ICD, tra Linee Guida e nuovi studi: qualcosa

cambierà nella profilassi primaria della

morte improvvisa?

Manlio CiprianiCardiologia 2 – Insufficienza Cardiaca e Trapianti

Dipartimento Cardiotoracovascolare “A. De Gasperis”

ASST Grande Ospedale Metropolitano Niguarda-Milano

DANISH-NEJM 2016 SCD = 4.3% versus 8.2%, HR 0.50; 95% CI 0.31 a 0.82; P=0.005

Circulation. 2017;135:201–203January 10, 2017

6 RCTs enrolling 2970 patients with NICM to study the efficacy of ICDs for primary prevention

Underuse of Cardiac Resynchronization and Implantable Cardioverter-Defibrillator Therapy in Outpatients with Chronic Heart Failure. Findings from IN-HF Outcome Registry.Fabrizio Oliva1, MD, Andrea Mortara2, Andrea Di Lenarda3, Manlio Cipriani1, Michele Senni4, Marco Metra5, Gianfranco Misuraca6, Gabriella Celona7, Mauro Gori4, Flavio Venturi8, Donata Lucci9, Aldo P. Maggioni9, Luigi Tavazzi10 on the behalf of

the IN HF Outcome Investigators*

Only 27% of patients with an indication to ICD and 35% to CRT were actually implanted.

Under submission

27%

Ripensare

Int J Cardiol 2017; in press

Circulation. 2016;134:2074–2

5 simple characteristics routinely assessed by EMS dispatchers on the phone in case of chest pain: Younger age, shortness of breath, absence of diabetes, absence of obesity, and short delay between pain onset and call to EM

Int J cardiol 2017

Old Tools New Tools

Clinical SuVT/VF LGE on cardiac MRI

LVEF<35% GLS

NYHA class RVEF

QRS duration > 120 msec Pedigree analysis/NGS

QRS morphology (LBBB)

PVS

Old and New Risk Stratifiers to Guide Device (ICD/CRT)

Management in Patients with Dilated Cardiomyopathy (DCM)

LGE = late gadolinium enhancement; GLS = global longitudinal strain; LBBB = left

bundle branch block; LVEF = left ventricular ejection fraction; MRI = magnetic

resonance imaging; NGS = next generation sequencing; NYHA = New York Heart

Association; PVS = programmed ventricular stimulation; RVEF = right ventricularejection fraction; SuVT = sustained ventricular tachycardia; VF = ventricular fibrillation

Expert Review of Cardiovascular Therapy: 2017

International Journal of Cardiology (2017)

A. Gulati et al. Circulation. 2013;128:1623-1633

Study Limitations-Referral bias, we studied consecutive patients with a broad rangeof phenotypic severity-Renal function-Evaluation of pulmonary arterial pressure

VSx VDx

LVEF < 35% LVEF > 35%

HR

In LVEF<35% RVD 2.98-fold higher risk of SCA or appropriate ICD therapy and in LVEF >35% 4.2-fold.

Circ Arrhythm Electrophysiol. 2017;10 (1)

Echocardiography

Radial strain (pos):

regional wall thickening towards LV center

Longitudinal strain (neg):

regional shortening from

base-to-apex

Circumferential strain (neg):

intramural circumferential

shortening

Componenti dello strain

La deformazione di un oggetto tridimensionale è descritta da

3 componenti ortogonali

RV Longitudinal Deformation Correlates With Myocardial Fibrosis in Patients With End-Stage Heart Failure

Lisi M, Cameli M. et al - J A C C : C A R D I O V A S C U L A R IMA G I N G , V O L . 8 , NO. 5 , 2 0 1 5

(J Am Coll Cardiol Img 2013;6:851–60)

Late Gadolinium Enhancement

From: Association of Fibrosis With Mortality and Sudden Cardiac Death in Patients With Nonischemic Dilated

Cardiomyopathy

JAMA. 2013;309(9):896-908. doi:10.1001/jama.2013.1363

Ankur Gulati, MDCardiovascular Magnetic Resonance Unit, Royal BromptonHospital, Sydney Street, London, SW3 6NP, England

Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy

Di Marco A. and al. J A C C : H E A R T F A I L U R E V O L . 5 , N O . 1 , 2 0 1 7

29 studies, 2948 pts – Arrhythmic endpoint: SVA, appropiate ICD therapy or SCD-LGE was significantly associated with end-point (OR: 4.3; p<0.001)

-(OR: 6.7;p<0.001) studies that performed multivariate anlysis-(OR: 5.2;p<0.001) studies LVEF>35%-(OR: 7.8:p=0.008 )studies primary prevention ICDs

December 2020 is the estimated completion date

GUIDEd Management ofMild-moderate LVS dysfuntion

SD risk stratification by

polyparametric approaches

J Cardiovasc Med 2016, 17:245–255

J Cardiovasc Med 2016, 17:245–255

J A C C : H E A R T F A I L U R E VO L . 5 , NO . 1 , 2 0 1 7

RVF

IV NYHA Class

1) ICD therapy is not recommended in patients with end-stage

(NYHA class IV) HF and in other patients who have an estimated

life expectancy of ,1 year

2)Patients with NYHA functional class IV HF that is refractory to

medical therapy have a life expectancy that is generally less than 1

year, unless cardiac transplantation is performed or a ventricular assist

device is placed

3)The role of ICD therapy for primary prevention of SCD in patients

with NYHA class IV HF with a narrow QRS complex has not been

studied in a randomized trial.

NYHA class IV and ICD

Guidelines indications

(N = 134 publications) reported original data from clinical trials explicitly defining advanced HF in adults. 108 pubs. included: 66 ambulatory pts, 42 pubs. hospitalizes pts

J Cardiac Fail 2016;22:569–577

Distribution of (A) NYHA class and (B)LVEFamong clinical trials that have used these criteria to define advanced HF

Use of the 8 most frequently used criteria to define advanced heart failure by era.

“New” Issues

>30% ICD Implants for Generator ExchangeEHRA: units pa -4,000 (32%) Italy, -2,000 (27%) UK, -20,000 (39%) Germany (includes CRT-D)

-40% of the patients showed an improved LVEF during follow-up-In 25%, LVEF improved to >35%.

Changes in LVEF were inversely associated with the risk of all-cause mortality and appropriate shocks.In patients whose follow-up LVEF improved to >35%, the risk of an appropriate shock was markedly decreased but still present, suggesting that improvements in ejection fraction alone may not be enough to warrant deferring ICD generator exchange.

Repeated LVEF assessments after ICD implantation can provide additional prognostic information and may also allow for more informed decision making regarding ICD generator replacement, especially in patients whose LVEF improved significantly

Shock

ATP/Shock

Replacing an ICD is still recommended

in all primary prevention patients

despite the lack of appropriate ICD

therapy during first battery service life.

Yap S-C, et al. Heart 2014;100:1188–1192

Of 403 patinets who required exchange

-68% had received noATP/shock;

-11% received ATP/shock; 24% of whom died anyway

2 prospective ICD registries of the cardiology department

(Rotterdam, the Netherlands and Basel, Switzerland)

Procedure-related complications (<30 days after ICD replacement)

occurred in 18 patients (7%)

Infection requiring intravenous

antibiotics (2,3%)

Repeated Levosimendan Infusions in Refractory Heart Failure: Single Center Experience

Total LevosimendanResponder(%)

LevosimendanNonResponder(%)

P

N 72 47 25

Age – yr 56(49-61) 56±10 51±13 0.07 Female - no.(%) 11(15) 5(11) 6(24) 0.17

AF – no (%) 32(44) 22(47) 10(40) 0.62 COPD 14(19) 12(25) 2(1) 0.12

BMI (Kg/m2) 24(21-27) 25±4 24±4 0.38 Hospitalized + inotropic agent-

no.(%)

20(29) 12(25) 8(32) 0.61

Ischemic cause of HF –no.(%) 35(49) 24(51) 11(44) 0.62

INTERMACS scale 1-3 –no.(%) 11(18) 4(9) 7(28) 0.04* Arrythmic pattern 16(22) 12(25) 4(16) 0.55

CRT-D – no (%) 38(53) 25(53) 13(52) 1.00 Ambulatory Therapy ACEi-no(%) 43(63) 30(64) 13(62) 1.00 BB-no(%) 66(98) 44(93) 22(88) 0.42 Anti-Ald-no(%) 60(88) 40(85) 20(80) 0.74 Diuretics HD-no(%) 44(66) 29(61) 15(60) 1.00 Digoxin-no(%) 25(37) 18(38) 7(28) 0.44 Amiodaron-no(%) 20(30) 15(32) 5(20) 0.41 Ivabradine-no(%) 10(67) 5(11) 5(20) 0.30 Allopurinol-no(%) 39(68) 28(60) 11(44) 0.23 Statins-no(%) 28(41) 22(47) 6(24) 0.08 Right heart catheterization RAP (mmHg) 9(±5) 9(7-10) 10(5-14) 0.42

mPAP (mmHg) 37(±12) 37(±12) 35(±9) 0.63 PCWP (mmHg) 25(±7) 25(±8) 24(±7) 0.70

CI (L/min/m2) 1.6(±0.3) 1.6(±0.3) 1.5(±0.4) 0.37

PVR (Wood) 7.3(±5.6) 7.4(±6) 7.1(±4.4) 0.87

Echocardiographic parameters LVEF - % 25(±7) 25(±7) 24(±6) 0.47

LV EDD mm 66(±10) 66.4(63.7-69) 64.2(58-70.3) 0.43 LV VTD ml 227(±88) 230(±93) 218(±73) 0.64

IM severa-no(%) 34(55) 25(53) 9(36) 0.22 TAPSE mm 14(±3) 14.1±3 14.7±7 0.67

RV diameter (4 chamber view) mm

42(±6) 40.3±8.1 42.4±5.3 0.44

IT severa-no(%) 17(58) 12(26) 5(20) 0.77 Laboratory values

NT-proBNP (ng/L) 4052(2244-6893)

5239(±6098) 9842(±13914) 0.12

Bil tot (mg/dL) 1.12(0.7-1.6) 1.24(±0.75) 1.34(±0.77) 0.67 Creatinine (mg/dL) 1.13(0.9-1.4) 1.2(±0.6) 1.3(±0.4) 0.73

MDRD 62(47.8-80.1) 70.8(±31) 57.2(±20) 0.11 Urea (mg/dL) 57(43-88) 65.3(±41.3) 84.3(±52.4) 0.17

Sodium (mmol/L) 138(±3.9) 138.6(±3.3) 136.3(±4.5) 0.03* Hb (g/dL) 13(11.4-14) 12.5(±2.2) 12.6(±1.9) 0.90

Lymphocytes (%) 24.4(±9) 24.9(±10) 23.4(±8) 0.64 Ac. Uric (mg/dL) 7(±2.3) 7.4(±2.3) 6.3(±2.5) 0.19

Cholesterol (mg/dL) 134(112.3-153.3)

133.4(±47) 143(±46) 0.55

ADHFproBNP survival score 1-year survival probability

78(53.1-92) 80.7(67.1-92.3) 52.3(42.2-91.5) 0.14

LR 40.4%

LNR 20.0%

3-YearHR 2.80 (95%CI 1.56-5.00; p=0.001)

No. at

risk

LR 47 36 25 9 7

LNR 25 8 3 1 0

Patients with advanced heart failure treated with Levosimendan: levosimendanresponders (LR - >2 infusions) versus levosimendan non responder (LNR – only 1 or 2infusions)

Niguarda Ca’ Granda Hospital experience from January 1st 2006 to December 31st 2014 (n=72)

Median survival 500 days for LRs Versus 80 days for LNRs

Listing to TxC\MCS

1 – 20

20 – 40

40 – 60

60 – 80

> 80

PADOVA* 86

MILANO NIGUARDA* 83

TORINO SAN G. BATTISTA* 41

MILANO SAN RAFFAELE* 51

ROMA SAN CAMILLO 27

VERONA* 31

PALERMO ISMETT* 30

BERGAMO 21

UDINE 18

SIENA* 21

CHIETI 11

BOLOGNA* 14

NAPOLI MONALDI 9

BARI* 11

MILANO HUMANITAS* 7

MILANO MONZINO 7

ROMA GEMELLI* 5

CATANIA 5

PERUGIA 4

PAVIA* 7

TOTALE 489

All Adult LVAD Implants – by Region and Center

Period: 2010-2015*

20 Centers

* Preliminary data

The Journal of Heart and Lung Transplantation, Vol 32, No 2, February 2013

The Journal of Heart and Lung Transplantation, Vol 32, No 2, February 2013

Arrhythmias in Patients with Cardiac Implantable Electrical Devices after Implantation of a Left Ventricular Assist Device.Rosenbaum, Andrew; Kremers, Walter; Duval, Sue; Sakaguchi, Scott; John, Ranjit; Eckman, Peter

ASAIO Journal. 62(3):274-280, May/June 2016.

Time-dependent effects on clinically significant arrhythmias after LVAD implantation, including evidence that early LVAD-related arrhythmias may be caused by the unique arrhythmogenic effects of VAD implant

The role of implantable cardioverter-defibrillators in patients

with continuous flow left ventricular assist devices — A meta-

analysis

International Journal of Cardiology 222 (2016) 379–384

This meta-analysis demonstrates that there is no survival benefit with ICD in heart failure patients supported with continuous flow LVAD

[BTT] patients (224 patients, 149 with ICD versus 75 without ICD), an active ICD was not associated with a higher probability of survivzal [OR 1.47, 95% CI 0.78–2.76; p = 0.23].

Individualizzare l’indicazione ad ICD in

base a

-Profilo di rischio non solo dell’eventuale primo

impianto ma anche delle sostituzioni

• Età

• Copatologie (IRC, BMI,…)

• Stato settico\infiammatorio

• Storia di aritmia V\SV e interventi ICD

pre e post-impianto

• Profilo coagulatorio (TAO+ASA

\\TAO+ASA+Clopidogrel)

• DT vs BTT\BTC

-Rititolazione delle OMT (Beta-bloccante)

-”End of life”

ICD in MCS

Quando non dovrebbe essere impiantato un defibrillatore

(Circulation . 2009; 120:835-842.)

They found that patients with an annual risk of death more than 20% did not receive any benefit from ICDimplantation

JA C C : H E A R T F A I L U R E V O L . 2 , N O . 6 , 2 0 1 4

-The survival benefit of the

ICD exists but is attenuated

with increasing age .

-There was no evidence that

age modifies the association

between ICD treatment and

rehospitalization.

Circ Cardiovasc Qual Outcomes - 2015

Perm J 2016 Winter;20(1):27-32

Age

Trial (year) Pts Pts > 75 y/o (n) Pts > 75 y/o (%)

Prevenzione I

MADIT (1996) 196 18 9.18

MUSTT (1999) 704 96 13.6

MADIT II (2002)

1232 204 16.6

DEFINITE(2004)

458 43 9.4

SCD-HeFT(2005)

2521 236 9.4

Prevenzione II

AVID (1997)CIDS (2000)CASH (2000)

1963 252 13

> 80%

Percentuale di pazienti > 75 aa nei trial ICD

Senni M. Circulation 1998

…The current ACC/AHA guidelines do not specify an age criterion for selection of candidates for ICD. The only contraindications fordevice implantation are patients who do not have a reasonable expectation of survival with an acceptable functional status for atleast 1 year, even if they meet ICD implantation criteria specified in the Class I, IIa, and IIb recommendations (level of evidence C)…

Epidemiologia dello Scompenso Cardiaco: distribuzione

secondo fasce d’età

ICD nei pazienti anziani

A 81 anni un italiano medio non ha un’aspettativa di vita > 1 anno

Ann Intern Med. 2010;153:592-599

Elderly: > 65 yrs DEFINITE, SCD-HeFT, IRIS;> 60 yrs MADIT II, DINAMIT

Younger

Elderly

Between 2004 and 2011, 6,311 patients were enrolled (5,174 men; VSFE 29% ± 9%); 1,510 subjects were ≥ 75 years (23.9%; mean age 78 ± 3 years).

1. The association between prognosis and age was partially influenced by co-morbidities2. Patients ≥75 years showed higher mortality rates, independent of their estimated class of

risk (MADIT score) ->Functional disability might also play an important role3. In the youngest patients (<65) prognosis was correlated only with cardiologic variables4. Age was a significant predictor of mortality in patients aged 65 to 74 years or more,

becoming, for patients ≥ 75 years, the sole determinant of reduced survival rate.

Am J Cardiol 2014;113:1691e 1696

Nel mondo reale …....è venuto in bicicletta e mi ha chiesto il Viagra??!!

Lifespan

Good quality of life Poor quality of life

Desirable from good medical care

Undesirable from medical care?

Shift in modality to die

Quality of life and Medical care

The objective of this study was to develop a model to predict mortality within the first year after ICD implantation. A retrospective analysis of 469 consecutive pts.

Am Heart J 2006;151:397- 403

G Ital Cardiol 2017;18(1):67-79

ICD registrati nel 2015= 15 363 - 85% circa dell’attività impiantistica in Italia.-1235 (8.0%) sono sopravvissuti ad ACC-553 (3.6%) hanno presentato sincope come sintomo principale all’esordio aritmico-273 (1.8%) hanno presentato vertigini o pre-sincope-Rispetto 2014/+ 4.6% impianti in prevenzione primaria

Data from the PROSE-ICD study - 1,189 patients

-6 clinical factors (age ≥75 years, NYHAclass III/IV, atrial fibrillation, eGFR <30mL/min/1.73m2,

diabetes, and use of diuretics)

-3 biomarkers (TNF-αRII, pro-BNP, and cTnT)

Heart Rhythm. 2015

L’età mediana 71 anni (63 I quartile;78 III quartile). -La prevenzione primaria ha riguardato il 77.3% dei primi impianti, quella secondaria il 22.7%.

-Arresto cardiaco è stato riportato nell’8.0%. -ICD monocamerali sono stati utilizzati nel 29.3% dei primi impianti, -ICD bicamerali nel 34.6%-ICD biventricolari nel 36.1%.

G Ital Cardiol 2017;18(1):67-79

G Ital Cardiol 2017;18(1):67-79

G Ital Cardiol 2017;18(1):67-79

G Ital Cardiol 2017;18(1):67-79

G Ital Cardiol 2017;18(1):67-79

Does Anyone Really Believe the Results of the DANISH Trial?—Implanting an ICD in Non-Ischemic Cardiomyopathy Patients

Conclusion: ICD

• Little Difference in Selection Criteria between 2012 to 2016• More emphasis on co-morbility/expected longevity

• Change in Recommendations on Programming

• New Recommendation on Generator Exchange

Highlights

• Sudden cardiac death (SCD) is a major issue of

public health.❖> 350.000 deaths per year in the United States, accounting for almost half of cardiovascular mortality

•Two strategies have been used for reducing SCD

burden: prevention and resuscitation.

•However, survival rate remains low.❖ Survival to hospital discharge was estimated to be only 7.9% among out-of-

hospital cardiac arrests that were treated by emergency medical services personnel (JAMA 2008)

The study population was comprised of 6451 patients including 3207 whites and 2910 blacks.

N Engl J Med. 1993; 329:600–606.

Incidence of sudden cardiac arrest according to age, sex, and race in the Chicago CPR project.

Structural heart disease in cardiac arrest survivors

Circulation. 1996;93:1170 –1176CAD coronary artery disease; DCM, dilated cardiomyopathy; VHD, valvular heart disease

• In 5% of SCDs or cardiac arrests, a significant cardiac abnormality is

not found after extensive evaluation or at autopsy.

• CHD predisposes to SCD in 3 general settings:

• (1) acute myocardial infarction

• (2) ischemia without infarction

• (3) structural alterations such as scar formation or ventricular

dilatation secondary to prior infarction or chronic ischemia

• In autopsy studies, stable plaques and chronic changes alone are

found in ≅50% of SCD patients with CHD suggesting that plaque

rupture and acute mycoardial infarction (MI) is present in some, but

not the majority, of SCD cases.

-Circulation 1995-N Engl J Med. 1997-Circulation. 1998

SCD and CHD

Patients who actually received an ICD were mostly men (92% vs 79%; p=0.001), and as compared to not implanted ones were significantly younger (65±12 vs 68±12; p=0.001), more often with an ischemic aetiology (65% vs 47%; p=0.001) and with significantly more severe left ventricular dysfunction both in term of LVEF and cardiac volumes. -Co-morbidities such as COPD, diabetes, history of renal failure and permanent AF were similar in implanted and not implanted ICD subgroups.-NYHA functional class II (87%).-Amiodarone was used more frequently in ICD implanted patients subgroup (30% vs 17%; p=0.001).

Critical pathways leading to electric instability and sudden cardiac death

(Circulation. 2012;125:620-637.)

Interaction between a transient event and underlying substrate

First cardiac rhythm documented at time of sudden arrhythmic death.

Am Heart J. 1989

Incorporating DANISH into practice exposes

the problem of reliance on static guidelines.

The practice of medicine changes faster than

ever. DANISH not only informs the narrow

decision to implant ICDs in patients with

heart failure, it should also intensify our

focus on the quality of evidence we use.

I'm not suggesting this trial should

completely stop the use of ICDs in patients

with nonischemic heart failure. Rather, it

reinforces a basic principle: our patients

need doctors, not installers of devices.

John Mandrola, MD - 28.08.2016Clinical Electrophysiologist, Baptist Medical Associates, Louisville, Kentucky

www.medscape.com