INHERITED CARDIOVASCULAR DISEASE UNIT

Risk Stratification in HCM is Feasible

Using a Clinical Score (PRO)

IT’S DIFFICULT!

1. COMPLEXITY

Hypertrophic Cardiomyopathy

Davies M. SGHMS

Hypertrophy

Fibrosis

Disarray

Sarcomeric protein gene mutation

Calcium

transients

Impulse

generation

Impulse

propagation

Modulators:

Fixed:

Genetic

(Histology)

Variable:

Haemodynamics

Ischaemia

Autonomic

Exercise

+ = Ventricular

Arrhythmia

Cell Organ

2. THE DATA

mean n=1238 pts

mean n=176 patients

Young, very symptomatic, ↑ LVOTO

Study marker size is weighted to study cohort size

0.81%

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Cum

ula

tive S

urv

ival

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Years

16 patients (19±8 yrs)

59% (95% CI 33-84)

at 5 years

Elliott P et al JACC 1999; J Am Coll Cardiol 1999;33:1596-601

6.1±4.0 (0.5-14.5)yrs

Secondary prevention

Youth

Genotype

Family History

NYHA III/IV

Exercise capacity

Syncope

Severe LVH

Large gradient

Diastolic dysfunction

Abn Exercise BP

Ischaemia

Atrial fibrillation

Non-sustained VT

Inducible VT/VF

Fractionation

Family History

Syncope

Exercise BP

NSVT

LVH

“Risk Factors”

1.0

0.9

0.8

0.7

0.6

0.5

0.4 0 25 50 75 100 125 150 175

Follow-up (months)

Cu

mu

lative

Su

rviv

al

Log Rank p<0.002

N=630

Elliott PM et al. Lancet 2001;357:420-24

0

2

1

3

Log Rank for Trend p=0.0001

PP Dimitrow et al. EHJ 2010

Principle of risk stratification

5 RF

4 RF

3 RF

2 RF

1 RF

No risk factors

Incre

asin

g r

isk o

f V

F

This is a clinical risk score

LVOTO

Late Gad

Apical Aneurysm

Compound mutations

IS THERE A HIERARCHY OF

RISK FACTORS?

Single Risk

Factor:

O’Mahony C. et al. Heart 2013

CAN WE USE GENETICS/CMR

AS ARBITERS?

Genetics/LGE as predictors of SCD

FH SCD

Syncope

Age

LVOTO

LA size

AF

MWT

NSVT

SCD

LGE

Genetics

?

Complex genotypes and SCD

Double mutations

• Richard et al; Circ 2003 – 7/197 (4%)

– No detailed follow-up data

• Van Driest et al; JACC 2004 – 10/397 (2.5%)

– No detailed follow-up data

• Ingles et al; JMG 2005 – 4/80 (5%)

– All SCD were not genotyped

Triple mutations

• Girolami et al; JACC

2010

– 4/488 (0.8%)

– 2 MWT>30mm

– Outcomes

• 3 dilated LV with HF

with 1 pt having ICD

shocks

• 1 pt aborted SCD

CMR AND SCD RISK PREDICTION

JC Moon et al. JACC 2004

LGE studies and SCD

• 7 centres

• N=1293 but highly selected

• FU 3.3y

• Visual greyscale method (similar to 6SD)

0

.25

.5.7

5

1

No LGE with LGEModel

ROC AUC 95% CI

SCD risk model:

1) %LGE

1) Four conventional SCD

risk factors collapsed as 1

continuous variable

1) maximal LV thickness.

A Flett et al. JACC CVS Imaging 2011

O’Mahony C et al. Eur Heart J. 2014 Aug 7;35(30):2010-20

Major limitation = group prognostication on relative risk

Patient

assessment

0 RF 0.5%/y SCD

1 RF 0.6%/y SCD

↑ risk by 1.4

≥2 RF 1.6%/y SCD

↑ risk by 3.3

O’Mahony C. et al. Heart 2013

CANDIDATE PREDICTORS

Demographic

Age

Historical

Syncope

Family history of SCD

ECG /

Holter

NSVT

Echo

MWT

LV diastolic size

LVOT gradient

LA size

C O’Mahony et al. Circ AE 2013

0

1

2

3

4

5

6Hazard Ratio

O’Mahony C et al. Eur Heart J. 2014 Aug 7;35(30):2010-20

HCM Risk-SCD model for predicting 5 year

risk

O’Mahony C et al. Eur Heart J. 2014 Aug 7;35(30):2010-20

IMPLICATIONS?

Validation: discrimination

• C-index • probability that of a randomly

selected pair of subjects, the

subject with SCD first has the

worse predicted prognosis

• HCM Risk-SCD: 0.70

(95% CI: 0.68, 0.72)

• ACC/ACCF: 0.54

(95% CI: 0.51, 0.56)

0

.25

.5.7

5

1ACCF/AHA 2011 HCM Risk-SCD

C-index 95% CI

5-year SCD probability: 10.9%

5-year SCD probability: 5.1%

Asymptomatic

MWT 25mm

NSVT

LA=45 mm

22 year old

LVOT gradient 70mmHg

56 year old

LVOT gradient 28mmHg

Prevention of Sudden Cardiac

Death

Recommendations for ICD in

each risk category take into

account not only the absolute

statistical risk, but also the

age and general health of the

patient, socio-economic

factors and the psychological

impact of therapy.

Take Home Messages

• Sudden Death is uncommon in patients with HCM

• The risk of SCD can be estimated using simple

non-invasive assessment and HCM RISK-SCD

• Future refinement of risk prediction should be

based on robust modelling and not simply “expert

opinion” alone.

REBUTTAL

“INDIVIDUALS” VERSUS

GROUPS

Majority of

deaths occur in

low risk

populations

BUT

The proportion

of patients at

low risk that die

is very small

N SCD % Annual SCD

≥ 2 RF 412.0 32.0 7.8 1.6

1 RF 1074.0 27.0 2.5 0.5

0 RF 1580.0 25.0 1.6 0.3

• Method #1: Relying on past experience and

training to make an intuitive prediction.

• Method #2: Relying wholly on a statistical

prediction model developed to be used in that

situation.

• Method #3: Taking account of the output of

the statistical prediction model but possibly

modifying it on the basis of professional

experience and intuition.

This study confirms and greatly extends previous reports that

mechanical prediction is typically as accurate or more accurate

than clinical prediction.

No SCD

SCD

No SCD

SCD

Risk of SCD

Risk of SCD

“The impossible dream”

Risk Stratification in HCM is Feasible

Using a Clinical Score

YES

• “We aren’t dealing with groups, we

are dealing with this individual

case.”

• It is doubtful that one can profitably

debate this cliché in a case

conference, since anyone who puts

it quite this way is not educable in

ten minutes.

What will Dr Maron say?

• SCD is a devastating consequence of HCM

• The ICD is life saving

• HCM is a heterogeneous disease and therefore

not suitable for complex “mathematical” solutions

What will Dr Maron say?

And yet…

• We can identify high risk patients using selected

risk factors

• When in doubt do an MRI and all will be clear

Just how unpredictable is HCM?

• LA size is associated with AF and stroke

• End-stage disease has a poor prognosis

• LVOTO responds well to surgery

• Patients over 60 have a lower incidence of SCD

Etc…