disclosures how to identify and manage familial … · 2019-11-05 · 10/30/2019 1 ccs...

10/30/2019

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CCS Guideline/Position Statement Workshop

How to Identify and Manage Familial Hypercholesterolemia

in Your Practice

Family Medicine Forum

November 1, 2019


Disclosures

• Liam Brunham• Honoraria: Amgen, Sanofi

• Clinical Trials: Cerenis, The Medicines Company

• Sanja Karalic• Honoraria: none

• Clinical Trials: none


Disclosure of Financial Support

• This program has not received financial support from any organization.

• This program has not received in-kind support from any organization.

• Potential for conflict(s) of interest:• N/A


Audience Participation

Go to: Slido.com

enter event code: Z492

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Learning Objectives

• To review the clinical features and prevalence of Familial Hypercholesterolemia

• To understand and apply the diagnostic criteria for Familial Hypercholesterolemia

• To recognize the importance of cascade screening in Familial Hypercholesterolemia

• To understand and implement first line treatment for patients with Familial Hypercholesterolemia



Case 1

• 46M found on routine screening to have total cholesterol of 7.2 mmol/L, LDL 5.1 mmol/L, HDL 1.6 mmol/L, TG 1.1 mmol/L

• Cardiac risk factors:• History of elevated lipids, first diagnosed at age 40

• No medications

• No known DM, HTN

• Nonsmoker

• Father died of MI at age 49


History

• Previously healthy

• NKDA

• No tobacco/EtoH/illicit drugs

• Family History of “high cholesterol”

• Father was heavy smoker, had fatal MI at age 49“high

cholesterol”

MI 49

?lipids

age 12 age 15

?lipids

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Physical Examination

• 130/80, HR 87bpm, RR 14, T36.9, 97%RA

• Cardiovascular: normal S1/S2, no S3/S4, no murmurs, no carotid bruit

• Respiratory: clear, no crackles, no wheezing, no increased WOB

• Abdominal: soft, nontender, no palpable masses

• Extremities: normal


Lab Values

• LDL-C 5.1 mmol/L

• HBA1C 5.5

• TSH normal

• Creatinine normal

• Liver enzymes normal

• CBC normal


Audience Question:

What is the most likely diagnosis in this patient?

Slido.com

Event code: Z492


Familial Hypercholesterolemia

• Genetic condition of impaired LDL clearance typically due to a defective LDL receptor secondary to a mutation in the LDLR gene

• Autosomal dominant inheritance

• Associated with very high risk of ASCVD

• High index of suspicion needed

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Lifelong elevates of LDL–C contributes to early atherosclerosis and cardiovascular disease

Inherited mutations in LDLR, ApoB, PCSK9, or LDLRAP1

Dysfunctional LDL receptors

Elevated LDL–CElevated LDL–C leads to the formation of atherosclerotic

plaques

Atherosclerotic plaques increase the risk of CVD

1. Nordestgaard BG et al. Eur Heart J. 2013;34:3478-90. 2. Hopkins PN et al. J Clin Lipidol. 2011;5(suppl 3):S9-S17. 3. Fahed AC, Nemer GM. Nutr Metab. 2011;8:23.


Audience Question:

What is the prevalence of FH?

Slido.com

Event code: Z492


FH is a Relatively Common Genetic Disease

• FH is the most common autosomal codominant hereditary disorder in the world

• Recent large meta-analysis estimates global FHprevalence is 1:250 people

30.4 million individuals affected worldwide

143,000 individuals affected in Canada

In some regions of Quebec, the prevalence is as high as 1 in 80

Prevalence of Selected Disorders

Akioyamen LE et al. BMJ Open. 2017 Sep 1;7(9):e016461Paquette M et al. Curr Opin Lipidol. 2018 Apr;29(2):59-64.

Disorder Prevalence

FH 1:250

Type 1 diabetes 1:260

HIV 1:600

Cystic Fibrosis 1:3000


Audience Question:

How would you diagnose FH in this patient?

Slido.com

Event code: Z492

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Recommendation #1

• We recommend that FH be defined using the DLCNC, Simon Broome Registry or FH Canada definition (Strong Recommendation, High-Quality Evidence).

• Values and preferences. There is no “gold standard” for the diagnosis of FH. Currently available definitions rely on a scoring system to increase diagnostic confidence.


Audience question:

At what level of LDL would you consider a diagnosis of FH?

Slido.com

Event code: Z492


Dutch Lipid Clinic Network CriteriaDutch Lipid Clinic Network (DLCN) Criteria for FH

Stratified by Total Score: Definite FH: > 8, Probable FH: 6-8, Possible FH: 3-5, Unlikely FH: < 3Score

Family History

• First-degree relative with known premature coronary and/or vascular disease, or • First-degree relative with known LDL–C > 95th percentile for age and sex

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• First-degree relative with physical manifestations of FH, or• Children aged < 18 years with LDL–C levels > 95th percentile for age and sex

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Clinical History • Premature CAD• Premature cerebral or peripheral vascular disease

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LDL–C (mmol/L)

• > 8.53 • 6.46 – 8.51 • 4.91 – 6.44• 4.01 – 4.89

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Physical Examination

• Tendon xanthomas• Arcus cornealis at age < 45 years

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DNA Analysis Functional mutation in LDLR, APOB, or PCSK9 8


Canadian Definition of FH

Ruel et al. Can J Cardiol. 2018;34:1210

MajorCriteria

MinorCriteria

FH ScreeningCriteria

*LDL-C ≥ 5.0 mmol/L (≥ 40 yr)• LDL-C ≥ 4.5 mmol/L (18-39 yr)• LDL-C ≥ 4.0 mmol/L (< 18 yr)

+

Yes No

**DNA Mutation or Tendon Xanthomas or LDL-C ≥ 8.5 mmol/L

Definite FH

Yes

1st-degree relative with high LDL-Cor

Proband or 1st-degree relative with ASCVD (< 55 yr men; < 65 yr women)

Probable FH

No

Severe Hypercholesterolemia

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Xanthelasmas

• Soft yellow thin plaques around the eyelids


Corneal Arcus

• White or grey ring around the cornea


Tendon Xanthomas

• Smooth, firm, mobile, skin-colored nodules within extensor tendons


Secondary causes of hypercholesterolemia

Condition Screening Test

Untreated hypothyroidism TSH

Nephrotic syndrome Albumin, Creatinine

Multiple myeloma SPEP

Biliary liver disease (not NASH) Bilirubin, liver enzymes

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Audience question:

How likely is it that the patient’s siblings and children also have FH?

Slido.com

Event code: Z492


Cascade Screening Is Recommended After a Diagnosis of FH in Probands

ManWoman Woman with HeFH

Man with HeFH

Probability of Detection

Diagnosed with FH

50% in first-degree

relatives

25% in second-degree

relatives

12.5% in third-degree

relatives

ProbandCascade screening is the process of family tracing for identification

of people at risk of a genetic condition

Guidelines and expert panels recommend testing all first-

degree relatives of patients with diagnosed FH


Recommendation # 2

• We recommend that cascade screening (lipid profile) protocols be implemented at the local, provincial and national level in Canada and offered to first-degree relatives of patients with FH (Strong Recommendation, Moderate-Quality Evidence).


Recommendation #3

• We recommend that genetic testing be offered, when available, to complement a diagnosis of FH and enable cascade screening (Strong Recommendation, High-Quality Evidence). The decision to request genetic screening should be made by the treating physician after discussion with the patient. A down-loadable form is available at www.FHCanada.net.

• Values and preferences. Patient preferences and confidentiality must be considered. Genetic testing is currently not available in most provinces.

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Which of the following statements regarding the patient’s risk of cardiovascular disease are false?

Audience Question

Slido.com

Event code: Z492


Recommendations regarding risk assessment:

• We recommend that current risk calculators (Framingham Risk Score, Pooled Cohort Equation, SCORE) should not be used to determine cardiovascular risk in patients with FH. (Strong Recommendation, Low-Quality Evidence)

• Such scores will underestimate ASCVD risk in patients with FH.

• We suggest that if available, genetic testing should be used to stratify the ASCVD risk in FH patients. (Weak Recommendation, Moderate-Quality Evidence)

• We suggest that conventional risk factors such as age, sex, HDL-C, hypertension, smoking, Lp(a) and diabetes be ascertained in patients with FH. (Weak Recommendation, Moderate-Quality Evidence)

Recommendations


Adapted from Horton et al. J Lipid Res. 2009;50:S172-S177.

Theoretical relationship between cumulative

cholesterol years and development of severe

atherosclerosis

Age (Years)

10

5

0

Cu

mu

lative

LD

L-C

g/d

L-Y

ea

rs

0 20 40 60 80

HoFH NormalHeFH

Threshold for CVD reached by:

• ~ Age 15 y in HoFH patients

• ~ Age 40 y in HeFH patients

• ~ Age >60 y in healthy individuals


Genetic testing for FH – impact on cardiovascular risk

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Treatment of FH

Which of the following statements regarding FH treatment are true?

Audience Question

Slido.com

Event code: Z492


Benefit of early statin treatment in FH


Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490

Effect of statin therapy on CHD-free survival in FH(P < 0.001 for difference)


Cardiovascular events occurred in 25% of parents by age 40 and 1% of children.

20 year follow-up of parents with FH who were untreated and children who started statins at age 14.

Early treatment of FH is very effective

Luirink et al. New England Journal of Medicine 2019;381:1547

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Lifestyle Factors: Canadian Cardiovascular Society Recommendations

“We suggest that patients with FH adopt a healthy lifestyle as recommended by the CCS guidelines2 on the diagnosis and treatment of dyslipidemias”

(Weak Recommendation, Low-Quality Evidence)

1. Brunham L et al. Can J Cardiol. 2018 Dec;34(12):1553-63. 2. Anderson TJ et al. Canadian Journal of Cardiology. 2016; 32: 1263-82.

No Smoking Healthy EatingAppropriate Body Weight

Physical Activity Stress Management


Some suggest a goal of LDL-C < 2.5 mmol/L for primary prevention in adults with FH2

Extrapolating from the general population

Target LDL-C Levels for Adults With FH: Canadian Cardiovascular Society Recommendations:

1. Brunham L et al. Can J Cardiol. 2018 Dec;34(12):1553-63. 2. Nordestgaard BG et al. Eur Heart J. 2013 Dec;34(45):3478-90a.

Primary Prevention

Goal for patients with FH without ASCVD is a 50% reduction from baseline (untreated LDL-C)

and LDL-C < 3.5 mmol/L

“In patients with FH and ASCVD, we suggest that targets should follow the recommendations of the CCS guidelines on the diagnosis and treatment of dyslipidemias

(LDL-C < 2.0 mmol/L and non-HDL-C < 2.6 mmol/L)”

(Weak Recommendation, Moderate-Quality Evidence)


Pharmacotherapy for FH: Canadian Cardiovascular Society Recommendations

Brunham L et al. Can J Cardiol. 2018 Dec;34(12):1553-63.

(Strong Recommendation, Low-Quality Evidence)

“Because the diagnosis of FH using validated clinical criteria and/or genotyping may occur at any age and imparts a high, lifelong risk of ASCVD,

we recommend a personalized treatment plan, taking into account, at a minimum, age, additional cardiovascular risk factors, psychosocial and socioeconomic factors,

and personal as well as family preferences, that should be developed as a shared decision Process”


• 60F• Baseline LDL-C 7.6 mmol/L• Hypertension on perindopril/indapamide• Impaired fasting glucose• Family history: brother had a fatal MI at age 27, other brother had stroke in 50s• Father died in 40s, unknown cause; mother had stroke at 62• Asymptomatic, no personal history of cardiovascular disease

• FH diagnosed at age 57 (never treated previously)• Reluctant to start statin

Case 2

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What treatment target would you aim for in this patient?

Audience Question

Slido.com

Event code: Z492


Classes of Lipid-Lowering Therapies for the Treatment of FH

HeFH=heterozygous familial hypercholesterolemia; LDL=low-density lipoprotein; LDL–C=low-density lipoprotein–cholesterol; PCSK9=proprotein convertase subtilisin-kexin 9; VLDL=very low-density lipoprotein.

1. Ference BA et al. Eur Heart J. 2017;38:2459-2472. 2. Ito MK et al. J Clin Lipidol. 2011;5(suppl 3):S38-S45. 3. Stadler SL et al. Am J Manag Care. 2017;23(suppl 9):S149-S155.

Adapted from Ference BA et al. Eur Heart J. 2017;38:2459-2472.

Lower plasmaLDL–C

PCSK9inhibitors

LDL clearance

Cholesterol pool

Statins

Conversion of hepatic cholesterol to bile acids by bile acid sequestrants

Intestinal cholesterol

absorptionBile acid sequestrants

Ezetimibe

NiacinVLDL

Upregulation of LDL receptors

Cholesterolsynthesis


Efficacy of Lipid-lowering Therapy for Patients With FH

Ezetimibe and PCSK9 inhibitors are recommended for patients with FH who do not meet their lipid targets on maximally tolerated statin therapy

Agent Reduction in LDL–C Levels

High intensity statin (rosuva 20 or 40mg, atorva40 or 80mg)

40–50%

Ezetimibe 15%–20%

PCSK9 Inhibitors 40%–70%

Bile acid resins 15–20%

Niacin 20%–30%

1. Goldberg AC et al. J Clin Lipidol. 2011;5(suppl 3):S1-S8. 2. Gidding SS et al. Circulation. 2015;132:2167-2192. 3. Fujisue K, Tsujita K. J Cardiol. 2017;70:101-106. 4. Ito MK et al. J Clin Lipidol. 2011;5(suppl 3):S38-S45. 5. Guyton JR, Capuzzi DM. Am J Cardiol. 1998;82:82U-84U. 6. Wolfe ML et al. Am J Cardiol. 2001;87:476-479.


Courtoisie Dr Jean Bergeron

Lipoprotein Apheresis for Patients with Homozygous FH

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• Consider FH in a patient with LDL>5 mmol/L (and family history)

• Initial treatment is to lower LDL-C by at least 50% using a statin

• Screen family members by testing lipid levels

• Consider referral to a specialist if:

• FH plus ASCVD

• Sub-optimal response to statin

• Statin intolerance

• “Severe” FH (LDL-C >8mmol/L)

Summary of Recommendations


Learning Objectives

• To review the clinical features and prevalence of Familial Hypercholesterolemia

• Lifelong elevation of LDL-C and early CVD; Affects 1 in 250 individuals

• To understand and apply the diagnostic criteria for Familial Hypercholesterolemia

• Consider when LDL-C > 5mmol/L; Canadian definition, Dutch criteria

• To recognize the importance of cascade screening in Familial Hypercholesterolemia

• 50% of first degree relatives affected; screen using lipid levels

• To understand and implement first line treatment for patients with Familial Hypercholesterolemia

• Statin therapy is indicated for all patients with FH; ezetimibe and PCSK9i can be added to reach treatment targets


Thank you!


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Session #: F168

Session Name: How to Identify and Manage

Familial Hypercholesterolemia in Your Practice

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disclosures how to identify and manage familial … · 2019-11-05 · 10/30/2019 1 ccs...

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