ICD e CRT nel grande anziano: come regolarsi ? S. Fumagalli, Firenze

SOD Cardiologia e Medicina Geriatrica, AOU Careggi e Università di Firenze

Quando l’evidenza dai trial è insufficiente: il grande anziano

tigullio cardiologia 2014

3-4 aprile Santa Margherita Ligure

20-39 40-59 60-79 >80

Perc

ent o

f Pop

ulat

ion

Age (years) 65-74 75-84 >85

Per 1

000

Pers

on Y

ears

Age (years)

Prevalence of HF National Health and Nutrition

Examination Survey

Incidence of HF Framingham Heart Study

Heart Disease and Stroke Statistics—2012 Update A Report From the American Heart Association

Roger VL, 2012

Men

Speranza di vita alla nascita (2011) Uomini – 79.4 anni Donne – 84.5 anni Speranza di vita a 65 anni (2011) Uomini – 18.4 anni ! 83.4 anni Donne – 21.9 anni ! 86.9 anni http://demo.istat.it/altridati/indicatori/2011/Tab_5.pdf

! Despite the compelling findings from several CRT trials, it must be recognized that patients enrolled in these studies were highly selected

! Specifically, few patients >75 were enrolled … ! Thus, RCT evidence for efficacy of CRT in patients

>75 years is lacking and, as previously noted, extrapolation of data from trials in much younger patients to the very elderly may not be justified due to age-related alterations in both the risks (higher) and benefits (potentially lower) in older patients

2011

Età media dei principali trial sugli ICD MADIT (1996) – 63 anni MUSTT (1999) – 66 anni MADIT II (2002) – 64 anni DEFINITE (2004) – 58 anni SCD-HeFT (2005) – 60 anni

Al-Khatib SM, 2013

Clinical characteristics of the patients enrolled in the InSync / InSync ICD Italian Registry, by age groups

Age Groups (years) N=1787 <65

(N=571) 65-74

(N=740) >75

(N=476) P

Age (years) 57 ± 7 70 ± 3 78 ± 3 / Men (%) 84 81 76 0.003 COPD (%) 5 7 6 0.088 Diabetes (%) 8 9 6 0.312 Renal failure (%) 3 8 4 0.001 >2 diseases (%) 2 4 3 0.099 CAD (%) 39 50 50 <0.001 LVEDD (mm) 70 ± 10 69 ± 9 68 ± 9 0.015 LVESD (mm) 60 ± 12 58 ± 10 57 ± 11 0.016 EF (%) 26 ± 8 26 ± 7 27 ± 8 0.123 QRS length (ms) 167 ± 33 165 ± 31 162 ± 32 0.136 Hospitalizations (n) 1.6 ± 1.4 1.6 ± 1.5 1.7 ± 1.4 0.256 Permanent AF (%) 11 18 21 <0.001 Diuretics (%) 87 89 88 0.415 Nitrates (%) 17 23 46 0.001 III Class AAD (%) 34 38 34 0.312 CAD: coronary artery disease; Hospitalizations: CHF hospitalizations in the previous 12 months; AAD: anti-arrhythmic drugs Fumagalli S,

2011

CRT-induced changes of left ventricular (LV) diameters during the follow-up, by age group The results of the InSync / InSync ICD Italian Registry

50

55

60

65

70

75

Baseline 6 months 12 months Follow-up

LV d

iam

eter

s (m

m) End-diastolic

End-systolic

** ** **

** **

**

** ** **

** ** ** **: p<0.001 vs. Baseline

<65 65 – 74 >75 Age groups (years)

66 66

64

69 70

68

53 54

51

58 60

57

Fumagalli S, 2011

15

25

35

45

Baseline 6 months 12 months Follow-up

(%)

LV ejection fraction

** **

**

** ** **

**: p<0.001 vs. Baseline

CRT-induced changes of LV ejection fraction during the follow-up, by age group The results of the InSync / InSync ICD Italian Registry

26 27

26

34

37

34

<65 65 – 74 >75 Age groups (years)

Fumagalli S, 2011

HR (95% CI)

p Value

Age <65 years 1 / 65-74 years 1.17 (0.80-1.69) NS >75 years 1.57 (1.06-2.35) 0.026 Men 1.38 (0.90-2.12) NS

Renal failure 1.29 (0.75-2.22) NS

Coronary artery disease 1.18 (0.87-1.60) NS

LVEF, per Δ % 0.96 (0.94-0.98) <0.001

Permanent AF 1.63 (1.16-2.30) 0.005

ACE-I / Anti-AII 0.72 (0.52-0.98) 0.038 β-blockers 0.49 (0.35-0.67) <0.001 CRT responder 0.37 (0.27-0.51) <0.001

Clinical predictors of prognosis in CRT patients in the InSync / InSync ICD Italian Registry The results of the multivariate Cox model

Fumagalli S, 2011

Prob

abili

ty o

f HF/

deat

h

Follow-up (years)

History of intermittent atrial tachyarrhythmia (N=140)

Age: 67 years*; Women: 19%* CRT-D: 51%*; LVEF: 28%; Antiarrhythmics: 39%* *: p<0.05 vs. No Hx of Atrial TA

Risk of Heart Failure / Death Comparing CRT-D to ICD in LBBB Patients With and Without History of intermittent atrial tachyarrhythmias (TA)

ICD

HR=0.50, 95%CI=0.27-0.93, p=0.028

Ruwald AC, 2014

No History of intermittent atrial tachyarrhythmia (N=1101)

0 1 2 3

0.1

0.2

0.3

0.4

0.5

0.0 4 0 1 2 3 4

CRT-D ICD

CRT-D

HR=0.46, 95%CI=0.36-0.59, p<0.001

Age: 61 years; Women: 32% CRT-D: 61%*; LVEF: 29%; Antiarrhythmics: 3%*

Biv. Pacing >92%: 95% Biv. Pacing >92%: 90%

6 Min Walk Test (Change, m)

Peak VO2 (Change, mL/min)

MIRACLE N=453, III-IV

MUSTIC SR N=58, III

MIRACLE ICD N=369, III-IV

CONTAK CD N=227, II-IV

60

40

20

0

-20

3

2

1

0

(N, NYHA Class)

Improvements in exercise capacity in patients with moderate-to-severe heart failure by CRT. A review of the results of clinical trials

Linde C et al, 2012

CRT Control

P<0.001 P=0.001

P=NS P=0.029

P<0.001

P=0.029

P=0.04 P=0.003

Bogale N et al., 2012

% o

f Pat

ient

s

Much better

A little better

No change

A little worse

Much worse

Dead

Patient self-reported global assessment and rate of death during follow-up

81%

Years

Surv

ival

(%)

Survival of octogenarians undergoing CRT compared with the age- and gender-matched general population

6 m – 4.2%

1 y – 10.5% 2 y –

21.1% 3.6 y – 49.4%

Percentages express FU mortality

Age: 83 years; CRT-D: 86.3%; LVEF: 25% (N=95)

All-cause mortality in octogenarians with advanced HF is only modestly worse compared to the general octogenarian population.

Therefore, … CRT should not be withheld based on age alone

Rickard J, 2014 !

Mor

te Im

prov

visa

/ M

orta

lità

Tota

le

0

0,2

0,4

0,6

<50 51-60 61-70 71-80 >80Gruppi di età (anni)

0,41

P=0.002

Mortalità Totale

Improvvisa

Gruppi di età (anni)

0

5

10

15

20

<50 51-60 61-70 71-80 >80

Mor

talit

à an

nual

e (%

)

11,7

4,8

Mortalità totale

Morte improvvisa

Krahn AD et al, 2004

The Amiodarone Trialists MetAnalysis - N = 6252, Follow-up: 16.8 mesi

Gruppi di età (anni) N = 6311 <65

(n=2470) 65-74

(n=2331) >75

(n=1510) P

Età (anni) 55±9 70±3 78±3 /

Uomini (%) 83.2 82.0 81.8 NS

Aritmie ventricolari (%) 43.0 42.9 44.2 NS

Fibrillazione atriale (%) 8.1 12.6 18.3 <0.001

Ipertensione (%) 45.0 59.0 60.5 <0.001

Ricoveri (%) 49.5 50.9 49.7 NS

LVEDV (mL) 218±88 202±75 183±67 <0.001

Frazione di eiezione (%) 29±10 29±8 29±8 NS

NYHA (%) I-II 54.6 44.3 40.6 0.001 III-IV 45.5 55.7 59.5 Amiodarone (%) 43.6 49.3 49.0 0.004

CRT (%) 62.4 70.7 67.8 <0.001

Aritmie ventricolari: aritmie ventricolari complesse; LVEDV: volume telediastolico del ventricolo sinistro; NYHA: classe NYHA; CRT: terapia di resincronizzazione

cardiaca!

23.9%!Caratteristiche cliniche, per gruppi di età!

Risultati dell’analisi univariata di Cox!

Age-related effects on mortality of the implantable cardioverter defibrillator. An analysis of the Italian Clinical Service® Project

database!

Fumagalli S, Marchionni N, Padeletti L, 2014 !

HR (95% CI)

Aritmie v. (Si vs. No)

IRC (Si vs. No)

BPCO (Si vs. No)

CAD (Si vs. No)

Gruppi di età (Δ·gruppo)

P<0.001

P<0.001

P<0.001

P<0.001

P=0.001

P<0.001

Diabete (Si vs. No) P=0.013

Frazione di eiezione (Δ·%)

Fattori clinici correlati alla mortalità Risultati del modello multivariato di Cox

Aritmie v. : aritmie ventricolari complesse; CAD: malattia coronarica; IRC: insufficienza renale cronica

Mortalità "#1.65 #22.6%

Age-related effects on mortality of the implantable cardioverter defibrillator. An analysis of the Italian Clinical Service® Project database

Fumagalli S, Marchionni N, Padeletti L, 2014 !

HR p Età (Δ·anno) / CAD (Si vs. No) 2.55 <0.001 IRC (Si vs. No) / Aritmie V. (Si vs. No) / FA (Si vs. No) 2.05 0.017 FE (Δ·%) / NYHA (III-IV vs. I-II) 2.10 0.001

HR p 1.07 0.018 1.68 0.002 2.38 <0.001 1.42 0.037

/ 0.95 <0.001

/

HR p 1.09 0.006

/ / / / / /

<65 anni 65-74 anni >75 anni

Fattori clinici correlati alla mortalità per gruppi di età Risultati del modello multivariato di Cox

CAD: malattia coronarica; IRC: insufficienza renale cronica; Aritmie V.: aritmie ventricolari complesse; FA: fibrillazione atriale; FE: frazione di eiezione del VS

Age-related effects on mortality of the implantable cardioverter defibrillator. An analysis of the Italian Clinical Service® Project database

Fumagalli S, Marchionni N, Padeletti L, 2014 !

67,7 67,5

67,1 66,9

65

67

69

2006-7 2007-8 2008-9 2009-10

Adv

erse

eve

nts

(%)

OM

T (%

)

CR

T (%

) A

ge (y

ears

) CRT: CRT among eligible patients OMT: optimal medical Tx ACE-i/ARB & β-blockers

Overall trends in quality of care metrics in the ICD Registry – N=367,153

P<0.001

P<0.001

P<0.001

P<0.01

Temporal Trends in Quality of Care among ICD Recipients: Insights from the NCDR®

Dodson JA, 2014

The ICD Registry is an initiative of the ACCF and the HRS

OMT (%)

CR

T (%

)

CRT: CRT among eligible patients OMT: optimal medical Tx ACE-i/ARB & β-blockers

Correlation among optimal medical therapy (OMT) and cardiac resynchronization therapy (CRT), for hospitals performing >50 procedures per year – N=367,153

R=0.17 - P<0.001

20

Dodson JA, 2014

40 60 80 100 0

20

40

60

80

100

The ICD Registry is an initiative of the ACCF and the HRS

Even

t-fre

e su

rviv

al

Follow-up (months)

All-cause death or cardiac hospitalization

Age – OMT: 62 vs. Non OMT: 67 years, p=0.003; LVEF: OMT: 28 vs. Non OMT: 27%, P=NS

Kaplan–Meier estimates of primary endpoint - survival free of cardiac hospitalization - (left) and all-cause death (right), in patients with and without OMT

Optimized MT N=14/56 (25%)

HR=2.08, 95%CI=1.17-3.71, p=0.013

Adlbrecht C, Eur J Clin Invest 2009

All-cause death

0 10 20

0.2

0.4

0.6

0.8

1.0

0.0 30 40 50

Non Optimized MT N=68/148 (45.9%)

P=0.002

0 10 20 30 40 50

Optimized MT N=1/56 (1.8%)

Non Optimized MT N=26/148 (17.6%)

CRT – N=95 CRT-D – N=110

OMT: Optimized Medical Therapy

Outcome after device implantation in chronic heartfailure is dependent on concomitant medicaltreatmentC. Adlbrecht*, M. Hulsmann*, M. Gwechenberger*, G. Strunk†, C. Khazen*, F. Wiesbauer*, M. Elhenicky*,S. Neuhold*, T. Binder*, G. Maurer*, I. M. Lang* and R. Pacher*

*Medical University of Vienna, Vienna, Austria, †Vienna University of Economics and Business, Vienna, Austria

ABSTRACT

Background Device implantation in chronic heart failure (CHF) for cardiac resynchronization therapy (CRT) withor without implantable cardioverter ⁄ defibrillator (ICD) is an established treatment option for symptomaticpatients under medical baseline therapy. Although recommended, the need for optimization of medical therapywas never proven. As in ‘the real world’, medical therapy is not always up-titrated to the desirable dosages; thisprovides the opportunity to evaluate the impact of optimizing medical therapy in patients who had received adevice therapy with proven effectiveness.

Materials and methods This observational cohort study retrospectively assessed the ‘real life’-effect of CRTcompared with that of CRT ⁄ ICD therapy and the impact of concomitant pharmacotherapy on outcome. Outcomeof patients with guideline recommended renin–angiotensin system inhibitor and ß-blocker dosages was com-pared with that of patients who failed to reach the desired dosages. Mean follow-up for the 205 CHF (95 CRTand 110 CRT ⁄ ICD) patients was 16Æ8 ± 12Æ4 months.

Results In the total study cohort, 83 (41%) reached the combined primary endpoint of all-cause death or cardiachospitalization [CRT group: 25 (26%), CRT ⁄ ICD group: 58 (52Æ7%), P < 0Æ001]. Multiple cox regression analysisrevealed non-optimized medical therapy at follow-up [HR = 2Æ080 (1Æ166–3Æ710), P = 0Æ013] and CRT ⁄ ICD vs.CRT [HR = 2Æ504 (1Æ550–4Æ045), P < 0Æ001] as significant predictors of the primary endpoint.

Conclusion Our data stress the importance of professional monitoring and titration of pharmacotherapy notonly in medically treated CHF patients but also in patients under device therapy by a heart failure unit or a special-ized cardiologist.

Keywords Cardiac resynchronization, device therapy, heart failure, medical therapy, outcome.

Eur J Clin Invest 2009; 39 (12): 1073–1081

Introduction

Device implantation in chronic heart failure (CHF) forcardiac resynchronization therapy (CRT) with or withoutimplantable cardioverter ⁄ defibrillator (ICD) is an establishedtreatment option for symptomatic patients under medicalbaseline therapy [1]. The Comparison of Medical Therapy,Pacing, and Defibrillation in Heart Failure (COMPANION)study demonstrated comparable outcomes for CRT andCRT ⁄ ICD combination devices, with a further reduction ofmortality in the combination therapy group compared withthat in the group undergoing medical therapy alone [2]. Ina large multicentre prospective observational study, lower

rates of sudden cardiac death were reported for CRT ⁄ ICDcompared with that for CRT; however, this did not trans-late into significant improvements of total mortality [3].Patients included in randomized trials were under optimalmedical baseline therapy before implantation andmedications were adjusted as appropriate at the scheduledfollow-up visits; this was suggested to be one plausibleexplanation for the low mortality rates [1].

Recently published data from the Multicenter AutomaticDefibrillator Trail (MADIT) II demonstrated the importance ofconcomitant medical therapy in patients with ICD for primary

European Journal of Clinical Investigation Vol 39 1073

DOI: 10.1111/j.1365-2362.2009.02217.x

ORIGINAL ARTICLE

P=0.072!P<0.001!

P<0.014!

Terapia farmacologica, per gruppi di età!

ACE-I: ACE-inibitori; Anti-ATII: antagonisti dell’angiotensina II!

Age-related effects on mortality of the implantable cardioverter defibrillator. An analysis of the Italian Clinical Service® Project

database!

Fumagalli S, Marchionni N, Padeletti L, 2014 !

Implantation year

Num

ber o

f Im

plan

ts

Early Mortality: death < 1year after ICD implant

Annual ICD implantation rates and incidence of early mortality (N=1062; implant years: 1997-2007)

Bhavnani SP, 2013

Num

ber w

ith E

arly

Mor

talit

y

All patients N=1062

Num

ber o

f Im

plan

ts

Early Mortality (EM): death < 1year after ICD implant; CCI: Charlson Comorbidity Index

Charlson Comorbidity Index: prevalence in the study cohorts (left) and associated risk of early mortality (right)

Bhavnani SP, 2013

Early Mortality N=110

No Early Mortality N=110

*: P<0.05 for the comparison between the EM and no EM groups

HR Early Mortality 0.5 1 3 6 15

5.14

4.81

4.30

2.38

0.97

9

P<0.001

129

137

156

153

181

CCI 0 – Ref. 221

Days to death

Follow-up: 3.1 years Mortality: 35% (EM: 10%)

Patie

nts

(%)

Knowledge about deactivation

In favor of deactivation

Yes No Yes No

Before implantation

Battery replacement

Decreased life

expectancy

During the dying

process

When the physician should discuss the issue of deactivation with patients?

N=294; Age: 59 years; Men: 72% Secondary prevention: 28%: Implantation: 2008-2012!

The only predictor of a favorable attitude toward device deactivation at end of life: «A worthy avoidance of shocks during dying», p<0.0001!

Pedersen SS, 2013 !

Location of death in 125 ICD patients ICD as a secondary prevention: 82% !

Kinch Westerdahl A, 2014 !

Age: 74+9 years ICD implanted: 2.6 years CRT-D: 35%

Mechanisms of death in 125 ICD patients ! Kinch Westerdahl A, 2014 !

Cardiac causes (N=74, 59%) Non Cardiac causes (N=51, 41%)

Kinch Westerdahl A, 2014 !

Shocks received 24-h before death (N)

Terapy for VT / VF : 32%

Episodes of VT / VF 24-h before death (N)

Patients with electrical storm: 24% !

DNR patients: 52% (65/125) ICD “on”: 65% (42/65) Treated patients: 24% (10/42)!

Key points

•  The incidence of SCD increases with age owing to increasing prevalence of CHD and CHF among elderly individuals

•  Elderly patients are more likely to have PEA or asystole at the time of SCD and are less likely to survive a cardiac arrest

•  The mortality benefit and cost-effectiveness of primary prevention ICD therapy in elderly patients is dependent on competing mortality risks

•  CRT has demonstrated mortality and HRQL benefits across age groups

•  A substantial and growing proportion of primary prevention ICD and CRT devices are being implanted in elderly patients, and additional outcomes data in this growing population are needed

In lieu of randomized trial data, long-term outcome data from registries will be required to evaluate both the clinical effectiveness and cost-effectiveness of ICD and CRT in the elderly population

2013

Impl

anta

tion

Rat

e / 1

00.0

00

Year

65-74

>75

55-64

45-54 20-44

Rate: 0.83 14.91 Mean age: 58.7 63.5 years

Age-specific ICD implantation rates per 100,000 of population in the Western Australian population (N=1593/2010113, 1995-2009)

Bradshaw PJ et al. Am Heart J 2013

0.5

0.6

0.7

0.8

0.9

0 2

Even

t Fre

e Pr

obab

ility

4 6 8 10

1.0

12 Months post Implant

Q1-0-92% N=467

Q4-100% N=362 P<.001 vs Q1

Q3-98-99% N=509 P=.0004 vs Q1

Q2-93-97% N=474 P=.0013 vs Q1

N=1812 - Age: 72±11 Men: 72% Follow-up: 10.7% months

Death & HF hospitalization by percentage of biventricular pacing (quartiles) Q2-Q4 vs Q1 – HR=0.56, p<0.00001

Koplan BA, J Am Coll Cardiol, 2009

Mortalità per MADIT II Score e per gruppi di età

MADIT II Score

HR=1.47 P<0.001

HR=1.31 P<0.001

HR=1.10 P=0.331

Age-related effects on mortality of the implantable cardioverter defibrillator. An analysis of the Italian Clinical Service® Project database

Fumagalli S, Marchionni N, Padeletti L, 2014 !

P<0.001!

P<0.001!

P<0.001!

P<0.001!

BPCO: broncopneumopatia cronico-ostruttiva; CAD: malattia coronarica;

IRC: insufficienza reale cronica!

Principali patologie associate, per gruppi di età!

Age-related effects on mortality of the implantable cardioverter defibrillator. An analysis of the Italian Clinical Service® Project

database!

Fumagalli S, Marchionni N, Padeletti L, 2014 !