Barry J. Maron, MD Director, Hypertrophic Cardiomyopathy Center

Minneapolis Heart Institute Foundation Minneapolis, Minnesota

Disclosures: Medtronic (Grantee) GeneDx (Consultant)

Debate: Risk Stratification in HCM is Feasible

Using a Clinical Score (CON)

The ESC-HCM-Sudden death prediction formula is as follows: Probability SCD at 5 years = 1 – 0.998 exp (Prognostic index);

where Prognostic index = [0.15939858 x maximal LV wall thickness (mm)] – [0.00294271 x LV maximal wall thickness2 (mm2)] + [0.0259082 x left atrial diameter (mm)] + [0.00446131 x maximal (rest/Valsalva) LV outflow tract gradient (mm Hg)] + [0.4583082 x family history SCD] + [0.82639195 x NSVT] + [0.71650361 x unexplained syncope] – [0.01799934 x age at clinical evaluation (years)].

“When something is so complicated, you are forced to take a leap of faith”

I First Started Getting Angry Calls Right Away

Rome: “I have low risk symptomatic patient who is myectomy candidate with very high risk score because his gradient is high.”

Cleveland: “All my patients have low scores…even those who clearly seem high risk. This ESC thing doesn’t make any sense.”

DON’T USE IT

HERE IS WHY

Study Population

Minneapolis Heart Institute; Tufts Medical Center 1629 consecutive HCM patients ≥ 16 years

(1992-2014)

• Age: 47 ± 17 years

• Risk stratified by: ACC/AHA 2011; ACC/ESC 2003

• Sudden death events: 35

• Primary prevention appropriate ICD interventions: 46

% P

atie

nts

Wit

h/W

ith

ou

t IC

D In

terv

en

tio

n/S

ud

den

De

ath

Appropriate ICD

Intervention

No Appropriate ICD

Intervention

ESC Risk Score

<4% <4% 4-6% 4-6% >6% >6% Risk/5y Risk/5y

<4% 4-6% >6% Risk/5y

Sudden Death

Assessment of ESC Sudden Death Risk Score (n = 1649)

60%

26%

63%

9%

70 patients left vulnerable to SD without protection from ICD… using ESC risk score

WHAT’S MISSING FROM ESC RISK MODEL?

• CMR and LGE • LV apical aneurysm • End stage (EF <50%)

LGE

LGE LGE

Extent of LGE vs. Sudden Death Risk in HCM

Follow-up (years)

Surv

ival

LGE (-) LGE < 10%

LGE 10-20%

LGE > 20%

Chan RH et. al. Circ 2014; 130(6): 484-95

QUESTIONABLE ADDITIONS TO ESC RISK MODEL

• Left atrial size • LV outflow gradient • Remote syncope

Mixed /no relation to SD risk

WHAT DOES WORK…?

Risk Stratification in HCM According to U.S. Guidelines

ICD Performance in High Risk Adults & Children with HCM

Evidence for Decreased HCM Mortality:

1000 Patients Presenting in Mid-Life (30-59y)

MHIF/ Tufts

0

0.5

1

1.5

2

% H

CM

Mo

rtal

ity

HCM-Related Mortality

0

0.5

1.5

1

6

General U.S. Population

0.8%/y

0.5%/y

1.5%/y

3-6%/y

Early HCM Referral Cohorts

HCM Cohorts: Prior to utilization

of current treatment strategies/

interventions

ICD intervention Heart transplant/myectomy

OHCA/defibrillation/hypothermia

Present HCM Cohort:

Contemporary treatment

ESC Prognostic Score…

1. Misclassifies most HCM patients with SD or ICD interventions with low risk scores

2. Fails to protect most patients from SD without ICDs

3. Is inferior to conventional risk stratification according to ACC/AHA (HCM) Guidelines

Risk stratification in HCM often requires fully informed patient and measure of physician judgment in shared decision making—not

possible with rigid math/stats prediction formula

ARE WE CLINICIANS…

OR STATISTICIANS??

Rebuttal

THERE REALLY IS NO MIDDLE GROUND HERE

INTUITIVELY…

How can a complex mathematical model with 7 variables, including 2 which have little

to do with SD, reliably predict SD in a heterogeneous genetic disease in which SD

events are uncommon (5%)?

Answer:

IT DOESN’T

% P

atie

nts

Wit

h/W

ith

ou

t IC

D In

terv

en

tio

n/S

ud

den

De

ath

Appropriate ICD

Intervention

No Appropriate ICD

Intervention

ESC Risk Score

<4% <4% 4-6% 4-6% >6% >6% Risk/5y Risk/5y

<4% 4-6% >6% Risk/5y

Sudden Death

Assessment of ESC Sudden Death Risk Score (n = 1649)

60%

26%

63%

9%

70 patients left vulnerable to SD without protection from ICD… using ESC risk score

Who Does ESC Risk Score Miss?

• Virtually all nonobstructive patients with massive LVH

• Most with syncope as single risk marker

• Many with family history of SD as single risk marker

• Some with 2 risk factors: family history SD + NSVT

General

• 30 y/o + syncope + LV 34mm

• 40 y/o + NSVT + LV 30mm

• 20 y/o + family history SD + LV >25mm

Specific

“Truth is what your contemporaries let you get away with.”

Richard Rorty, 1931-2007

WHAT’S MISSING FROM ESC RISK MODEL?

• CMR and LGE • LV apical aneurysm • End stage (EF <50%)

1.0

0.8

0.6

0.4

0.0

0 5 15 10 20

HCM patients without LV apical aneurysms

HCM patients with LV apical aneurysm

Log-rank test p<0.001

Years from First Evaluation

Su

rviva

l fre

e fro

m H

CM

re

late

d

mo

rta

lity a

nd

a

dve

rse

eve

nts

0.2

HCM Related Death or Adverse Clinical Events

in 70 Patients with LV Apical Aneurysms

8.1%/year

1.7%/year

70 patients left vulnerable to SD without protection from ICD… using ESC risk score

70 patients left vulnerable to SD without protection from ICD… using ESC risk score

70 patients are left vulnerable to sudden death without protection from the ICD…when using ESC risk score

No Risk Factors: Unnecessary ICD

Over-Treatment : ESC Risk Score

• LVOTG 100 mm Hg + LA 50mm (40 y/o)

• LVOTG 0 + LA 55mm (18 y/o)

• LVOTG 50 mm Hg + LA 40mm (20 y/o)

0

10

20

30

40

50

60

70

80

90

100%

Pat

ien

ts W

ith

/Wit

ho

ut

ICD

Inte

rve

nti

on

/Su

dd

en D

eat

h

Appropriate ICD

Intervention

No Appropriate ICD

Intervention

<4% 4-6% >6%

Risk/5y

Sudden Death*

<4% 4-6% >6%

Risk/5y

<4% 4-6% >6%

Risk/5y

<4% 4-6% >6%

Risk/5y

Survivors Without

ICDs/Events

ESC Risk Score

70 patients are left vulnerable to sudden death without protection from the ICD…when using ESC risk score

no risk

factors age

maximum

wall

thickness 16 18 20 25 30 35 40 45 50 55 60 65 70

10 1.80 1.74 1.68 1.53 1.40 1.28 1.17 1.07 0.98 0.90 0.82 0.75 0.68

12 2.17 2.09 2.02 1.85 1.69 1.55 1.41 1.29 1.18 1.08 0.99 0.90 0.83

14 2.56 2.47 2.38 2.18 1.99 1.82 1.67 1.53 1.39 1.28 1.17 1.07 0.98

16 2.94 2.84 2.74 2.51 2.29 2.10 1.92 1.76 1.61 1.47 1.34 1.23 1.12

18 3.31 3.19 3.08 2.82 2.58 2.36 2.16 1.98 1.81 1.65 1.51 1.38 1.26

20 3.63 3.50 3.38 3.10 2.83 2.59 2.37 2.17 1.99 1.82 1.66 1.52 1.39

22 3.90 3.76 3.63 3.32 3.04 2.78 2.55 2.33 2.13 1.95 1.78 1.63 1.49

24 4.08 3.94 3.80 3.48 3.19 2.92 2.67 2.44 2.24 2.04 1.87 1.71 1.56

26 4.18 4.04 3.90 3.57 3.27 2.99 2.74 2.50 2.29 2.10 1.92 1.75 1.60

28 4.19 4.04 3.90 3.57 3.27 2.99 2.74 2.51 2.29 2.10 1.92 1.75 1.60

30 4.09 3.95 3.82 3.49 3.20 2.93 2.68 2.45 2.24 2.05 1.88 1.72 1.57

32 3.91 3.78 3.65 3.34 3.06 2.80 2.56 2.34 2.14 1.96 1.79 1.64 1.50

34 3.66 3.53 3.41 3.12 2.85 2.61 2.39 2.19 2.00 1.83 1.67 1.53 1.40

36 3.34 3.22 3.11 2.84 2.60 2.38 2.18 1.99 1.82 1.67 1.53 1.39 1.28

38 2.97 2.87 2.77 2.53 2.32 2.12 1.94 1.78 1.62 1.49 1.36 1.24 1.14

40 2.59 2.50 2.41 2.21 2.02 1.85 1.69 1.54 1.41 1.29 1.18 1.08 0.99

Calculated 5-year Risk in Patients Without Conventional Risk Factors (using left atrial size =44mm and LVOT gradient =12mmHG)

0

1

2

3

4

Sudden Death Appropriate ICDIntervention

No AppropriateIntervention

Survivors WithoutICDs/Events

Series 1

3.8

ESC

Ris

k Sc

ore

ICDs

3.2 3.3

2.1

ns

p < 0.001

Using the ESC Risk Score…

65 of our patients would have been vulnerable to sudden death without protection from ICDs.

CONTEMPORARY HCM MORTALITY BY AGE

<29 y 30-59 y >60 y Total

No. Patients

474 1000 428 1902

HCM Mortality

0.5%/y 0.5%/y 0.6%/y 0.5%/y

Evidence for Reduced HCM Mortality:

n=1000 Presenting 30-59y

What is possible………

Contemporary C-V treatment options offer HC patients a reasonable aspiration for

reduced mortality and extended longevity. The ICD has altered clinical course

affording the possibility of normal or near normal life expectancy.