A new era of medical therapy for peripheral artery disease
Until recently, medical therapy has always played a secondary role in the management of symptomatic peripheral artery disease, focusing on control of risk factors for atherosclerosis. Strict medical treatment had limited results in avoiding clinical outcomes caused by the evolution of atherosclerotic disease.
Among the most desirable pleiotropic effects of statins in PAD we can list the reduction of platelet activation, endothelial disfunction and inflammatory responses related to the progress of atherothrombotic disease.
Statins also have an important influence in the physiology of coagulation, decreasing thrombin generation and enhancing thrombomodulin expression which results in a synergic effect over endogenous anticoagulant processes.
The clinical benefits of statin therapy for patients going under major non-cardiac arterial surgery was well documented by Durazzo et al. In a prospective, double-blind trial comparing perioperative use of atorvastatin versus placebo, the authors observed a 18% absolute reduction in the composite outcome of death from cardiovascular causes, acute myocardial infarction, ischemic stroke and unstable angina for the statin group.
Recent investigations also showed the role of rivaroxaban in the prevention of cardiovascular events in patients with stable cardiovascular disease. The COMPASS study
The COMPASS PAD sub-study
Tocilizumab is a drug that targets interleukin-6 and is primarily used for therapy of several rheumatologic disorders. Recently, FDA has approved tocilizumab as a treatment for giant cell arteritis. The combined use of tocilizumab plus prednisone for 26 weeks resulted in a 53 to 56% sustained remission (absence of giant-cell arteritis signs and symptoms, erythrocyte sedimentation rate < 30 mm/h, C-reactive protein < 1 mg/dL) rate in 52 weeks against a 14-18% remission rate for the prednisone plus placebo group.
Evolocumab is a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor that leads to an expressive reduction in LDL-Cholesterol plasma levels. The Fourier clinical trial
Interleukin-1β is strongly related to inflammatory processes, as well as atherosclerosis formation and progression. Canakinumab is an interleukin-1β inhibitor, tested in a prospective, double blind trial against placebo for patients with previous myocardial infarction and persistent inflammatory activity defined by high-sensitivity C-reactive protein levels equal or above 2mg/L. The primary efficacy end point was a composite of cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death). There was a significant (14-15%) reduction in the composite end point for patients who received the higher doses of canakinumab (150mg or 300mg every 3 months) in the median follow-up time of 3.7 years.
Inclacumab directly links to P-selectin, a cell adhesion molecule, inhibiting its inflammatory and thrombotic effects.
In conclusion, we can see evidences of an important change in the scenario of clinical therapy of peripheral artery disease in the present and in a near future. These new therapeutic possibilities will change the fate of PAD patients in all stages of their disease, with a very likely impact in the future of surgical/interventional therapy.
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