L’ANGINA DOPO RIVASCOLARIZZAZIONE INCOMPLETA: SOLUZIONI TERAPEUTICHE

Enrico Natale

Unità Operativa Complessa di Cardiologia 1A. O. San Camillo - Forlanini, Roma

enrico natale

Effect of Completeness of Revascularization on Long-term Outcome of Patients With Three-Vessel Disease Undergoing Coronary Artery Bypass Surgery

A Report From the Coronary Artery Surgery Study (CASS) Registry

Bell MR, et Al: Circulation 1992;86:446-457

CCS III-IV

death,MI,reoperationand definite angina

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Effect of Completeness of Revascularization on Long-term Outcome of Patients With Three-Vessel Disease Undergoing Coronary Artery Bypass Surgery

A Report From the Coronary Artery Surgery Study (CASS) Registry

Bell MR, et Al: Circulation 1992;86:446-457

CCS I-II CCS III-IV

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Effect of Completeness of Revascularization on Long-term Outcome of Patients With Three-Vessel Disease Undergoing Coronary Artery Bypass Surgery

A Report From the Coronary Artery Surgery Study (CASS) Registry

Bell MR, et Al: Circulation 1992;86:446-457

CCS I-II CCS III-IV

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Garcia S, et Al: J Am Coll Cardiol 2013;62:1421–31

Favor CR Favor IR

Pooled Analysis for the

Occurrence of Total Mortality

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Garcia S, et Al: J Am Coll Cardiol 2013;62:1421–31

Favor CR Favor IR

Pooled Analysis in

CABG studies

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Garcia S, et Al: J Am Coll Cardiol 2013;62:1421–31

Favor CR Favor IR

Pooled Analysis in

PCI studies

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Head SJ, et Al. Eur J Cardiothorac Surg 2012;41:535–41

SYNTAX trial

Incomplete Revascularization by SYNTAX Score and Treatment

La rivascolarizzazione coronarica incompleta è un marker di complessità.

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La gran parte dei dati deriva da registri e studi post-hoc su CABG e PCI, con risultati disomogenei, talvolta contrastanti oppure di difficile interpretazione, spesso per l’assenza di una definizione condivisa di IR (anatomica o funzionale). Il grado di rivascolarizzazione dipende non solo dalle caratteristiche anatomiche delle lesioni, ma anche dalle comorbilità (diabete mellito, insufficienza renale, fragilità).

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Tonino PAL, et Al. N Engl J Med 2009;360:213-24

Fractional Flow Reserve versus Angiography for Guiding PCI

FAME study

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Tonino PAL, et Al. N Engl J Med 2009;360:213-24

Fractional Flow Reserve versus Angiography for Guiding PCI

FAME study

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The Fractional Flow Reserve VersusAngiography for Multivessel Evaluation

(FAME) trial indicated that, in patients with multivessel disease,

about one third ofangiographically significant stenoses

were actually hemodynamicallynot significant.

Circulation. 2012;125:2557-2559

Angina dopo rivascolarizzazione

coronarica incompleta

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Henderson RA, et Al. J Am Coll Cardiol 2003;42:1161–70

Seven-Year Outcome in the RITA-2 Trial:Coronary Angioplasty Versus Medical Therapy

Prevalence of angina over time

P = coronary angioplasty group M = medical group

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Boden WE, et Al. N Engl J Med 2007;356:1503-16

Optimal Medical Therapy with or without PCI for StableCoronary Disease. COURAGE Trial Research Group

Prevalence of angina during follow-up

P = 0.35P<0.001 P = 0.02

enrico nataleAlderman EL, et Al. J Am Coll Cardiol 2004;44:766 –74

Angiographic Results After PCI or CABG in BARI

100

80

60

40

20

0

Per

cent

age

of je

opar

dize

d m

yoca

rdiu

m Baseline 1-year 5-year

PCICABG17%

7%20%

25%

60%

P<0.001 P=0.01

Myocardial jeopardy at five years, and not initial treatment (PCI vs. surgery), was independently associated with late angina.

5-year angina prevalence

18%28%

P=0.03

enrico nataleAlderman EL, et Al. J Am Coll Cardiol 2004;44:766 –74

Angiographic Results After PCI or CABG in BARI

PCI CABG

enrico nataleIzzo P, et Al. Eur Heart J: Acute Cardiovascular Care 2012;1:158–169

> 30%

Soluzioni terapeutiche

Terapia farmacologica

2013 ESC guidelines on the management of stable coronary artery diseaseenrico natale

Terapia farmacologica

2013 ESC guidelines on the management of stable coronary artery diseaseenrico natale

Terapia farmacologica

2013 ESC guidelines on the management of stable coronary artery diseaseenrico natale

Terapia farmacologica

2013 ESC guidelines on the management of stable coronary artery diseaseenrico natale

2013 ESC guidelines on the management of stable coronary artery disease

Terapia farmacologica

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Ivabradina e rivascolarizzazione

coronarica incompleta

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RR

0 mV

-40 mV

-70 mV

• allunga la curva di depolarizzazione diastolica• blocco della corrente If frequenza-dipendente

Di Francesco D, et al. Drugs. 2004;64:1757-1765.

ivabradina

Inibizione della corrente If con ivabradina

e.natale

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Number of angina events (A) and nitroglycerin consumption (B)/mean±SD at the 3 study visits (n=884)

Antianginal Efficacy of Ivabradine in Patients With History of Coronary Revascularization

Zarifis J, et al. Angiology 2016

1 mese 4 mesi

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Antianginal Efficacy of Ivabradine in Patients With History of Coronary Revascularization

Zarifis J, et al. Angiology 2016

Angina CCS classification (% of patients) at visits 1 and 3 (N = 884)

Placebo

P=0.001

Years

Ho

spit

aliz

atio

n f

or

fata

l o

r n

on

fata

l M

I (%

)

Ivabradine

0 0.5 1 1.5 20

4

8

Fox K et al. Lancet 2008

Kaplan–Meier time-to-event plots, by treatment group in the prespecified subgroup with HR >70 bpm

CAD + LVEF < 40%

enrico nataleFox K, et al: N Engl J Med 2014;371:1091-99

SIGNIFYprimary end point: CV death or nonfatal myocardial infarction

19,102 pts (stable CAD and HR > 70, 12,049 CCS > II up to IV)

enrico nataleFox K, et al: N Engl J Med 2014;371:1091-99

SIGNIFYprimary end point: CV death or nonfatal myocardial infarction

19,102 pts (stable CAD and HR > 70, 12,049 CCS > II up to IV)

The annual incidence of the primary end point was relatively low (approximately 2.8%)

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Beta-Blocker Use and Clinical Outcomes in Stable Outpatients With CAD

Bangalore S, et al: JAMA 2012;308:1340-1349

REACH registry

primary outcome: a composite of cardiovasculardeath, nonfatal MI, or nonfatal stroke

Ranolazina e rivascolarizzazione

coronarica incompleta

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Understanding Angina at the Cellular Level

• Ischemia impairs cardiomyocyte sodium channel function

• Impaired sodium channel function leads to:– Pathologic increased late sodium

current– Sodium overload– Sodium-induced calcium

overload• Calcium overload causes diastolic

relaxation failure, which:– Increases myocardial oxygen

consumption– Reduces myocardial blood flow

and oxygen supply– Worsens ischemia and angina

Ranolazine

Ischemia

Late INa

Na+ Overload

Diastolic relaxation failureExtravascular compression

Ca++ Overload

Modified from Chaitman BR. Circulation. 2006;113:2462-2472Modified from Belardinelli L, et al. Eur Heart. 2006;8 (Suppl. A):A10-13.

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Cochrane Database of Systematic Reviews 2017, Issue 2

Comparison 3: Ranolazine (add-on therapy) 1000 mg bid vs placebo - Angina episodes frequency

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Cochrane Database of Systematic Reviews 2017, Issue 2

Sensitivity analysis 1: Studies at low risk of bias - Angina episodes frequency

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6560 NSTEACS pts within 48 hours who were treated with ranolazine(initiated iv and followed by oral ranolazine 1000 mg bid, n=3279) or matching placebo (n=3281), and followed up for a median of 348 days.

MERLIN-TIMI 36

Morrow DA et al: JAMA 2007;297:1775-1783

Kaplan-Meier Estimated Rates of the Primary EP (Cardiovasc Death, MI, or Recurrent Ischemia)

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MERLIN-TIMI 36

Morrow DA et al: JAMA 2007;297:1775-1783

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MERLIN-TIMI 36 Diabetes

No diabetes

Morrow DA et al: Circulation 2009;119:2032-2039

Kaplan–Meier estimated risk of recurrent ischemia at 1 year

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RIVER-PCI: study design

Weisz G et al: Lancet 2015 http://dx.doi.org/10.1016/S0140-6736(15)00459-6

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RIVER-PCI: ischemia-driven revascularization/hospitalization

Weisz G et al: Lancet 2015 http://dx.doi.org/10.1016/S0140-6736(15)00459-6

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Ranolazina non previene lo sviluppo di ischemia, ma

piuttosto ne riduce l’intensità.Ranolazina veniva somministrata a tutti i pazienti con IR

indipendentemente dal grado di angina residua (non dati clinici, né ischemia residua).L’incompletezza della rivascolarizzazione veniva valutata in

base ad anatomia/angiografia e non con test funzionali (FFR).In entrambi i bracci dello studio, l’angina migliorava dopo PCI

e la maggior parte dei pazienti non aveva angina significativa un mese dopo la rivascolarizzazione, pur incompleta.

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Take home message

La IR è un’evenienza sempre più frequente, e riflette il cambiamento della popolazione di pazienti con CI cronica, sempre più anziani, con comorbilità multiple e con lesioni coronariche complesse.

Indipendentemente dal tipo di rivascolarizzazione, la IR ha un peso prognostico importante su sopravvivenza ed eventi cardiovascolari maggiori, che sembra legato alla presenza di ischemia inducibile e vitalità.

La terapia medica, finalizzata al controllo dell’angina e alla prevenzione di eventi ischemici, ha un ruolo rilevante.

Ranolazina e ivabradina, risultano molto utili per i pazienti nei quali il controllo degli episodi anginosi e il miglioramento della qualità della vita rappresentano un obiettivo terapeutico importante, a prescindere da effetti prognostici a lungo termine, presenti in alcuni sottogruppi.

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