Peripheral arterial disease : Role of cilostazol

1- Background

a) Prevalence

Peripheral arterial disease (PAD) is a common cause of morbidity in the general population affecting from 4% to 12% of people aged 55 to 70 years and 20% of those over 70 years of age. The most common complaint is Intermittens Claudication (IC) which is usually diagnosed by a history of muscular leg pain on exercise relieved by short rests. The prevalence of IC would appear to increase from about 3% in patients aged 40 years to 6% in patients aged 60 years (1).

b) Risk Factors

The major Risk Factors (RFs) for PAD are the well defined atherosclerotic risks such as diabetes, impaired glucose tolerance, smoking and hypertension. These are considered important RFs for the development and progression of PAD. Because PAD is an atherosclerotic disease, lipid abnormalities are also important contributing RFs. Patients with increased low-density lipoprotein (LDL) cholesterol, as well as those with elevated triglyceride levels and decreased levels of high-density lipoprotein (HDL) cholesterol have been shown to be at increased risk for PAD. Increasing age, high blood pressure, elevated homocysteine levels, lipoprotein (a), and increased fibrinogen and blood viscosity have also been described as RFs for PAD (1-3).

c) Symptomatic and asymptomatic PAD

Only a half of elderly patients with documented PAD are symptomatic. Patients with PAD may fail to mention their symptoms to their physician, or don’t feel pain for a diabetic peripheral neuropathy, or may have sufficient collateral arterial channels to tolerate their arterial obstruction.

PAD is a marker for premature cardiovascular events, even in the absence of a history of myocardial infarction (MI) or ischemic stroke; patients with PAD have approximately the same relative risk of death from cardiovascular causes as do patients with a history of coronary or cerebrovascular disease. In addition, their death rate from all causes is approximately equal in men and women and is elevated even in asymptomatic patients. Due to the presence of the high risk of ischemic events, patients with PAD should be candidates for aggressive secondary prevention strategies to decreasing cardiovascular risk, as well as improving quality of life (2).

d) Diagnostic methods

Patients with PAD of the lower extremities have diminished or absent arterial pulses. Noninvasive tests used to assess lower extremity arterial blood flow include measurement of ankle and brachial artery systolic blood pressures, characterisation of velocity wave form, and duplex ultrasonography. Measurement of ankle and brachial artery systolic blood pressures using a Doppler stethoscope and blood pressure cuffs allow calculation of the ankle/brachial index (ABI), which is normally 0.9 to 1.2. An ABI of less than 0.90 is 95% sensitive and 99% specific for the diagnosis of PAD. The lower the ABI, the more severe the restriction of arterial blood flow, and the more serious the ischemia.

2- Existing treatment

In managing PAD, it is critically important to deal with the high risk of developing severe and often fatal cardiovascular complications. The first priority is to aggressively modify RFs that enhance the progression of atherosclerosis and induce atherosclerotic complications. It is also important, however, to increase walking distance (as evaluated with treadmill test), improve quality of life, and reduce or jam the arterial injury.
The initial approach to the treatment of limb symptoms should focus on lifestyle and RFs modification and exercise added with medical treatment.

a) Lifestyle and Risks factors modification

Any lifestyle change that reduces the RFs for PAD is beneficial. Stopping or decreasing smoking undoubtedly reduces the progression of PAD (1-3). Dietary management to decrease weight and control serum lipid levels is also beneficial. The National Cholesterol Education Program – Adult Panel Three (NCEP-ATP III) as well as the TASC II guidelines recommend that patients with objective evidence of PAD receive dietary and pharmacologic therapy to achieve LDL cholesterol < 100 mg/dL (1).

b) Exercise

Various studies have shown significant improvement in pain-free walking distance and maximum walking distance in patients who followed a supervised exercise program for 6 months or longer (4).

c) Antiplatelet Drugs

The antiplatelet drugs reduce significantly the incidence of vascular death, nonfatal myocardial infarction, and nonfatal stroke. In the Clopidogrel versus Aspirin in Patients at Risk for Ischaemic Events (CAPRIE) trial, clopidogrel resulted superior to aspirin in the treatment of patients with PAD (5).

d) Naftidrofuryl

It is a 5-hydroxytryptamine type 2 antagonist and may improve muscle metabolism, and reduce erythrocyte and platelet aggregation. Naftidrofuryl has been available for treating IC for over 20 years in several European countries. In a meta-analysis of several studies involving a total of 1266 patients the ratio of relative improvement in pain-free walking distance after use of Naftidrofuryl compared with placebo was 1.37. Patients in the Naftidrofuryl group walked 37% further than patients in the placebo group. The number of patients responding to Naftidrofuryl (improvement by more than 50%) was 22% higher than the number responding to placebo. In the studies included in this meta-analysis the dose of 600 mg/ day was administered (6)

e) Pentoxyphilline

Pentoxyfilline lowers fibrinogen levels, and by operating in cell metabolism improves red cell and white cell deformability and thus lowers blood viscosity. This drug is associated with modest increases in treadmill walking distance over placebo, but the overall clinical benefits remained open to discussion 7).

f) Buflomedil

Buflomedil has an alpha-1 and -2 adrenolytic effects that result in vasodilatation. This drug has antiplatelet effects, results in improvements in red cell deformability and weakly antagonizes calcium channels. Buflomedil's benefit is small in relation to safety issues and its narrow therapeutic range (8).

g) L-Arginine

L-arginine has the ability to enhance endothelium-derived nitric oxide and, thus, improve endothelial function. Long-term administration of L-arginine may even impair functional capacity (1). Further studies would be needed to determine if this treatment would have benefit and no unacceptable risk.

h)  5-hydroxytryptamine antagonists

Ketanserin is a selective serotonin antagonist that lowers blood viscosity and also vasodilator and antiplatet drug. This treatment doesn’t improve pain free walking time compared to placebo, but in patients treated with potassium-wasting diuretics could increase risk of mortality causing arrhythmic events (9); therefore, this drug cannot be recommended at this time. AT-1015 is a selective 5-hydroxytryptamine antagonist that causes toxic side effects at high dose (10).

i) Prostaglandins

Prostaglandins in patients with claudication can be used by intravenous or oral administration; several studies in Europe and in USA have shown opposite results (11). The overall evidence does not support the use of this drug class for claudication (1).

3- New treatment

A drug with evidence of clinical utility in claudication is Cilostazol, a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. The benefits of this drug have been described in several studies (12). Propionyl-L-carnitine (an acyl form of carnitine) helping muscle metabolism has increased pain free walking time (13-14). New future Drugs are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF); they are mitogenic agents that stimulate the development of new vessels, improving blood flow in ischemic lands (15).

a) Cilostazol

Because of its antiplatelet and vasodilating effects (16) Cilostazol is widely used in clinical practice for prevention of stent thrombosis and stent restenosis. (17). It also reduces the risk of stroke by approximately 40% (18) and prevents recurrence of cerebral infarction (19). Cilostazol has been recommended in the international guidelines, TASC II (1), as first-line therapy for peripheral arterial disease because it improves the symptoms and quality of life (1, 20-22).
It inhibits type III phosphodiesterase (PDE) activity in platelets (22) and in arterial (23) and bronchiolar (24) smooth muscle cells, thereby increasing the intracellular levels of cAMP through blocking its hydrolysis. Increased intracellular cAMP inhibits thromboxane A2 production and hence platelet aggregation by inhibiting phospholipase and cyclooxygenase in the platelets (22). Cilostazol inhibits activation-dependent alpha-granule release and P-selectin expression on the surface of platelets. The vasodilator occurs by blocking release of calcium ions from intracellular storage granules within the smooth muscle cells, thus inhibiting the contractile proteins. It also exhibits antiproliferative effects on smooth muscle cells and has beneficial effects on high density lipoprotein-cholesterol and triglyceride levels.

In Europe Cilostazol is contraindicated in patients receiving CYP3A4 or CYP2C19 inhibitors because significant drug interactions are observed when Cilostazol is coadministered with other agents that inhibit cytochrome P450 (CYP) 3A4 (e.g. erythromycin or diltiazem) or CYP2C19 (e.g. Omeprazol) and in the US it is recommended that dosage reduction for Cilostazol be considered in cases of coadministration of Cilostazol and CYP3A4 or CYP2C19 inhibitors. Conversely, Cilostazol itself does not appear to inhibit CYP3A4. As already reported coadministration of Cilostazol with aspirin or warfarin did not result in any clinically significant changes to coagulation parameters, bleeding time or platelet aggregation (25).

The benefits of this drug have been described in a meta-analysis of six randomiqed, controlled trials involving 1751 patients, including 740 on placebo, 281 on Cilostazol 50 mg twice-daily (BID), 730 on Cilostazol 100 mg BID. The 73 on Cilostazol 150 mg BID and 232 on pentoxyfilline 400 mg thrice-daily (TID) were excluded from the analysis (12). This analysis demonstrated that the net benefit of Cilostazol over placebo in the primary endpoint of peak treadmill performance ranged from 50 to 70 meters depending on the type of treadmill test performed. Cilostazol treatment also resulted in a significant overall improvement in the quality of life measures from the WIQ and SF-36. In another study, comparing Cilostazol to pentoxyfilline, Cilostazol was more effective (26). Side effects included headache, diarrhea, and palpitations. An overall safety analysis of 2702 patients revealed that the rates of serious cardiovascular events, and all-cause and cardiovascular mortality were similar between drug and placebo groups (27).

A recent randomised, double-blinded, placebo-controlled safety study of Cilostazol (CASTLE study) enrolled a total of 1899 subjects with a clinical diagnosis of PAD and symptoms of claudication. Cilostazol was administered at a primary dose of 100 mg twice daily. The dose could be reduced to 50 mg twice daily if patients experienced an adverse event that might have been drug related. The treatment lasted 2 years. The rates of bleeding events were similar in patients who used aspirin, aspirin plus clopidogrel, or anticoagulants at anytime during the course of the study and this study had shown no different incidence of mortality in two groups (21).

Cilostazol had got a better antiplatet function in patients with type 2 diabetes mellitus who have reduced platelet inhibition compared with non-diabetics following P2Y (12) receptor blockade; this is why these patients can’t respond well to clopidogrel. A pilot study enrolled 25 patients and analyzed the antiplatet action of Cilostazol in Patients with type 2 diabetes mellitus. The patients on dual antiplatelet therapy were assigned to receive Cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment assignments for another 14 days. The P2Y (12) reactivity index, determined through flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein, was the primary endpoint measure. Cilostazol adjunctive treatment in type 2 diabetes mellitus patients on standard dual antiplatelet therapy enhances inhibition of platelet P2Y (12) signaling (28).

A recent study has also shown a better antiplatet action in patients with coronary stent. During 1 year 127 patients successfully treated with endovascular therapy, for de novo femoropopliteal lesions, were randomised to receive Cilostazol (200 mg/d) or ticlopidine (200 mg/d) in addition to aspirin (100 mg/d). Freedom from target lesion revascularisation and all adverse events (restenosis, amputation, and death) was significantly higher in the Cilostazol group than in then ticlopidine group, even though bleeding complication rates were similar between the two groups (29).The impact of cilostazol on left ventricular volume and function was evaluated in patients with acute myocardial ischemia, the group of patients treated with this drug had a higher heart rate and numerous arrhythmias, but cilostazol had no adverse influence on LV remodeling or LV function (30). 

Cilostazol was generally well tolerated. Adverse events reported are diarrhea, abnormal stools, infection, rhinitis and peripheral edema in comparison with pentoxyfilline which adverse events were headache, diarrhea, abnormal stools and palpitations. Events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal.

b) Propionyl-L-carnitine

PAD patients have Carnitine metabolism alterations. This effect is associated with an increase in total Carnitine content in the ischemic muscle and a decrease in plasma lactate concentration on exercise, the latter probably resulting from a reduction in the ratio of acetyl–coenzyme A (acetyl-CoA) to CoA. Indeed, Carnitine is a physiological modulator of the mitochondrial pool of acetyl-CoA, and acetyl-CoA is an end-product inhibitor of pyruvate dehydrogenase. Through the action of Carnitine acetyltransferase (CAT), Carnitine depletes acetyl-CoA and releases free CoA and acetyl Carnitine, which, may be transported out of the cell and released in the bloodstream. This acyl scavenging process, which requires adequate availability of Carnitine, becomes crucial under conditions of limited oxygen availability, when the shortage of free CoA limits the mitochondrial oxidation of both pyruvate and  -ketoglutarate, and the concurrent accumulation of CoA esters results in inhibition of the enzymes involved. Indeed, increased levels of short-chain acylcarnitines, mostly acetylcarnitine, occur in muscle and plasma of normal subjects performing maximal exercise (31). In such patients, Carnitine supplementation restores a normal Carnitine homeostasis, improves the efficiency of oxidative phosphorylation and lessens symptoms of claudication (13). Propionyl-L-Carnitine, one of the most potent analogues of Carnitine, restores normal Carnitine homeostasis, improves the efficiency of oxidative phosphorylation and lessens symptoms of claudication.

In two multicentric trials, with a total of 730 patients with PAD, the treatment with Propionyl-L-Carnitine improved symptoms compared to placebo. Maximal walking distance and distance walked at onset of claudication showed significant improvement. This treatment improved quality of life and had minimal side effects when compared with placebo (13, 31). Additional trials in the broad population of patients with claudication will be necessary to establish the overall efficacy and clinical benefit of these drugs.

To obtain satisfactory results, it is important select a target population for Propionil-L-Carnitine therapy. Patients who had a decrease in acetylcarnitine with exercise and had high resting levels of this ester had a significantly lower walking capacity; these patients responded well to this treatment. In fact, Propionyl-L-Carnitine induced a significant improvement in time to initial claudication pain. Patients who had a significant increase in plasma acetylcarnitine concentration at peak exercise and a plasma concentration of acetylcarnitine at rest similar to that in general population did not modify exercise performance with this treatment (13).

c) VEGF and bFGF

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) stimulate the development of new vessels. When bFGF protein was given intra-arterially, patients with claudication had an improvement in exercise performance (17). Newer applications deliver the agent as gene therapy in a viral vector given intra-muscularly. A recent study tried repeated administration of VEGF gene in rabbit’s ischemic muscle and showed at 90 days of repeated transfection, gene expression decreased significantly, but neovessel densities did not.

Thus repeated VEGF gene transfection resulted in increased microvasculature, which, in turn, afforded effective protection against ischemic muscle damage (32). When bFGF protein was given intra-arterially, patients with claudication had an improvement in exercise performance.

Conclusion:

Treatment for PAD requires many steps and there are numerous suggested drugs but not all hold sufficient supporting evidence of clinical utility in claudication. Treatment goals are to relieve symptoms, improve exercise performance and daily functional abilities. Useful steps toreach these results today are the modification of risk factors and of lifestyle first, exercise rehabilitation second and drug treatment last.

Cilostazol and Propionyl L carnitine are both excellent drug treatments in patients with claudication. They are likely to increase the maximal walking distance and distance walked at onset of pain and improve patient’s quality of life with minimum side effects.  Propionyl L Carnitine may improve muscle metabolism but needs more scientific support. The TASC II recommends Cilostazol and Naftidrofuryl as the best treatments for peripheral artery disease, and define cilostazol as having “the best overall evidence for treatment benefit in patients with claudication” (1).