Convention

della

CARDIOLOGIA LOMBARDA

Ruolo della terapia medica nel paziente con

rivascolarizzazione incompleta o ischemia residua

Giorgio Caretta

U.O. di Cardiologia

A.O. ‘’Istituti Ospitalieri’’ di Cremona

Villa Poggio Pirelli

Induno Olona (VA), 27 Marzo 2015

Wallentin L et al. Lancet 2000;356:9–16

Wallentin L et al. N Engl J Med 2009 361:11

De Bruyne B et al. N Engl J Med 2012 367;11

Boden BE et al. N Engl J Med 2007;356:15

Poole-Wilson et al. ACTION Lancet 2004;364:849-57.

Fox K et al. N Engl J Med 2014

De

ath

/ M

I (%

)

Months of follow up

Stable angina (COURAGE)

Stable angina (FAME II)

SIGNIFY trial (stable CAD)

ACTION trial (stable CAD)

16

12

8

4

0

0 2 4 6 8 10 12

Death/MI ≈ 2.5 – 3.8%

Mortality ≈1.2 – 2.4%

Event Rates in CAD disease: Stable Angina vs ACS.

Death / MI after 12 months

UA/NSTEMI (FRISC II)

UA/NSTEMI/STEMI (PLATO)

Pursnani S et al Circ Cardiovasc Interv. 2012;5:476-490

Mortality

Benefit of invasive treatment in stable CAD

Pursnani S et al Circ Cardiovasc Interv. 2012;5:476-490

Freedom from angina

Benefit of invasive treatment in stable CAD

“… in revascularization era…

…ischaemia does still exist!”

Angina after revascularization: data from COURAGE

Weintraub WS et al. N Engl J Med 2008 359;7

Angina after revascularization: data from FREEDOM

Seropian IM et. al J Am Coll Card 2014;63:1593-603

Need of anti-anginal drugs in patients with CAD

Simoons M et al. Eur Heart J 2010

Ischemia despite revascularization: why?

• Incomplete revascularization

• Stent restenosis

• Bypass graft occlusion

• Atherolscerosis progression

• Small vessels stenosis

• Microvascular disease

Incidence of incomplete revascularization

Head SJ et al. Eur J Cardiothorac Surg. 2012 Mar;41(3):535-41.

Complete revascularization?

From Berry C et al. Eur Heart J (2007) 28, 278–291

Patients With Coronary Artery Disease Unsuitable for Revascularization

12

Jolicoeur EM et al. Can J Card 2012;28:S50-59

How much is too much?

Khouzam RN et al. J Am Coll Cardiol. 2010;56(19):1605-1605

Quali opzioni terapeutiche?

Montalescot G. ESC Guidelines Eur Heart J 2013

Traditional anti-ischemic therapy therapy and the treatment gap

Spertus JA et al. Am Heart J. 2001 Apr;141(4):550-8.

Sinus node inhibition: Ivabradine

If current is an inward Na+/K+ current that activates pacemaker cells of the SA node.

Ivabradine:

- selectively blocks If in a current-dependent fashion

- reduces slope of depolarization, slowing HR

40

20

0

–20

–40

–60

0.5

Potential (mV)

Control Ivabradine 0.3 µM

Time

(seconds)

Colin P et al. Am J Physiol Heart Circ Physiol 2003

Di Francesco D. Curr Med Res Opin. 2005;21:1115-22.

Efficacy of If Inhibition with Ivabradine in Different Subpopulations

with Stable Angina Pectoris

Tendera M et al. Cardiology 2009;114:116–125

Efficacy of If Inhibition with Ivabradine in Different Subpopulations

with Stable Angina Pectoris (ASSOCIATE Trial)

Tendera M et al. Cardiology 2009;114:116–125

Traditional mechanisms of action

Understanding Angina at the Cellular Level

Ischemia

Late INa

Na+ Overload

Diastolic relaxation failure

Extravascular compression

Ca++ Overload

Modified from Chaitman BR. Circulation. 2006;113:2462-2472

Modified from Belardinelli L, et al. Eur Heart. 2006;8 (Suppl. A):A10-13

Increase ATP consumption

and O2 demand Electrical abnormalities

Arrhytimas

Ranolazine

Hemodynamic changes vs Ranolazine dose

MARISA - FDA Review Documents, NDA 21-256, December 9, 2003

Heart Rate

0

20

40

60

80

100

Placebo 2.7 ± 0.1 5.9 ± 0.3 9.4 ± 0.4

Ranolazine Concentration (µM)

Be

ats

/min

Arterial Blood Pressure

0

20

40

60

80

100

120

140

160

Placebo 2.7 ± 0.1 5.9 ± 0.3 9.4 ± 0.4

Ranolazine Concentration (µM)

mm

Hg

Systolic

Diastolic

Anti-Ischemic Effects with Ranolazine monotherapy with Chronic

Sever Angina

***

*** ***

***

*** ***

*** ***

***

** ***

***

**

*** *** ***

***

***

Placebo

500 mg bid

1,000 mg bid

1,500 mg bid

400

440

480

520

560

Exercise

duration

Time

to angina

Time to 1-mm

ST-depression

Exercise

duration

Time

to angina

Time to 1-mm

ST-depression

Tim

e, s

ec

Peak Trough

Chaitman BR, et al. J Am Coll Cardiol 2004;43:1375-82

MARISA Study

Placebo + background therapy

750 mg bid ranolazine + background therapy

CARISA Study

0

5

Me

an

nit

rog

lyce

rin

do

ses/

we

ek

at

12 w

ee

ks

4

3

2

1

2.1*

3.1

0

1

2

3

4

3.3

2.5*

Me

an

nu

mb

er

of

an

gin

a a

ttack

s/w

ee

k

at

12 w

ee

ks

Nitroglycerin use Angina frequency

Chaitman BR, et al. JAMA 2004;291:309-16

Ranolazina

Placebo

Pe

rce

ntu

ale

pz.

(%

)

25

20

15

10

5

0 Angina

ingravescente Incremento della

terapia anti-anginosa

Ischemia

ricorrente

8.1

5.6

16.4

12.5

21.1

16.5

HR 0.77 0.77 0.78

95% lC 0.59-1.00 0.64-0.92 0.67-0.91

Valore p 0.048 0.005 0.002

MERLIN: efficacia in pazienti con angina cronica (endpoint secondari)

13) Wilson SR, et al. J Am Coll Cardiol. 2009; 53;1510-1516

Should we expect improvements in outcome with

new anti-anginal drugs?

Components of Primary Endpoint

CV Death or MI (%) Recurrent Ischemia (%)

Days from Randomization

Ranolazine 13.9%*

(N=3,279)

Placebo 16.1%*

(N=3,281)

0 180 360 540

HR 0.87 (95% CI 0.76 to 0.99)

P =0.030 0

5

10

15

20

0

5

10

15

0 180 360 540

Ranolazine 10.4%*

Placebo 10.5%*

HR 0.99 (95% CI 0.85 to 1.15)

P =0.87

20

Days from Randomization

*KM Cumulative Incidence (%) at 12 months

Morrow DA et al. JAMA 2007; 297: 1775-83

Does Ivabradine reduces primary end point in

angina patients?

n=1507

P=0.05

Years

0

5

10

15

20

0 0.5 1 1.5 2

Cu

mu

lati

ve in

cid

en

ce

fo

r P

EP

* (%

)

-24% Placebo

Ivabradine

Primary end point (PEP) : CV death + hospitalization for HF or MI

Ivabradine n=654 (3.03% PY) Placebo n=611 (2.82% PY)

HR = 1.08 [95% CI 0.96-1.20] P=0.20

9550 9297 9077 8611

9552 9311 9130 8656

Time from randomization (months)

Ivabradine 5570

5649

3776

3749

1832

1836

349

365

Numbers at risk

Pati

en

ts w

ith

eve

nt

(%)

Placebo

Placebo Ivabradine

Primary composite end point

Total population n=19.102

Primary composite end point

(angina population: CCS class ≥II, n=12 049)

Ivabradine n=459 (3.37% PY) Placebo n=390 (2.86% PY)

HR = 1.18 [95% CI 1.03-1.35] P=0.018

6037 5869 5712 5428

6012 5859 5747 5463

3483

3502

2387

2350

1197

1178

227

232

Time from randomization (months)

Placebo Ivabradine

Pati

en

ts w

ith

eve

nt

(%)

Ivabradine

Placebo

Numbers at risk

Treatments

Dihydropyridine

CCBs

Nicorandil

Ranolazine

Beta-blockers

Others (nitrates,

diltiazem, verapamil)

Ivabradine

Studies in patients

with stable CAD

CAMELOT

ACTION

IONA

MERLIN

Meta regression analysis

CIBIS-II

BEAUTIFUL, SIGNIFY

Findings

No impact on mortality or MI in

CAMELOT

ACTION: no reduction in CV events

Primary endpoint reduced, but no

impact on mortality or non fatal MI

No reduction of CV in subanalysis in

angina pectoris

Evidence only in post-MI and CHF

No prognositic data in stable CAD

patients

No impact on mortality/MI

Anti-anginal drugs and outcomes in stable CAD

Low risk populations?

No impact of disease progression?

Anti-anginal drugs and outcomes in stable CAD

Weisz G et al Am Heart J 2013;166:953-959.e3.

Conclusioni

• Nonostante un uso diffuso della rivascolarizzazione l’angina persiste in molti

pazienti con CAD e incide sulla qualità di vita

• L’aumento della sopravvivenza dopo eventi acuti e l’invecchiamento della

popolazione incrementa la prevalenza dei pazienti con angina refrattaria

• L’aggiunta dei recenti farmaci anti-anginosi migliora i sintomi in tutte le

tipologie di pazienti studiati ma non migliora la prognosi

• Necessità di studiare i farmaci anti-ischemici in popolazioni con ischemia

documentata e a rischio maggiore

Convention

della

CARDIOLOGIA LOMBARDA

Ruolo della terapia medica nel paziente con

rivascolarizzazione incompleta o ischemia residua

Giorgio Caretta

U.O. di Cardiologia

A.O. ‘’Istituti Ospitalieri’’ di Cremona

Villa Poggio Pirelli

Induno Olona (VA), 27 Marzo 2015

Convention

della

CARDIOLOGIA LOMBARDA

Ruolo della terapia medica nel paziente con

rivascolarizzazione incompleta o ischemia residua

Giorgio Caretta

U.O. di Cardiologia

A.O. ‘’Istituti Ospitalieri’’ di Cremona

Villa Poggio Pirelli

Induno Olona (VA), 27 Marzo 2015

Rivascolarizzazione nella cardiopatia ischemica

Cornarografie, n. PCI, n. (%) CABG, n. (%)

USA 1.983.000 954.000 (48.1%) 397.000 (20.0%)

Italia 270.521 138.030 (51.0%) -

Cremona 1.020 547 (53.6%) -

• Circa 35-40% delle angioplastiche in pazienti con malattia coronarica stabile

• Circa il 15% dei pazienti sottoposti a coronarografia non sono rivascolarizzabili.

Go AS et al. Circulation. 2014;129:e28-e292

Montalescot G. ESC Guidelines Eur Heart J 2013

Giornale Italiano Cardiologia Invasiva 2;2013

Revascuarization rate: data from BARI 2D

Frye RL et al. N Engl J Med 2009;360: 2503 – 2515.

Benefit of invasive treatment in NSTE/ACS

Bavry AA et al. J Am Coll Cardiol 2006;48:1319–1325

Ranolazina: studi clinici principali

CARISA

N=823

Angina

cronica

Ranolazina

vs placebo

in aggiunta

alla terapia standard

ERICA

N=565

Angina

cronica

Ranolazina vs placebo

in aggiunta ad

amlodipina 10 mg

MARISA

N=191

Angina

cronica

Ranolazina

monoterapia

vs placebo

MERLIN-

TIMI 36

N=6560

Sindromi

Coronariche Acute

Non-STE Ranolazina vs placebo

in aggiunta alla

terapia standard

Chaitman JAMA 2004; 291:303-316 Chaitman JACC 2004; 43:1375-82

Stone, JACC 2006; 48:566-75 Morrow JAMA, 2007; 297:1775-1783

Sinus node inhibition: Ivabradine

Colin P et al. Am J Physiol Heart Circ Physiol 2003

MERLIN: recurrent ischemia after NSTE-ACS

Recurrent Ischemia (%)

Days from Randomization

Ranolazine 17.3%

(N=3,279)

Placebo 20.0%

(N=3,281)

HR 0.87 (95% CI 0.76 to 0.99)

P =0.030

0.0

0

0.0

5

0.1

0

0.15

0

.20

0

.25

0 180 360 540

Morrow D, et al. JAMA 2007;297:1775-83

Effect of ivabradine on symptoms

(angina population: CCS class≥ II, n=12 049)

Patients (%)

24.8

19.4

0.31 0.55

P<0.01

Elective revascularization

Ivabradine 2.8% Placebo 3.5% HR 0.82 (0.67–

1.01), p=0.058

Fox K et al. N Engl J Med 2014

Coronary artery disease and angina

1 Go AS et al. Heart Disease and Stroke Statistics – 2013 Update. Circulation. 2014;129:e28-e292 2 Lenzen MJ, et al. Eur Heart J 2005;26:1169-79. 3 Daly CA et al. Eur Heart J. 2005;26:996–1010 4 Boden WE, et al. N Engl J Med 2007;356:1510.

• Coronary artery disease (CAD) is the leading cause death worldwide,

contributing to over of 7.8 million of deaths annually.1

• ~ 10 million European adults have chronic angina

• 53% of patients with angiographically proven coronary artery disease originally

present with stable angina2

• The Euro Heart Survey reports that, at diagnosis, 60% of patients with angina

are moderately/severely limited in their daily activities3

• A significant number of patients with angina pectoris cannot be efficiently

controlled. These patients have disabilities and their quality of life deteriorates4

• Results (n = 1957)

− ~ 1 in 5 patients had angina 1 year post-MI

−Of these, ~ 1 in 5 had angina daily or weekly

− Patients tended to be

−Younger

−Nonwhite males

−Prior CABG or baseline angina

− Index hospitalization (recurrent angina)

− Among outpatient variables, patients were more likely to

• Continue smoking

• Undergo PCI or CABG after the index hospitalization

• Have new, persistent, or transient depression

Angina Prevalence One Year Post-MI

Maddox TM, Reid KJ, Spertus JA, et al. Arch Intern Med. 2008;168:1310-1316

• ~ 10 million European adults have chronic angina

• 53% of patients with angiographically proven coronary artery disease originally present with stable angina1

• 1 year after diagnosis, 22% have undergone PCI2

• > 25% of patients experience angina up to 5 years post-PCI with optimal medical care3

1Lenzen MJ, et al. Management and outcome of patients with established coronary artery disease: the Euro Heart Survey on coronary

revascularization. Eur Heart J 2005;26:1169-79. 2Daly C, et al. The impact of guideline compliant medical therapy on clinical outcome in patients

with stable angina: findings from the Euro Heart Survey of stable angina. Eur Heart J 2006;27:1298-304. 3Boden WE, et al. Optimal Medical

Therapy with or without PCI for Stable Coronary Disease. N Engl J Med 2007;356:1510.

Burden of Stable Angina in Europe

Serruys PW, et al. N Engl J Med. 2001;344:1117-1124

Continued angina and anti-anginal medication use 12 months after revascularization for angina (n=1205)

100%

Stenting group

Surgery group

Pre

vale

nce

(%

of

pati

en

ts)

21%*

79%* 81%*

11%

59% 62%

0%

20%

40%

60%

80%

Continued

angina

Continued

antianginal

medication

Continued angina

and/or antianginal

medication

*p < 0.001

Galectin-3 in pre-HF risk prediction after acute coronary syndrome

46

Grandin EW, et al. Clin Chem. 2012; 58: 267-63

• 15% nonrevasc with symp

• Secondary prev

• Medical therapy

• What the challenge? 4-5%/y (2.5% CV) low mort

• OMT: imporve QoL, angina q, nitro, ACE-i,BB, Ca++, ranolazine the

only in 20y, L-arginine.

• Increase density microcirc induce angiogens LTMR, periop 4-5%,

induction on angio not certain; VGEF PGDF did not, EECP,

shockwave, SCPS,