of cardiovascular events, so an attempt to reduce cardiovascular mortality and morbidity in patients with PAD should include lipid-lowering therapies. Diet is the first step for lowering serum cholesterol, along with statin therapy, which is mandatory. Although other lipid-lowering therapies have been tested, some of them being relatively successful concerning the stabilization of atherosclerotic lesions, the improvement of symptomatology or the reduction of cardiovascular risk, the benefits of statin therapy are multiple, so statins represent, so far, the standard therapy for primary and secondary prevention of cardiovascular disease. The largest study on cholesterol-lowering therapy in patients with peripheral artery disease (the Heart Protection Study) showed that treatment with simvastatin 40 mg daily reduced the rate of major vascular events by about a quarter, independent of the baseline cholesterol, and also reduced the rate of peripheral vascular events by 16%, mainly because of a relative reduction of non-coronary revascularizations (including amputations) [3]. Simvastatin treatment reduced the rate of first major vascular events in patients with PAD without pre-existing coronary disease, and also prevented the occurrence of subsequent events. Interestingly, this risk reduction was independent of the severity of pre-existing peripheral arterial disease: similar risk reduction was observed in patients with prior peripheral arterial revascularizations or amputations and in patients with less severe PAD.

These results have been further supported by the data of a Cochrane meta-analysis, which analyzed 17 lipid-lowering trials and revealed a 26% reduction of cardiovascular events in patients with PAD treated with statins, mainly due to a reduction in coronary events [4]. Although a number of lipid-lowering drugs were assessed, the most consistent benefits on cardiovascular mortality and morbidity were shown by statins, particularly simvastatin, when used in patients with high serum cholesterol (≥ 3.5 mmol/L).

Improvement of quality of life

Regarding functional capacity, lipid-lowering therapy has also proved to be beneficial, multiple studies showing an improvement of walking performance and claudication.

The same Cochrane meta-analysis mentioned above showed the impact of different lipid-lowering drugs on PAD symptoms [4]. Although there was not a significant change of ABI after lipid-lowering treatment, an improvement in the total walking distance and pain-free walking distance was observed.

The results of POSCH (Program on the Surgical Control of the Hyperlipidemias) showed that cholesterol reduction by partial ileal bypass surgery leads to a reduction in the development of clinically evident PAD and of ABI values, although no changes were observed in the peripheral arteriograms after a mean follow-up period of 10 years[5].

The Scandinavian Simvastatin Survival Study demonstrated a reduction by 38% of the risk of new or worsening intermittent claudication in the simvastatin group vs the placebo group, over a follow-up period of 5.4 years [6]. This study demonstrated the beneficial effects of statins in slowing the process of atherosclerosis, no matter its location, by also reducing the incidence of carotid bruits and of new or worsening angina. In addition, simvastatin treatment showed improvement in total walking distances and pain-free walking distances in two other studies [7,8]. Short-term therapy (6 months) with simvastatin 40 mg/day improved not only the walking performances, but also the resting and post-exercise ABI and the symptoms of claudication, quantified with self-assessment questionnaires. Moreover, these effects proved to be significant even at the 3 months evaluation [7]. However, the benefits seem to be higher with long-term treatment. A placebo-controlled study by Aronow et al showed an improvement in the pain-free walking time of 54 sec after 6 months and 95 sec after one year, supporting the long-term intensive statin treatment in patients with PAD [8].

Although simvastatin was the most common used statin in studies of PAD, it appears that atorvastatin can also improve the symptomatology of patients with PAD [9]. Two atorvastatin dosing arms, 10 mg/day and 80 mg/day were compared to a placebo group in a study. As expected, a significant reduction in total cholesterol, LDL-cholesterol and triglycerides levels was noticed, as well as a significant increase in HDL-cholesterol in both arms receiving atorvastatin (without a significant difference between these two dosing arms), compared to the placebo group. Although neither the ABI across groups, nor the primary end-point of maximal walking distance showed a significant change compared to placebo, the pain-free walking distance improved by 63% in the 80 mg atorvastatin treatment group.

Pleiotropic effects of statins

The beneficial impact of statins in patients with PAD is explained not only by their lipid-lowering properties, but also by their pleiotropic effects.

Statins play an important role in stabilization and regression of atherosclerotic lesions, a fact supported by studies that used imaging methods. Pravastatin therapy slowed the progression of peripheral atherosclerosis in men <70 yo with coronary artery disease, serum cholesterol between 155 and 310 mg/dL and triglycerides <354 mg/dL, as demonstrated by ultrasonographic measurements of carotid and femoral intima-media thickness (IMT) during a 2-year time period, although the clinical implications on symptoms and functional capacity were not verified [10]. Although peripheral artery atherosclerosis appears to be a marker of systemic atherosclerosis, the evolution of atherosclerosis in peripheral arteries showed a poor correlation with the evolution of atherosclerosis in coronary arteries. This observation demonstrates the great variability in atherosclerosis not only in different individuals, but also in different locations in the same patient.

Low doses of atorvastatin (20 mg/day) also showed a significant effect on common femoral artery IMT, the difference being noticeable beginning with the 4^th week of treatment [11]. This rapid effect was attributed to the anti-inflammatory properties of statins.

Besides stabilization and regression of atherosclerotic plaques, statins were shown to reduce inflammation (reflected in lower levels of hs-CRP, fibrinogen, serum neutrophils) which, in patients with PAD, correlates with better survival and event-free survival rates (mean follow-up period of 21 months) [12]. This reduction in the risk of mortality and the composite risk of myocardial infarction and death was noticed especially in patients with high inflammatory status; patients with low inflammatory activity (quantified as hs-CRP < 0.42 mg/dL) had no such benefit from statin treatment. Therefore, one of the most important mechanism by which statins improve the outcome in atherosclerotic patients may be the reduction of vascular inflammation.

Furthermore, statins were shown to improve the endothelial dysfunction and the reduced levels of nitric oxide associated with dyslipidemia, which, in turn, leads to an improvement of blood flow in the microcirculation [13]. However, the impact of statin treatment on vasodilation through increasing the nitric oxide in lower extremity arteries has not been assessed yet in large studies.

Non-statin lipid-lowering therapy

Although data from the Framingham Study indicated that the lipid profile of patients with PAD is that of metabolic syndrome (high level of triglycerides and low level of high-density lipoprotein)[14], the impact of lowering the other lipid fractions in patients with PAD has been studied less than the effect of lowering the LDL-cholesterol (LDL-C)level.

A study evaluated the effect of benzafibrate on cardiovascular events in patients with PAD and demonstrated a significant reduction in triglycerides level by 23.3% and in LDL-C level by 8.1%, as well as a rise in HDL-C level by 8% [15]. However, the clinical benefits were not as satisfactory. Benzafibrate treatment showed a reduction in the incidence of non-fatal coronary events, but failed to prove any benefits regarding coronary heart disease and stroke. Colestipol plus niacin in the Cholesterol Lowering Atherosclerosis Study (CLAS) also led to a decrease of serum triglycerides and an increase of high-density lipoprotein cholesterol (HDL-C), along with a decrease in LDL-C, which correlated with a slower progression of atherosclerosis in femoral arteries, although less marked than expected, considering the previous results in coronary artery disease [16].

Ezetimibe, another lipid-lowering drug which proved to lower LDL-C when added to statins, was also assessed in patients with PAD [17].One study tried to evaluate the evolution of atherosclerotic plaques in the superficial femoral artery by using magnetic resonance imaging in patients with PAD, treated with statin or statin plus ezetimibe. Statin initiation, with or without ezetimibe, proved to stop the progression of atherosclerosis. Interestingly, adding ezetimibe to patients previously treated only with statin led to a progression in peripheral atherosclerosis, despite a 22% decrease in LDL-C. These results correlate with those of a different study which compared the effects of niacin added to statin to ezetimibe added to statin therapy [18]. Although the combination of ezetimibe plus statin led to a greater reduction in LDL-C, the use of niacin in addition to statin led not only to a rise in HDL-C, as expected, but also to a significant reduction in cardiovascular events and regression of carotid intima-media thickness over a follow-up of 14 months. On the contrary, there was a paradoxical increase in the carotid intima-media thickness in patients with lower LDL-C levels among those treated with ezetimibe. Although this study did not assess peripheral arteries, it seems that ezetimibe does not reduce the cardiovascular risk and does not prevent the progress of disease in patients with PAD.

Monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) have emerged in the last years as a promising new class of drugs very effective in lowering LDL-C. A recent meta-analysis that included 24 trials evaluated the effects of PCSK9 antibodies on dyslipidemic patients who had not reached LDL-C goals with statin therapy or who were statin intolerant [19]. PCSK9 inhibition led to a 47% reduction in LDL- cholesterol and the relative reduction was similar in patients receiving statin therapy and those that did not receive statin therapy, which makes PCSK9 inhibitor a good adjunct treatment in patients with a non-sufficient response to statins. More importantly, PCSK9 inhibitors showed a significant reduction in all-cause mortality, cardiovascular mortality and myocardial infarctions. However, although these results are encouraging, larger studies are required in order to better characterize these drugs and to assess their possible role in peripheral atherosclerotic disease.

Guideline recommendations

The European Society of Cardiology guidelines for the diagnosis and treatment of peripheral artery disease recommend a target LDL-C below 100 mg/dL, optimally below 70 mg/dL (class 1 recommendation), in all patients with PAD, regardless of the baseline LDL-C levels. When the target level cannot be reached, a reduction >50% in LDL-C should be attempted [1]. These recommendations are similar to those of the American College of Cardiology (ACC)/American Heart Association, which suggest a target LDL-C level <100 mg/dL (class I recommendation) in all patients with PAD, and an LDL-C level <70 mg/dL for patients at very high risk of ischemic events (class 2a recommendation). For patients with PAD and high triglycerides/low HDL-C, but normal LDL-C, ACC has a class 2a recommendation for the use of fibric acid derivatives [20].

How low is low enough?

Although a threshold for LDL-C is recommended by the guidelines, there are still questions about the optimal treatment regimen that should be adopted in patients with PAD. How intensive should statin therapy be and what is the threshold at which the possible benefits of statin therapy are outweighed by their adverse effects? A study that included over 1,300 patients over a period of 15 years showed that higher doses of statins and lower LDL-C levels are both independently associated with improved outcome in patients with PAD [21]. This finding comes to support the benefits of statins beyond their lipid-lowering properties. Concern is raised, however, by the fact that too low cholesterol levels might affect serotonin and steroid hormone production, as well as cell membrane function (as cholesterol is an important constituent of cell membranes), with severe health consequences. Although some initial studies suggested that a lower cholesterol level might increase the incidence of non-cardiovascular deaths (by violence or suicide), recent trials (with statins and PCSK9 inhibitors) have weakened such an association. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER Trial) assessed the impact of low levels of LDL-C (bellow 50 mg/dL) on cardiovascular events and adverse effects [22]. During a median follow-up period of 2 years, the rates of adverse effects were similar in the placebo and rosuvastatin groups, except for muscle symptoms. Although these symptoms were more frequent in the rosuvastatin group, they were not different in rosuvastatin-treated patients with LDL-C lower or higher than 50 mg/dL. Rates of neuropsychiatric disorders, renal dysfunction, hemorrhagic stroke and cancer were not significantly different between patients treated with statins that reached a LDL-C level < 50 mg/dL and patients that received placebo. Moreover, rosuvastatin reduced the rate of cardiovascular events by 44% compared with placebo and by 65% in patients that attained an LDL-C < 50 mg/dL. The all-cause mortality was also reduced by 20% in patients receiving rosuvastatin and by 46% in patients that attained LDL-C < 50 mg/dL, which clearly shows that the benefits of intensive statin treatment outweigh the possible adverse effects.

What should be monitored during lipid-lowering therapy?

There is limited evidence regarding the monitoring of lipid-lowering therapy. European Society of Cardiology guidelines recommend a first assessment of the response to therapy at 8 (+/- 4) weeks, and annual follow-up monitoring once the patient has reached the targets. However, this monitoring interval is arbitrary [23]. Similarly, American College of Cardiology guidelines recommend a fasting lipid panel within 4-12 weeks after initiation of treatment, followed by other assessments every 3 to 12 months[24]. Although there is no clear evidence of a high risk of adverse effects at low LDL-C levels, the American guidelines suggest decreasing the dose of statin if two consecutive values of LDL-C are below 40 mg/dL.

The most common adverse effect of statins is myalgia (a class side effect), without creatine kinase (CK) elevations; rhabdomyolysis (CK >10000 IU/L or CK >10 x ULN [upper limit of normal] with serum creatinine elevation) is a far less common side effect. Considering this evidence, both European and American guidelines on the management of dyslipidemias do not recommend routine measurements of creatine kinase in patients receiving statin therapy [23,24]. After assessment of the baseline CK, further measurements should be reserved for patients who exhibit muscle symptoms, especially for patients at risk (elderly patients, on multiple medications, or with liver or renal disease). Severe or moderate muscle symptoms should prompt for discontinuation of statin treatment and evaluation of symptomatology. After the symptoms disappear and no other contraindication exists, the American guidelines recommend the same dose or a lower dose of the same statin [24]. If this is not tolerated, a different statin at a low dose can be used, with further increase of dosage. At the same time, other possible causes for myalgia must be excluded. According to European guidelines, statin therapy should be stopped if CK rises above 5 x ULN with no further indications regarding the period of discontinuation, other possible options being left to the decision of the clinician [23].

Both the European and American guidelines recommend baseline measurement of hepatic aminotransferases levels (ALT) before initiation of statin treatment. The ACC/AHA recommend further measurements of liver enzymes only if symptoms of hepatotoxicity arise (fatigue, loss of appetite, dark-colored urine, yellowing of the skin). On the other hand, European guidelines support routine measurements of ALT at 8 weeks after starting statin treatment and annually thereafter, if liver enzymes are not significantly elevated (<3 xULN) [17]. Higher values may prompt for treatment interruption, with the possibility of reintroduction of therapy after the ALT values return to normal.

Statins also appear to modestly increase the risk of type 2 diabetes. However, the benefits of statins outweigh this possible side effect and no particular recommendations regarding diabetes screening have been made. Furthermore, patients who develop diabetes during statin treatment are encouraged to continue the statin therapy, in order to reduce the cardiovascular risk.

In conclusion, patients with PAD are in the high cardiovascular risk category due to systemic atherosclerosis. Therefore, the first major step in treating these patients is risk factor modification, dyslipidemia representing one critical point to be addressed. Until further studies assess the effectiveness of other novel lipid-lowering drugs, statins remain the key drugs to be used since they have demonstrated a clear reduction in cardiovascular and cerebrovascular events. Moreover, although other therapies seem to effectively improve the lipid profile, they are yet to be assessed regarding the possible benefits they could have on cardiovascular risk and the symptomatology of patients with PAD. Further studies should also improve our understanding of the role statins play in endothelial dysfunction, microcirculation and inflammation, in order to better use them in clinical practice.