Presentazione di PowerPoint - Società Triveneta di Chirurgia

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 …..
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
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 TNFRII (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
Eventi avversi
Iloprost
40
%
35
30
25
20
PGE1
36,6
19,4
15
10
5
0
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.
Miglioramento dop 6 mesi
Miglioramento al termine del
trattamento
Placebo
% Risposte cliniche
50
45
50
40
29
30
p<0.05
20
10
0
50
40
42
26
30
P<0.01
20
10
0
Vivi con un arto sano dop 6 mesi
Amputazioni maggiori
Iloprost
Iloprost
Placebo
64
Placebo
47
50
40
42
31
30
%
60
Placebo
40
Guarigione o riduzione dell’ulcera;
riduzione del dolore
70
%
% Risposte cliniche
Iloprost
Iloprost
P<0.05
30
20
20
10
10
0
0
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
Iloprost
Iloprost
Placebo
45
50
38,8
40
49
34
35
40
26
30
20
% eventi
% Risposte cliniche
60
Placebo
30
25
22,60
20
15
11
10
10
5
0
0
n=185/381
n=85/324
Amputazioni
Mortalità
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)
Outcome alla dimissione
80
70
60
50
40
30
20
10
0
P<0.001 70
61
Controllo
Alprostadil
70
P<0.001 73,6
63,9
60
% Pazienti
% Pazienti
Alprostadil
Outcome dopo 6 mesi
50
40
Controllo
P=0.074 57,5
P>0.2
40,5
52,6
42,6
30
20
10
0
End-point Periferico
End-point combinato
RR:0.87
End-point Periferico
End-point combinato
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
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 (%)
143
141
Major amputation
19 (13%)
17 (12%)
Death
19 (13%)
13 (9%)
Composite all
45 (32%)
40 (28%)
Patient
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”.
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
5.1. For patients with symptomatic PAD and
Use of prostanoids in critical limb ischemia (CLI)
critical leg ischemia/rest pain who are not candidates
● Previous studies with prostanoids in CLI suggested
for vascular intervention, we suggest
improved healing of ischemic ulcers and reduction
the use of prostanoids in addition to previously
in amputations [A].
recommended antithrombotic therapies (aspirin
● However, recent trials do not support the benefit of
75-100 mg daily or clopidogrel 75 mg daily)
prostanoids in promoting amputation-free survival [A].
(Grade 2C) .
● There are no other pharmacotherapies that can be
recommended for the treatment of CLI [B].
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
Critical limb ischaemia in peripheral vascular disease:
intravenous iloprost
17 December 2013
Effectiveness
Evidence summary:unlicensed or off-label medicine
Safety
• In a Cochrane review of prostanoids for people with •Common adverse events associated with intravenous
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
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.
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
Risposta clinica globale
% pazienti
stadio 3
80
70
60
50
40
30
20
10
0
stadio 4
Criteri di risposta alla terapia:
75
66
41,8
• Diminuzione o scomparsa del dolore
• Guarigione completa delle ulcere; riduzione uguale o
46,3
superiore al 50%
Intention to treatment
• Demarcazione della necrosi
• Giudizio medico di risposta globale
On treatment
Mortalità a 6 mesi
Amputazioni a 6 mesi
Responders
26,9
20
14,5
15
9,2
5,6
16,1
% Mortalità
25
10
Non Responders
20
30
% amputazioni
Responders
Non Responders
15
9,4
10
11,1
6,3
5
5
0
0
stadio 3
stadio 4
stadio 3
stadio 4
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 highrisk 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
Anticoagulation
Use of dual antiplatelet therapy is not routinely recommended
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
Naftidrofuryl
Has a role in acute limb ischaemia and graft occlusion; further research is needed to
evaluate the best agent and infusion technique
Insufficient evidence to recommend use
Cilostizol
Insufficient evidence to recommend use
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.