Overview of treatments for Peripheral Arterial Disease (PAD)

Treatment of cardiovascular diseases (CVDs) is often fraught with difficulties stemming from the very nature of the cardiovascular system and the many organ systems dependent on its flawless function. The challenges are even greater if there is more than one CVD at play and if it has few, if any, symptoms, delaying proper treatment and management.

Atherosclerosis of arteries of the lower-extremities, most commonly referred to as peripheral artery disease (PAD) or, emphasizing the afftected area, lower-extremity artery disease (LEAD), fits the description perfectly. It affects an increasing number of individuals worldwide (e.g. just in 2010 alone, more than 202 million individuals had the disease), but there are probably far more of them since PAD is more often asymptomatic (nearly 40% of patients) than symptomatic (only about 10% of cases) and can be reliably diagnosed only with the use of modern diagnostic methods [1, 2, 3]. On top of that, there is significant comorbidity (not surprisingly as diagnosis of atherosclerosis in the lower extremities is indicative of its possible presence in other arterial beds) with a myriad of other, far more serious CVDs and non-cardiovascular conditions (i.e. diabetes).

Coronary artery disease (CAD) is a good example as nearly 42% of patients with PAD also have this deadliest of CVDs (an estimated 9.43 million deaths in 2016) and they suffer worse outcomes (including higher mortality rate) than those with either disease [4, 5, 6, 7]. The detrimental effects of comorbidity on the severity of outcome were likewise documented in those with PAD and a history of cerebrovascular issues (stroke, transient ischaemic attacks) with the distinction that those patients with such a diagnosis fare even worse than those with PAD and CAD [8].

Intermittent claudication, the most typical symptom of PAD, is far more prevalent in diabetics: 3.5 times more in males and 8.6 times more in females.

Diabetes mellitus is in a league of its own when it comes to PAD, both in terms of increased incidence (alteration of atherogenic process) and greater prevalence of symptoms and severity of complications. Intermittent claudication, the most typical symptom of PAD, is far more prevalent in diabetics: 3.5 times more in males and 8.6 times more in females (in comparison with non-diabetics of respective gender) [9]. Additionally, between 50% and 76% of patients with critical limb ischaemia (CLI) are also diabetic and have worse outcomes (higher amputation rates, mortality) than non-diabetics [10, 11 12]. Diabetes naturally (negatively) affects other comorbid CVDs as well, necessitating a holistic approach to treatment in such patients.

Conservative vs. invasive treatments

Treatment and management of PAD should initially be conservative, although those with an advanced form of the disease, particularly if they already have severe intermittent claudication or even arterial (insufficiency) ulcers (ischaemic ulcers/wounds), or a history (diagnosis) of comorbid conditions (CVDs, diabetes, etc.) generally require a more aggressive (surgical) approach. This does not, however, diminish the contribution of even the most trivial (at first glance) conservative measures, like lifestyle modification (reduction of risk factors like smoking, unhealthy eating, and bodyweight with an increase in physical activity and diligent control of hyperglycaemia), which have compounding positive effects on recipients of other types of treatment. Studies have shown that secondary risk reduction (lifestyle changes) in patients with both PAD and diabetes improves recovery post revascularisation [13].

In addition to lifestyle modifications, conservative treatment of PAD also consists of medications that target risk factors for atherosclerosis, i.e. hyperlipidaemia and hypertension, and reduce the likelihood of thrombosis. Hyperlipidaemia is most commonly managed with statins (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin and pitavastatin and others) and there is considerable evidence of their efficiency in decreasing the incidence of cardiovascular events and mortality [14]. Results of the Heart Protection Study (HPS) conducted in the United Kingdom have shown that patients (with CAD or other arterial occlusive arterial disease, including PAD or diabetes) who were subjected to a daily regime of 40 mg of over a 5-year period had a 12% reduction in total mortality, 17% reduction in vascular mortality, 27% reduction in stroke, 24% reduction in CAD-related events and a 16% reduction in (non-coronary) revascularisation procedures [15].

Hypertension is a significant risk factor for PAD, though it also contributes to increased risk of adverse outcomes in patients with already diagnosed disease.

Hypertension is a significant risk factor for PAD, though it also contributes to increased risk of adverse outcomes in patients with already diagnosed disease (lowering blood pressure through lifestyle modification or medication leads to a reduction of cardiovascular events) [16]. It is recommended to keep the pressure at 140/90 mmHg or lower (not just in patients with PAD) [17]. The list of recommended medications likewise includes angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which have a proven record of reduction of cardiovascular events in patients with PAD [18, 19].

In addition to antihypertensive measures, patients derive significant benefits from an antiplatelet therapy—clopidogrel is particularly effective in the reduction of adverse outcomes [20]. Some patients with symptomatic PAD, i.e. suffering from intermittent claudication, may also benefit from medications like cilostazol (phosphodiesterase III inhibitor) and naftidrofuryl (5-hydroxytryptamine type 2 antagonist), which increase the pain-free walking distance [21].

The benefits of a conservative approach become limited in patients with an advanced stage of PAD, with arterial ulcers or CLI and in immediate danger of possible limb loss, which require surgery to restore acceptable blood flow. The most common surgical procedures are bypass surgery, endovascular intervention, atherectomy and angioplasty with stent placement. Bypass surgery is one of the most common procedures, but is superseded in a significant portion of patients (not in all as some are better candidates for bypass than other procedures) by another, less risky procedure (bypass surgery has high mortality and complication rates) [23].

This less risky procedure is endovascular intervention which is associated with fewer procedural complications in the 30-day period after surgery and higher revascularisation rates at 1 and 3 years post procedure in patients with symptomatic PAD [24]. Atherectomy (endovascular removal of atheromatous tissue with the goal of enlarging the treated lumen) is an even more specialised procedure involving endovascular devices for removal of plaque with the use of integrated cutting/drilling/sanding tool or an excimer laser (photoablation of plaque)—the procedure has proven to be especially useful for treatment of PAD in the infrainguinal space [24]. Angioplasty with stent placement (not a standard part of the procedure, but restenosis is more frequent in the absence of stenting) is another endoscopic procedure with several important benefits for the patient, including shorter hospitalisation and fewer complications, but less durable patency [25].

Clinicians tasked with treating and management of PAD have many tools and methods at their disposal, although they hardly outweigh preventive measures that would decrease the incidence of the disease or contribute to its early diagnosis.