Farmaci vasoattivi e riabilitazione Società Triveneta di Chirurgia 3° Meeting Euganeo di Chirurgia Vascolare ISCHEMIA CRITICA DEGLI ARTI INFERIORI TRA TERAPIA MEDICA, CHIRURGIA E TRATTAMENTI ENDOVASCOLARI Farmaci vasoattivi e riabilitazione Nello Zanatta - Conegliano 14 novembre 2014 - Este

Algorithm for treatment of the patient with critical limb ischemia 50% 25% 25% 6 months later 40% will lose their leg up to 20% will die TASC II Working Group, 2007

Adherence to Guideline‐Recommended Therapy Is Associated With Decreased Major Adverse Cardiovascular Events and Major Adverse Limb Events Among Patients With Peripheral Arterial Disease Armstrong E J et al. J Am Heart Assoc 2014;3

Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement E. Benoit et al. J Vasc Surg 2012;55:781-9

ISCHEMIA CRITICA: FISIOPATOLOGIA possibili sedi di intervento Rivascolarizzaizone Farmaci vasodilatanti Framaci “microcircolatori” Pentossifillina Naftidrofurile Cilostazolo Prostanoidi Antiaggreganti Anticoagulanti Lambert M.A. et al. J Intern Med 2013; 274: 295–307.

PROSTANOIDI Analoghi sintetici di PGI2 PGE1: Alprostadil iloprost treprostinil, epoprostenol, Beraprost ….. PGE1: Alprostadil Gryglewski RJ Pharmacological Reports, 2008; 60: 3-11

PROSTANOIDI PG e TX sono ormoni paracrini, sintetizzati in molti differenti tessuti, per agire localmente Non sono immagazzinati, ma continuamente sintetizzati e rilasciati nella circolazione Sono inattivati al primo passaggio attraverso i polmoni Tempi di vita media da 30 sec. a qualche minuto Si rivolgono a diversi gruppi di recettori, diversamente sensibili ai singoli prostanoidi e diversamente distribuiti nei tessuti e negli organi

Effetti dei prostanoidi Sono dotati di potenze elevatissime, e responsabili di una eccezionale varietà di effetti farmacologici Iloprost: EP1 > IP >> FP > EP3 = EP4 > DP1 > EP2 > TP PPARα/δ Treprostinil: DP1 = EP2 > IP > EP1 > EP4 > EP3 > FP > TP PPARα/ Alprostadil: EP1IP > EP2 > EP4 > EP3 Ricciotti E et al. Arterioscler Thromb Vasc Biol. 2011;31:986-1000.) Whittle B.J. et al.BiochemicalPharmacology84(2012)68–75

Alcuni effetti sul sistema cardiovascolare PROSTANOIDI: Alcuni effetti sul sistema cardiovascolare Effetto anti-aggregante piastrinico Effetto anti-coagulante indiretto (↑ tPA, ↓ PAI-1; ↓ F 1+2) Effetto inotropo positivo (iloprost) Regolazione proliferazione e fenotipo leiomiociti vascolari (IP/PPAR) Riduzione dell’incremento di permeabilità vasale nella flogosi Incremento delle cellule progenitrici endoteliali circolanti (iloprost) Riduzione della produzione di TNF-α e dell’espressione del recettore TNF- RII (iloprost) Neoangiogenesi (↑ VEGF via PPAR-α) (iloprost) L’angiogenesi indotta da iloprost è simile a quella indotta da VEGF Meini S. et al.2010

Effetti collaterali dei prostanoidi Flushing, cefalea, nausea e vomito Ipotensione, dolori addominali crampiformi, diarrea, sudorazione, astenia, sensazione di calore Dolori crampiformi ai polpacci, artralgie, parestesie, senso di stanchezza, ipertermie, febbre, senso di freddo, stato confusionale, agitazione, apatia, ipertensione arteriosa, tachicardia, aritmia Schellong S et. Al: Prostaglandins LeukotEssentFatty Acids.2004 Jun;70(6):503-9.

Treatment of limb threatening ischaemia with intravenous iloprost: a randomised double-blind placebo controlled study. U.K. Severe Limb Ischaemia Study Group. P<0.01 p<0.05 Guarigione o riduzione dell’ulcera; riduzione del dolore P<0.05 Eur J Vasc. Surg 1991 Oct;5(5):511-6.

A meta-analysis of randomized placebo control trials in Fontaine stages III and IV peripheral occlusive arterial disease Iloprost0,5-2 ng/Kg/m’x 6h/die per un periodo variabile da 2 –4 settimane Loosemore T et alt. IntAngiol1994;13:133–142

Prostanoids for Chronic Critical Leg Ischemia A Randomized, Controlled, Open-Label Trial with Prostaglandin E1 Scopo: valutare l’efficacia di Alprostadil (60 μg/die per 3-4 settimane) in 771 pazienti affetti da AOP stadio LF III e IV (rispetto a 789 pz in terapia convenzionale) P<0.001 P<0.001 P=0.074 P>0.2 RR:0.87 RR:0.92 End-point periferico: amputazioni maggiori o persistenza della CLI (dolore a riposo o ulcere) End-point combinato: end-point periferico, morte per qualsiasi causa, eventi vascolari maggiori non fatali (IMA, ICTUS) The ICAI Srudy Group Ann Intern Med. 1999;130:412-421

Parenteral therapy with lipo-ecraprost, a lipid-based formulation of a PGE1 analog, does not alter six-month outcomes in patients with critical leg ischemia RCT multicentrico, in doppio cieco vs placebo: Lipo-ecraprost (60 μg ev per 5 giorni a settimana per 8 settimane) in pazienti con CLI non rivascolarizzabili Concluso prima del termine previsto per inefficacia Circulase investigators J Vasc Surg 2006;43:752-9

(— ) iloprost; ( - - - ) placebo Adjunctive parenteral therapy with lipo-ecraprost, a prostaglandin E1 analog, in patients with critical limb ischemia undergoing distal revascularization does not improve 6-month outcomes (Circulase investigators J Vasc Surg 2007;45: 953-61) Event Placebo n (%) Lipo-ecaprost n (%) Patient 143 141 Major amputation 19 (13%) 17 (12%) Death 13 (9%) Composite all 45 (32%) 40 (28%) Effects of Perioperative Iloprost on Patency of Femorodistal Bypass Grafts. The Iloprost Bypass International Study Group (Eur J Vasc Endovasc Surg:1996;12, 363-371) Vein grafts p=0.71 prosthetic grafts p=0.78 (— ) iloprost; ( - - - ) placebo

Prostanoids for critical limb ischaemia. Ruffolo AJ, Romano M, Ciapponi A. Cochrane Database Syst Rev 2010 Jan 20;(1) Prostanoids vs placebo Prostanoids seem to have efficacy regarding rest-pain relief ( (RR 1.32), and ulcer healing (RR 1.54). Iloprost also shows favourable results regarding major amputations (RR 0.69, 95% CI 0.52 to 0.93)”. Authors’ conclusions “Despite some positive results regarding rest-pain relief, ulcer healing and amputations, there is no conclusive evidence based on this meta-analysis of the long-term effectiveness and safety of different prostanoids in patients with CLI. Further well-conducted, high quality randomised double-blinded trials should be performed”.

Number of Participants Number of Participants Alprostadil in Peripheral Arterial Occlusive Disease (PAOD) Stage IV (ESPECIAL) Scopo: dimostrare la superiorità di Alprostadil (40g in 50-150 soluzione fisiologica x 2/die) rispetto al placebo nella guarigione delle ulcere ischemiche e nella frequenza delle amputazioni maggiori in pazienti con PAD al IV stadio. Studio in doppio cieco randomizzato vs placebo; previsti 2 gruppi sequenziali di arruolamento (stadio 1 e 2) con interim analisi dopo stadio 1; Complete Healing of Ischemic Necroses and Ulcerations at 12 Weeks After the End of Study Drug Treatment Number of Participants Alprostadil (414) Plaebo (424) P Stage 1 (n=253, n=251)   49 43 0.2587 Stage 2 (n=161, n=173) 27 30 0.3463 Occurrence of Major Amputations at 24 Weeks After the End of Study Drug Treatment Number of Participants Alprostadil (414) Plaebo (424) P Stage 1 (n=253, n=251)   32 49 0.0173 Stage 2 (n=161, n=173) 20 13 0.1154 Alprostadil Placebo Complete Healing of Ischemic Necroses and Ulcerations at 24 Weeks After the End of Study Drug Treatment   108 103 All-cause Mortality During the Course of the Study (up to 196 Days)   20 15 ClinicalTrials.gov Identifier: NCT00596752; Last updated: July 21, 2014

LINEE GUIDA TASC II Working Group, 2007 CHEST 2012 Recommendation 28 Use of prostanoids in critical limb ischemia (CLI) ● Previous studies with prostanoids in CLI suggested improved healing of ischemic ulcers and reduction in amputations [A]. ● However, recent trials do not support the benefit of prostanoids in promoting amputation-free survival [A]. ● There are no other pharmacotherapies that can be recommended for the treatment of CLI [B]. 5.1. For patients with symptomatic PAD and critical leg ischemia/rest pain who are not candidates for vascular intervention, we suggest the use of prostanoids in addition to previously recommended antithrombotic therapies (aspirin 75-100 mg daily or clopidogrel 75 mg daily) (Grade 2C) .

TRATTAMENTO ARTERIOPATIA P E R I F E R I C A NEL DIABETICO A M D / S I C V E / S I D / S I R M - DOCUMENTO CONSENSO TRATTAMENTO ARTERIOPATIA P E R I F E R I C A NEL DIABETICO Dicembre 2012 9.1. Vasodilatatori Nel trattamento della Arteriopatia Ostruttiva degli Arti Inferiori nei pazienti diabetici la terapia medica con prostanoidi , intesa come infusione endovena di analogo stabile della prostaciclina (PGI2) Iloprost/Alprostar per 3- 4-settimane non rappresenta una alternativa alla rivascolarizzazione chirurgica ……… ……. La terapia con prostanoidi nel trattamento della ischemia cronica degli arti inferiori assume rilevanza nell’alleviare il dolore nell’attesa di rivascolarizzazione chirurgica, nel migliorare la perfusione post-rivascolarizzazione e nel migliorare la qualità di vita

Evidence summary:unlicensed or off-label medicine Critical limb ischaemia in peripheral vascular disease: intravenous iloprost 17 December 2013 Evidence summary:unlicensed or off-label medicine Effectiveness Safety In a Cochrane review of prostanoids for people with critical limb ischaemia unsuitable for surgery, intravenous iloprost statistically significantly reduced major amputations, improved rest-pain relief and improved ulcer healing compared with placebo. The effect on total amputations (major plus minor) was not statistically significant. The quality of the evidence was graded as low or very low using the GRADE approach. In an RCT in people undergoing femorodistal bypass surgery for critical limb ischaemia; perioperative intravenous and intra-graft iloprost compared with placebo did not improve graft patency, clinical status, or reduce amputations at 1 year follow up Common adverse events associated with intravenous iloprost in the Cochrane review and RCT included pain at the infusion site, headache, flushing, nausea and vomiting, and hypotension. A dose-comparison RCT included in the Cochrane review found a significant dose response in adverse events with intravenous Iloprost The RCT in people undergoing femorodistal bypass surgery for critical limb ischaemia reported there was no difference between the placebo and iloprost groups in major adverse events such as myocardial infarction, cerebrovascular accident or death from any cause in the fortnight after surgery.

PAZIENTI NON RIVASCOLARIZZABILI: 191 stadio 3 e 658 stadio 4 Treatment of patients with peripheral arterial occlusive disease Fontaine stage III and IV with intravenous iloprost: an open study in 900 patients PAZIENTI NON RIVASCOLARIZZABILI: 191 stadio 3 e 658 stadio 4 Criteri di risposta alla terapia: Diminuzione o scomparsa del dolore Guarigione completa delle ulcere; riduzione uguale o superiore al 50% Demarcazione della necrosi Giudizio medico di risposta globale Staben P, Albring M. Prostaglandins Leukotrienes Essential Fatty Acids 1996; 54: 327-33

Come individuare i responders ? Valutazione della TCpO2 supina al piede sintomatico nel follow-up a lungo termine (12 mesi) in diabetici con ischemia critica degli arti inferiori, non rivascolarizzabile, sottoposti ad uno (responders) o due cicli (responders tardivi e non responders) di terapia infusionale con iloprost Melillo E. et al. Trends Med 2006; 6(3):201-234.

RIABILITAZIONE NELLA ISCHEMIA CRITICA Goals of Medical Evaluation Before Exercise Rehabilitation To confirm diagnosis of PAD and IC To confirm absence of Critical limb ischemia Unstable angina Decompensated heart failure Uncontrolled cardiac arrhythmias Severe or symptomatic valvular disease Other conditions that could be aggravated by exercise including, but not limited to, severe joint disease, uncontrolled diabetes, or uncontrolled hypertension To screen for exercise-induced myocardial ischemia & arrhythmias Exercise stress testing is preferred Careful questioning for symptoms is an alternative

RIABILITAZIONE VASCOLARE NELL’ISCHEMIA CRITICA DEGLI ARTI INFERIORI Protocollo riabilitativo integrato e multidisciplinare: - inquadramento diagnostico globale/correzione fattori di rischio - possibilità di rivascolarizzazione - terapia farmacologica ev / terapia analgesica - trattamento delle lesioni - programma di attività fisica: esercizi di mobilitazione attiva e passiva a letto: trofismo muscolare, mobilità articolare, riduzione dell’edema, aumento del flusso microcircolatorio effetto antalgico esercizi in palestra in posizione supina o seduta (allenamento di vari gruppi muscolari) training aerobico su cyclette (15 min.) ripresa della deambulazione anche con ortesi da scarico Prior M. Minerva Cardioangiol 2010; 58 (Suppl.1 N°6): 121-2

Influence of upper- and lower-limb exercise training on cardiovascular function and walking distances in patients with intermittent claudication pain-free (claudication) distance maximum walking distances These findings suggest that the symptomatic improvement after upper-limb exercise training may result, in part, from systemic cardiovascular effects rather than localized metabolic or hemodynamic changes. Walker RD et al. J Vasc Surg 2000;31:662-9

Medical management of critical limb ischaemia: where do we stand today? Treatment Outcome Smoking cessation Reduces risks of cardiovascular events, disease progression and amputation Combination of bupropion and nicotine replacement therapy is most efficacious Lipid lowering Lowering LDL levels reduces risks of mortality and cardiovascular events Statins are the recommended primary agents Antihypertensive agents Reduce risk of cardiovascular events ACE inhibitors may have additional benefit beyond blood pressure lowering Blood sugar control (in diabetic pat) More evidence needed about effect on PAD may reduce incidence of cardiovascular events (…optimal glycaemic control is advised on the basis that it reduces the incidence of cardiovascular events in this high-risk group) Homocysteine lowering Insufficient evidence to show benefit in PAD Antiplatelet agents Aspirin reduces risks of cardiovascular events and arterial occlusion Clopidogrel can be used as an alternative to aspirin Use of dual antiplatelet therapy is not routinely recommended Anticoagulation Anticoagulation (either warfarin or heparin) is not recommended for prevention of cardiovascular events or vessel occlusion as a primary treatment Anticoagulation may be used as an adjuvant therapy following autogenous grafts in selected patients Thrombolysis Has a role in acute limb ischaemia and graft occlusion; further research is needed to evaluate the best agent and infusion technique Naftidrofuryl Insufficient evidence to recommend use Cilostizol Pentoxifylline No benefit for use in CLI Prostaglandins No convincing evidence of benefit Gene therapy/growth factors Early trials show promise and safety but further evidence needed Stem cell therapy Early trials show promise but more evidence needed Evidence for use in CLI in bold, Insufficient evidence to support or refute use in italics, Evidence of no benefit in CLI in bold italics Lambert M.A. et al. J Intern Med 2013; 274: 295–307.