8th annual cardiovascular update ebook

Wednesday February 25, 2015 St. Joseph’s Health CentreEducation Centres A&B

Faculty:

Peter Mitoff, MD, FRCPCRichard Choi, MD, FRCPC, Chair Mark Fisher, MD, FRCPC, ChiefLukasz Drzymala, MD, FRCPCGiridhar Logsetty, MD, FRCPC

CARDIOVASCULAR UPDATE

Handout Package

Table of Contents

Hypertension 2015: Practical Tips & Pearls Giridhar Logsetty, MD

p. 4

Lipids and Cardiovascular Risk: Is There Anything New for 2015? Richard Choi, MD, Chair

p. 15

Cases in Combined Oral Antithrombotics: When Less is MorePeter Mitoff, MD

p. 23

90 Is the New 50! Cardiovascular Disease in the Very ElderlyMark Fisher, MD, Chief of Cardiology

p. 28

The Good, the Bad and the Ugly: Cardiac Test Results to Ignore and to RecallLukasz Drzymala, MD

p. 37

Quick Reference Guide for SJHC Cardiologists p. 44

Request for Cardiology Imaging Consultation Referral Form p. 45

Department of Medical Education & Scholarship 2015 Curriculum

p. 46

IN PARTNERSHIP WITH

SUPPORTED BY

Hypertension 2015: Practical Tips and Pearls

Dr. Giri LogsettyDivision of Cardiology, St. Joseph’s Health Centre

Conflict Disclosure Information

Speaker: Dr. Giri Logsetty

Title of Talk: Hypertension 2015: Practical Tips and Pearls

Financial Disclosure None

Grants / Research Support None

Speakers Honorarium None

Consulting Fees None

Patents None

Other None

Mitigating Potential Bias

• Only published data will be presented in this program andrecommendations will be based on published Guidelines

Objectives

Back to basics:

1. Why do we treat Hypertension?2. Are we measuring BP properly?3. Are we following the guidelines? (CHEP 2014)4. Case Studies in Hypertension – Tips/Pearls5. What is the cost to my patients?

Guideline Comparisons of Goal BP and Initial Drug Therapy for Adults With Hypertension

Date of download: 12/31/2014

From: 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8)

JAMA. 2014;311(5):507-520. doi:10.1001/jama.2013.284427

Copyright © 2014 American Medical Association. All rights reserved.

Janeway, 1913

Janeway TC. Arch of Intern Med, 1913

Why Do We Treat Hypertension?

• CHF 50%• Stroke 30-40%• MI 20-25%

Blood Pressure Lowering Treatment Trialists' Collaboration, BMJ 2008

Take Home Point

• Starting at BP of 115/75mmHg, each increase of 20/10 mmHgin blood pressure DOUBLES the risk of CV disease

Lewington S, et. al. Lancet 2002:360:1903-13.

Prevalence of Hypertension in Canada

of those age 18 to 39



21.8%Number of

Canadian adults 18+ suffering

from hypertension

*Interpret with caution; coefficient of variation between 16.6% and 33.3%.Data are from the Canadian Health Measures Survey, Cycle 2, Statistics Canada.

…have hypertension.

3.3%*

21.8%

52.4%

CHEP 2014 Recommendations

What’s new?

• More guidance for treating to target: revisions in some BP targets, thresholds AND limits

• New targets for health behaviour management-especially in regards to dietary sodium intake

2014

Impact of health behaviours on blood pressure

InterventionSystolic BP(mmHg)

Diastolic BP(mmHg)

Diet and weight control ‐6.0 ‐4.8

Reduced salt/sodium intake ‐ 5.4 ‐ 2.8

Reduced alcohol intake (heavy drinkers) ‐3.4 ‐3.4

DASH diet ‐11.4 ‐5.5

Physical activity ‐3.1 ‐1.8

Relaxation therapies ‐3.7 ‐3.5

Multiple interventions ‐5.5 ‐4.5

Clinical Guideline : Methods, evidence and recommendations National Institute for Health and Clinical Excellence (NICE) May 2011

2014

High Risk of Developing Hypertension in Those with High Normal Blood Pressure

• Individuals with high-normal blood pressure are at high risk of progression to overt hypertension.

• Annual follow-up of patients with high normal blood pressure isrecommended.

Objectives

Back to basics:


I. Accurate Measure of Blood PressureAssess blood pressure at all appropriate visits

When should blood pressure be measured?

• Health care professionals should know the blood pressure of all of their patients and clients.

• Blood pressure of all adults should be measured whenever it isappropriate using standardized techniques.– To screen for hypertension

– To assess cardiovascular risk

– To monitor antihypertensive treatment

I. Accurate Measurement of Blood Pressure

• Automated office blood pressure measurements can be used in the assessment of office blood pressure*.

• When used under proper conditions, automated office SBP of 135 mmHg or higher or DBP values of 85 mmHg or higher should be considered analogousto mean awake ambulatory SBP of 135 mmHg or higher or DBP of 85 mmHg or higher*.

*see notes

Use of Standardized Measurement Techniques is Recommended when Assessing Blood Pressure

• When using automated office oscillometric devices such as the BpTRU, the patient should be seated in a quiet room alone.

• With the device set to take measures at 1 minute intervals, an initial measurement is taken by a health professional to verify that the device isregistering a measurement.

• The patient is left alone after the first measurement and the device automatically takes subsequent readings.

VII. Home Measurement of Blood Pressure

Home BP measurement should be encouraged to increase patient involvement in care

• Which patients?– Uncomplicated hypertension

– Suspected non-adherence

– Office-induced blood pressure elevation (white coat effect)

– Masked hypertension

Average BP > 135/85 mm Hg should be considered elevated

Potential Advantages of Home Blood Pressure Measurement

• More rapid confirmation of the diagnosis of hypertension

• Improved ability to predict cardiovascular prognosis

• Improved blood pressure control

• Can be used to assess patients for white coat hypertension (WCH) and masked hypertension

• Reduced medication use in some (WCH)

• Improved adherence to drug therapy

Not all Patients are Suited to Home Measurement

• Undue anxiety in response to high blood pressure readings

• Physical or mental disability prevents accurate technique or recording

• Arm not suited to blood pressure cuff (e.g. conical shaped arm)

• Irregular pulse or arrhythmias prevent accurate readings

• Lack of interest

Most patients can be trained to measure blood pressurePeriodic reassessment of technique and retraining is desirable

VII. Suggested Protocol for Home Measurement of Blood Pressurefor the diagnosis of hypertension

• Home blood pressure values should be based on:– Duplicate measures,

– Morning and evening,

– For an initial 7-day period.

• First day home BP values should not be considered.

• The following six days blood pressure readingsshould be averaged.

• Average BP equal to or over 135/85 mmHg should be considered elevated (for those patients whose clinicBP target is less than 140/90 mmHg).

Advice for patients on when to contact a health care professional based on high average home blood pressure readings

Systolic BP (mmHg)

Diastolic BP reading

Less than 130 Less than 85 Usual follow-up

130-179* 85-109* Check reading again using the correct technique. If readings remain high, discuss with your healthcare provider at your next regularly scheduled appt.

180 – 199* 110-119 Check reading again using the correct technique. If the readings remain high, schedule an appointment with your doctor to discuss your treatment plan.

More than 200*

More than 120 Check reading again using the correct technique. If the readings remain high, schedule an urgent appointment with your doctor to discuss your treatment plan.

(Resource available at www.hypertension.ca in the 3-Minute Hypertension Action Tool or www.heartandstroke.ca/BP)

*Patients with diabetes, chronic kidney disease or who are at high risk of cardiovascular events require individualized advice.

Home Measurement: Doing it RightPreparation

DO

• Read and carefully follow the instructions provided with the device

• Relax in a comfortable chair with back support for 5mins

• Sit quietly without talking or distractions (e.g. TV)

DON’T

• Measure if stressed, cold, in pain or if your bowel or bladder are uncomfortable

• Measure within 1 hour of heavy physical activity

• Measure within 30mins of smoking or drinking coffee

DO• Put the cuff on a bare arm

• Support the arm on a table so it is at heart level

• Record two readings in the morning and evening daily for 7 days (discarding the first days readings) to help diagnose hypertension

• Measure and record your blood pressure (as above) for several days before an appointment with a health care professional

Home Measurement: Doing it RightPreparation

VII. Home Measurement of BP: Confirm Contradictory HomeMeasurement Readings

If office BP measurement is elevated and home BP is normal or vice versa

Repeat home monitoring or perform 24-hour ambulatoryblood pressure monitoring

VIII. Ambulatory BP Monitoring

Beyond the diagnosis of hypertension, ABPM measurement may also be considered for selected patients for the management of HTN

Which patients?

– Untreated• Mild (Grade 1) to moderate (Grade 2) clinic BP elevation and without

target organ damage.

– Treated patients• Blood pressure that is not below target values despite receiving

appropriate antihypertensive therapy.

• Symptoms suggestive of hypotension.

• Fluctuating office blood pressure readings.

VIII. Ambulatory BP Monitoring

How to?

• Use validated devices

• How to interpret?– Mean daytime ambulatory blood pressure >135/85 mmHg is considered elevated.

– Mean 24 h ambulatory blood pressure >130/80 mmHg is considered elevated.

A drop in nocturnal BP of <10% is associated with increased risk of CV events

Clinic, Home, Ambulatory (ABP) Blood Pressure Measurement Equivalence Numbers

Description Blood Pressure mmHg

Home pressure average 135 / 85

Daytime average ABP 135 / 85

24-hour average ABP 130 / 80

A clinic blood pressure of 140/90 mmHg has a similar risk of a:

Follow-up Algorithm For High Blood Pressure Using Ambulatory Blood Pressure Measurement

24-h ABPM

Consistent with HTN

Awake BP>135 SBP or

>85 DBPor

24-hour>130 SBP or

>80 DBP

Awake BP< 135/85

and 24-hour< 130/80

Continueto follow-up

Patients with high normal blood pressure should be followed annually.

• 30-40% of patients with white coat hypertension diagnosed based on a single ABPM session will have true hypertension on retesting.

• Some patients with white coat hypertension develop sustained hypertension.

• Patients with white coat hypertension may be followed with home BP measurement or repeat ABPM could be considered every 1-2 years

Follow-up Algorithm For High Blood Pressure Using Ambulatory Blood Pressure Measurement

BP: 140-179 / 90-109

ABPM (If available)

Diagnosisof HTN

Awake BP>135 SBP or>85 DBP or

24-hour>130 SBP or

>80 DBP

Awake BP<135/85

and24-hour<130/80

Continue to follow-up

Clinic BPM

Diagnosisof HTN

Hypertension visit 3

>160 SBP or >100 DBP

>140 SBP or>90 DBP

< 140 / 90

Diagnosisof HTN


<160 / 100

Hypertension visit 4-5

ABPM or HBPMor

Home BPM

>135 SBP or >85 DBP

< 135/85

Diagnosisof HTN


Patients with high normal blood pressure (office SBP 130-139 and/or DBP 85-89) should be followed annually.

Repeat Home BPM

If< 135/85

or

II. Criteria for the Diagnosis of Hypertension and Recommendations for Follow-up Objectives

Back to basics:


Population SBP DBP

Diabetes 130 80

High risk (TOD or CV risk factors) 140 90

Low risk (no TOD or CV risk factors) 160 100

Very elderly 160 NA

II. Indications for PharmacotherapyUsual blood pressure threshold values for

initiation of pharmacological treatment

TOD=target organ damage

*This higher treatment target for the very elderly reflects current evidence andheightened concerns of precipitating adverse effects, particularly in frail patients. Decisions regarding initiating and intensifying pharmacotherapy in the very elderly should be based upon an individualized risk-benefit analysis.

2014

Population SBP DBP

Diabetes <130 <80

All others < 80 y.a. (including CKD) <140 <90

Very elderly (≥ 80 years) <150* NA

Treatment consists of health behaviour ±pharmacological management

II. Indications for PharmacotherapyRecommended Treatment Targets

*This higher treatment target for the very elderly reflects current evidence andheightened concerns of precipitating adverse effects, particularly in frail patients.Decisions regarding initiating and intensifying pharmacotherapy in the very elderly should be based upon an individualized risk‐benefit analysis.

2014

III. Treatment of Adults with Systolic/Diastolic Hypertension without Other Compelling Indications

TARGET <140/90 mmHg

INITIAL TREATMENT AND MONOTHERAPY

*BBs are not indicated as first line therapy for age 60 and above

Beta-blocker*

Long-actingCCB

Thiazide ACEI ARB

Lifestyle modificationtherapy

ACEI, ARB and direct renin inhibitors are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential

A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target

Take Home Point

Important to note that prevailing evidence from meta-analyses in 2008 and 2009, 2007 AHA statement, and 2013 European Society of Hypertension/ESC guidelines:

“BP reduction is the major determinant of reducing CV risk in both younger and older patients with HTN, and NOT the choice of agent.”

Case 1 - Elevated Cr with ACEi/ARB

58 yr old woman with HTN/DM and mild CKD(Cr = 159, eGFR = 31)

Rx Perindopril 4mg daily for HTN 1 week later, Cr = 190

What should you do?


An increase of sCr of 10-20% above baseline, isnormally seen

Frequently, Cr levels will return to baseline or normal,as BP is lowered

If larger rise in Cr seen, consider: Bilateral renal artery stenosis CKD CHF


• ARF can develop – rise >50% from baseline• In CONSENSUS II, ARF occurred in 2.4% of subjects

• If increase in Cr > 30%:

– reduce ACEi/ARB dosage or stop–Assess for volume depletion, esp. if also on diuretic.

Case 2 - ACEi/ARB and Hyper K

58 yr old woman with HTN/DM Rx Perindopril 4mg daily for HTN 1 week later, K = 5.8 (from 4.2mmol/L at baseline)

What should you do?


Develops in 10% of outpatients within 1 year of initiation

At risk: DM and pre-existing impaired renal function

The Renin–Angiotensin–Aldosterone System and Regulation of Potassium Excretion in the Kidney

Palmer BF. N Engl J Med 2004;351:585-592.

Risk Factors for Hyperkalemia with the Use of Drugs That Interfere with the Renin–Angiotensin–Aldosterone System.


Approach to Patients at Risk for Hyperkalemia Caused by Inhibitors of the Renin–Angiotensin–Aldosterone System.



• In our patient with K >5.5• Approach:

Dietary HxOTC and herbal supplements?salt substitute

After dietary advice, repeat K level, 1 week later 5.0


Important non-pharmacologic High K substances:

Herbal remedies (hidden source of K) Noni juice - 56 mmol K per L Alfalfa Dandelion Horsetail Nettle Chan su (topical aphrodesiac): extract from toad skin that mimics

toxicity of digitalis Other digitalis like substances: milkweek, lily of the valley,

Siberian ginseng, and hawthorn berries.

Case 3 - HTN and Gout

65 yr old man with HTN/DM/CHF Current Rx: perindopril 8, bisoprolol 10Past intolerance to CCB (swelling)

You wonder if Thiazide is safe...

1. Gout2. Blood Sugar

What effect does thiazide have on uric acid levels?

• HPDF Study, increases in uric acid levels were seen• However, gout was rare, occurring in 18 of 3693 patients over 5

years (0.5%)

• Health Professionals FU study (multivariate risks)

– 2.31 for presence of HTN– 1.99 for weight gain > 30 lbs– 1.77 for diuretic use


• Rise in serum uric acid is small and dose related

• 25mg HCT expected to cause increase of 47.5 ug/L inserum uric acid level

• Uric acid 2mg/dl = 119umol/L

• Uric acid 6 mg/dl = 357 umol/L

• HCT not absolutely contraindicatedin patients at risk for or with gout

Handler, J. Journal of Clinical Hypertension, 2010 Vol 12, Issue 9


• Gout is more strongly related to loop diuretics than thiazide.

• Losartan has a urocosuric effect (clinical benefit unknown)–Losartan causes a decrease between 20-80umol/l– (doses of 25 – 200mg daily)

What About Blood Sugar With Thiazides?

Case 4– NSAIDs and Antihypertensive Rx

• 62 yr old man with well controlled hypertension

• Develops significant OA of the hip, requiring chronicNSAID therapy

• Rx: Naproxen 250mg PO BID, Ramipril 10mg daily

• BP becomes poorly controlled >160/90 mmHg

Case 4 – NSAIDs and Antihypertensive Rx

• NSAIDs inhibit prostaglandin-mediated Vasodilatation,and promote Na and H20 retention–This works against BP medication

• Vasodilating CCBs are least affected by thismechanism

• E.g. Indomethacin reduced efficacy of Enalapril bynearly 50%, with almost had no effect on nifedipine

• (Aspirin also has little effect on antihypertensives)

Figure 1. Effects of rofecoxib and celecoxib on clinic systolic BP in patients given ACE inhibitors, β-blockers, and calcium antagonists.

White W B Hypertension.2007;49:408-418

Copyright © American Heart Association, Inc. All rights reserved.

Objectives

Back to basics:


ACE Inhibitors CostRamipril 2.5/5/10 0.15/0.15/0.19Perindopril 2/4/8 0.65/0.82/1.13Trandolapril 1/2/4 0.69/0.79/0.98Lisinopril 5/10/20 0.14/0.16/0.29ARBCandesartan 4/16/32 0.17/0.29/0.29Irbesartan 150/300 0.30/0.30Losartan 50/100 0.31/0.31Valsartan 160/320 0.28/0.28Olmesartan 20/40 1.08/1.08

Costs of Various Common Antihypertensives

www.healthinfo.moh.gov.on.ca

CCB CostFelodipine 0.52./0.56/0.84Amlodipine 0.24/0.36

Nifedipine 20/30/60 1.27/0.62/0.94Verapamil 120/180/240 n/a/0.52/0.51Diltiazem 120/180/240/300 0.36/0.48/0.64/0.80

BB/Diuretic CostBisoprolol 5/10 0.10/0.15Metoprolol 50/100 0.06/0.14Atenolol 50/100 0.14/0.24HCTZ 25/50 0.02/0.02Chlorthalidone 50 0.12Indapamide 1.25/2.5 0.07/0.12

Costs of Various Common Antihypertensives

Summary

• Hypertension treatment improves patient risk of CHF ( 50%)Stroke ( 30-40%), MI ( 20-25%)

• Adults > 60: 160/90 mmHg• Adults < 60: 140/90 mmHg *consider special populations DM/CKD/Black

• Home BP monitoring and Ambulatory BP measurement canbe useful in identifying patients with true hypertension

• BP reduction is the major determinant of reducing CV risk,not the choice of agent

Richard Choi, MD, FRCP(C)Staff Cardiologist, St. Joseph’s Toronto

February 25, 2015

Lipids and Cardiovascular Risk:Is there anything new for 2015?

CV Update 2015


Speaker: Dr. Richard Choi

Title of Talk: Lipids and Cardiovascular Risk –Is there anything new for 2015?

Financial Disclosure Company

Grants / Research Support Servier

Speaker Honorarium Amgen, AstraZeneca, Merck and Pfizer

Consulting Fees Novartis

Patents None

Other None

Disclosure of Commercial Support

This program has received financial support from companies sponsoring in the form of an educational grant (Amgen, AstraZeneca, Merck, Pfizer and Valeant)

Potential for conflict(s) of interest:

Dr. Choi has in the past received honoraria from Amgen, AstraZeneca, Merckand Pfizer whose products are being discussed in this program

Amgen, AstraZeneca, Merck, Pfizer and Valeant may benefit from the sale of a product that will be discussed in this program (Evolocumab, Rosuvastatin,Ezetimibe, Atorvastatin, and Colesevelam)

Mitigating Potential Bias

Only published (or presented) data will be presented in this program and recommendations will be based on published Guidelines

Objectives

1. To understand the changes made tooutpatient lab reports and lipid values.

2. To understand the key changes from theupdated Canadian Lipid Guidelines.

3. To apply the updated risk assessmenttools, treatment thresholds and treatmenttargets

Take Home Messages

Fasting labs for treatment, nonfasting for targets

nonHDLc represent ‘total atherogenic particles’ and is an alternate treatment target

Screen patients you think may have an indication fortreatment and would benefit from knowing their risk

No one should have an LDL higher than 5 and if they do, consider a diagnosis of familial hypercholesterolemia

LDL continues to be the primary target for treatment and goals remain as < 2.0 mmol/L for high/intermediate risk

A healthy lifestyle, high potency statin and add-ontherapy with cholesterol absorption inhibitors representthe current treatment approach to get to target

Why did outpatient lab reports change?

Nonfasting samples, nonHDL cholesteroland the elimination of Tc:HDL

Why did outpatient lab reports change?Nonfasting lipids are now an option

OAML policy change - 2013 NONFASTING labs – easier for pts, helps

monitor adherence and ensure targets are met− LDL changes little between F/NF states –

mean changes are 0.1 mmol/L (up to 0.2)

FASTING labs – use them to make treatmentdecisions as they are the most accurate− trigs the most from F/NF state – but trigs are the

least useful lipid parameter in decision making

− Less practical disrupted BS control in DM, impacts physical well-being in the elderly

http://www.oaml.com/documents/NonfastingLipidOAMLCommuniqueFINALNov2013_000.pdf

Why did outpatient lab reports change?What happened to the Tc:HDL ratio?

LDL is still cornerstone for treatment and targets Previously Tc:HDL applied as 2o target

− Helps to better assess risk if HDL or Written out of lipid guidelines worldwide – why? Two reasons:

− Chance of error magnified in some cases Multiple measured values each w/their own error

− Ratio less predictive when the HDL is high

So what took its place and why?−non-HDLc and apoB (Quebec)

Why did outpatient lab reports change?What is nonHDLc?

Non-HDLc is the ‘sum of all bad cholesterol’− Simple calc: ‘Tc - HDL = nonHDLc’

More physiologic than a ratio of Tc to HDL Useful at all levels of HDL (unlike Tc:HDL) Related to apolipoprotein B or apoB

− This is the primary protein in LDL - later discovered to exist in all forms of bad cholesterol (incl. trigs)

− There is NO apoB in HDL

So nonHDLc & apoB are ways to quantitate totalcirculating atherogenic particles

Non‐HDLc (or apoB) represent total atherogenic particles LDL-C Remains the Primary Target with Emerging Role for Non-HDL-C and ApoB as Alternate Targets

Strong, High: Strong Recommendation, High-quality EvidenceStrong, Moderate: Strong Recommendation, Moderate-quality Evidence

Anderson TJ, Grégoire J, et al. 2012 Update of CCS Dyslipidemia Guidelines. Can J Cardiol. 2013;29:151–167.

Risk Level

Initiate Therapy If

PrimaryTarget LDL-C

Alternate Target

High FRS ≥ 20%

Consider treatment in all (Strong, High)

≤ 2 mmol/L or ≥ 50% decrease in LDL-C

(Strong, High)

• ApoB ≤ 0.8 g/L• Non HDL-C ≤ 2.6

mmol/L (Strong, High)

IntermediateFRS 10%-19%

• LDL-C ≥ 3.5 mmol/L (Strong, Moderate)

• For LDL-C < 3.5 consider if: Apo B ≥ 1.2 g/L or

Non-HDL-C ≥ 4.3 mmol/L (Strong, Moderate)


(Strong, Moderate)

• ApoB ≤ 0.8 g/L• Non HDL-C ≤ 2.6

mmol/L (Strong,Moderate)

LowFRS < 10%

• LDL-C ≥ 5.0 mmol/L• Familial

hypercholesterolemia(Strong, Moderate)

≥ 50% decrease in LDL-C (Strong,

Moderate)

Primary PreventionFrom low to medium risk and the incorporation of non-HDLc (apoB)

LDL-C Remains the Primary Target (with Emerging Role for Non-HDL-C and ApoB as Alternate Targets)



Risk Level

Initiate Therapy If

PrimaryTarget LDL-C

Alternate Target

LowFRS < 10%

• LDL-C ≥ 5.0 mmol/L• Familial

hypercholesterolemia(Strong, Moderate)

≥ 50% decrease in LDL-C (Strong, Moderate)

Very high lipids (like very high BP) should betreated regardless of age− You wouldn’t leave a 30 year old with SBP 180

for fear of lifelong medications likewise a high LDL (of 5 or more) must be addressed in all cases

What is the role of lipids in developing atherosclerosis and CV events?

Interplay of multiple CV risk factors Develop ‘fatty streaks’ as early as adolescence

which plaques rupture clinical CV events Most pts have good BP/sugar control for many

years until bad genetics/lifestyle ’catch up’ to us− But genetic dyslipidemias high lipid levels

generally been present from early on in life

So who are the ‘unlucky’ with an LDL of > 5?− Concepts of - familial hypercholesterolemia (FH) and

‘Cumulative LDL Burden’ (analogous to pack-years)

− More common than we might think

‘Cumulative LDL Burden’ - Higher LDL-C Burden in FH Patient Results in Earlier Onset of CHD

The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.

Adapted from: Nordestgaard BG, et al. European Heart Journal. 2013;34:3478-3490.

200

100

50

03 6

Age in Years

Cu

mu

lativ

e L

DL

-C (

mm

oL)

0

150

Female Sex

THRESHOLD FOR CHD

9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

Homozygous FH 12.5 Years

Without FH 55 - Years

Heterozygous FH

35 - Years

Heterozygous FH

48 - YearsHeterozygous

FH 53 - Years

START LOW DOSE

STATIN

START HIGH DOSE

STATIN

Smoking HypertensionDiabetesTriglyceridesHDL-CLipoprotein(a)

Diagnostic Criteria for Familial Hypercholesterolemia: Simon Broome Register

Marks D, et al. Atherosclerosis.2003;168(1):1-14.

Familial hypercholesterolemia is defined as:

1. Total cholesterol > 6.7 mmol/L or LDL-C > 4.0 mmol/L in a child < 16 years or Total cholesterol > 7.5 mmol/L or LDL-C > 4.9 mmol/L in an adult. (Levels either pre-treatment or highest on treatment)

PLUS

2. Tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt)

OR

3. DNA-based evidence of an LDL receptor mutation or familial defective ApoB-100

Possible familial hypercholesterolemia is defined as:

#1 Above PLUS ONE OF the following• Family history of myocardial infarction: below age 50 in 2nd degree relative or below

age 60 in 1st degree relative

• Family history of raised cholesterols:>7.5 mmol/L in adult 1st or 2nd degree relative or > 6.7 mmol/L in child or sibling <16 yrs

So a POSSIBLE diagnosis of FH can come from:

Adult LDL of 5 or morePLUS

Early positive family history of clinical CAD− < 50 years of age in 2nd degree relative

− < 60 years of age in 1st degree relative

Not that hard to identify a few patients in yourpractice that fit these criteria ‘Definite’ FH is harder to identify

FH More Common than Previously Thought

Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:431-438; Moorjani S, et al. Arteriosclerosis.1989;9(2):211-6; Al-Sarraf A, et al. Can J Cardiol. 2013;29:6-9; Nordestgaard BG, et al. Eur Heart J. 2013;34(45):3478-90; http://www.geneticalliance.org.uk/education3.htm.

FH is One of the Most Common of Inherited Diseases

Frequency per 1,000 births

Heterozygous FH

Haemophilia

Dominant ostosclerosis

Adult polycstic kidney disease

Huntington’s disease

Cystic fibrosis

Duchenne muscular dystrophy

Sickle cell anemia

Phenylketonuria

0 1 2 3 4 5

FH Homozygote

• 1 in 1 million

• May be as high as 1 in 80 in some populations (e.g. French Canadians) due to founder effect, but don’t rule out other populations

FH Heterozygote

• 1 in 200 to 500

Case Study #1 – low risk, high LDL

30M - no RF - father had MI at 52, SBP < 120 mm Hg

Tc 7.2, tg 2.4, LDL 5.2, HDL 1.05, non-HDL 6.1

Guidelines - all LDL > 5 MUST be treated

Audience question – statin + lifestyle vs lifestyle alone?

Raw FRS is 2.3% - double for early positive FHx CAD − Modified FRS (corrected for FHx) is 4.6% still low risk

Intense lifestyle changes LDL by max 20% –expect LDL to drop into the 4’s so can hold off statin

What will happen with age or RF? - Recalculating FRS…− At 40, 5.6% and 11.2% corrected (Int risk, treat if LDL > 3.5)

− At 35, if SBP to 130-139, 5.6% and 11.2% corrected

− So he deserves closer scrutiny than most 30 year olds as he may cross threshold for drug Tx in next 5-10 years

2012 CCS Lipid Guidelines – Why we Screen? We Screen to Treat

Ultimately we screen to make treatment decisions

Your decision to treat will be triggered if:

The LDL is > 5, regardless of age and regardless of risk

− Screen the ‘healthy young’ if you think there is anyplausible chance of FH

The LDL is > 3.5, AND they are intermediate risk or more− Age, male gender and modifiable risk factors drive a

higher level of risk and so intermediate risk is common

− An LDL of > 3.5 is quite common

They have any LDL, because if they have clinical CVD orare high risk, it needs to be lowered

2012 CCS Lipid Guidelines – Who to Screen

Figure 1. Approach on who and how to screen for dyslipidemiaAnderson TJ, Grégoire J, et al. 2012 Update of CCS Dyslipidemia Guidelines. Can J Cardiol. 2013;29:151–167.

And anyone with clinical CV disease (CAD, CVD, PAD)

Case Study #2 – still low risk, but > 5%

45M - no RF/FHx of CVD, no clinical CVD, SBP < 120 mmHg


FRS is 5.6% with vascular age of 45 – low risk but >5%

Canadian 2012 Guidelines – no drug Tx as LDL is < 5.0 mmol/L

For FRS 5-10% annual monitoring/risk calculation

Meta-analysis (CTT) – if FRS is 5 years of statin therapy 11 events/1000 treated benefit exceeds all known risks of statins

US guidelines statin Tx if risk is > 7.5%

Canadian guidelines did not feel justified recommending a statin for the 5-9% risk patients so settled on regular monitoring as above

LDL-C Remains the Primary Target with Emerging Role for Non-HDL-C and ApoB as Alternate Targets or Indications for Therapy



Risk Level

Initiate Therapy If

PrimaryTarget LDL-C

Alternate Target

IntermediateFRS 10%-19%

• LDL-C ≥ 3.5 mmol/L (Strong, Moderate)

• For LDL-C < 3.5 consider if: Apo B ≥ 1.2 g/L or

Non-HDL-C ≥ 4.3 mmol/L (Strong, Moderate)


(Strong, Moderate)

• ApoB ≤ 0.8 g/L• Non HDL-C ≤ 2.6

mmol/L (Strong,Moderate)

Case Study #3 – intermediate risk (#2 + 10 yrs)

55M - no RF/FHx of CVD, no CVD, SBP < 120 mmHg


FRS now 11.2%, intermediate risk, vascular age of 57

Audience question – statin + lifestyle vs lifestyle alone?

Take home message – ‘Use Alternate Targets’

Treatment trigger if LDL is > 3.5 (but 3.4 here)

2o target of non-HDLc justifies Tx > 4.3 (target)

Recommend lifestyle modification ± statin

Treatment goals - LDL < 2.0 (non-HDLc < 2.6)

Statin Therapy is the Mainstay of LDL Lowering and Reduces LDL-C by up to 60%*

*As per Canadian Product Monographs1. Crestor (rosuvastatin) Product Monograph. AstraZeneca. May 1, 20132. Lipitor (atorvastatin) Product Monograph. Pfizer. Sep. 4, 2012.3. Pravachol (pravastatin) Product Monograph Bristol-Myers Squibb Canada.

Jan. 11, 2013.4. Mevacor (lovastatin) Product Monograph. Merck. Jul. 24, 2012.

0% 10% 20% 30% 40% 50% 60%

Atorvastatin 10 mg 20 mg 40 mg

Simvastatin 10 mg 20 mg 40 mg

Pravastatin 10 mg 20 mg 40 mg

Lovastatin 20 mg 40 mg 80 mg

Fluvastatin 20 mg 40 mg

5. Zocor (simvastatin) Product Monograph. Merck. Jun. 6, 2012.6. Lescol (fluvastatin) Product Monograph. Novartis. Sep. 27,

2012.7. Adapted from Jones P, et al. for the CURVES Investigators.

Am J Cardiol. 1998;81:582-587.

Rosuvastatin 10 mg 20 mg5 mg 10 mg 20 mg 40 mg

80 mg

Doubling the statin dose results in a further 6% LDL

reduction

Lessons from WOSCOPS 20 year followupHow 5 years of Pravastatin changed outcomes

Pravastatin 40 mg vs placebo− 1989-1995, F/U 4.9yrs

6K+ men 45-64yrs

LDL 4.9 to 3.6 mmol/L (26%)

20 year F/U - registries

Benefit after 5 years of statin

Continued widening of Txbenefit through 20+ years

No adverse safety signal

New concepts of:

− ‘Legacy effect’

− ‘Gain in event free years’

From Dr. C. Packard presentation – American Heart Association Meeting 2014.

New concepts help our understanding

‘Legacy effect’− 5 years of LDL of 1.3 mmol/L ( 26%) Tx benefit

− Not only maintained but even FURTHER realized well after its conclusion as curves continued to widen

− ‘Cumulative LDL Burden’ less LDL exposure earlier in life, plaque burden less plaques available to rupture less clinical CV events (CV death/stroke/MI)

‘Gain in event free years’ − There will always be events (sadly, ‘no guarantees’)

− BUT 5 yrs of statin make your event curve shift

− To approximate the odds of those who are younger

High Risk Primary prevention and Secondary prevention

LDL-C Remains the Primary Target with Emerging Role for Non-HDL-C and ApoB as Alternate Targets



Risk Level

Initiate Therapy If

PrimaryTarget LDL-C

Alternate Target

High FRS ≥ 20%

Consider treatment in all (Strong, High)


(Strong, High)

• ApoB ≤ 0.8 g/L• Non HDL-C ≤ 2.6

mmol/L (Strong, High)

Case Study- #4, high risk – 2o prevention

55M - prior MI – high risk with known/established CVD


Initiated Atorvastatin 80 mg od - treated lipid profile:


Achieved LDL target of < 2.0 and 50% LDL reduction

However, 2o target of non-HDL is > 2.6 so he still has residual risk from a persistently atherogenic lipid profile

Audience question – do nothing further, push lifestyle, statin switch, or combination lipid lowering therapy?

Non Statin Alternatives as Adjuncts -Current Options

1. Suchy D et al. Pharmacol Rep. 2011;63:1335-48.; 2. MedlinePlus, NIH USA. Accessed May 30, 2014.; 3. Ruparelia N, et al. Curr OpinCardiol. 2011;26: 66–70.; 4. Cziraky MJ et al. J Manag Care Pharm. 2008;14(8 Suppl):S3-28; 5. Creider JC, et al. Nat. Rev. Endocrinol. 2012;8:517–528.; 6. AIM-HIGH Investigators. N Engl J Med. 2011;365:2255-67.; 7. HPS2-Thrive Collaboration Group. Eur Heart J. 2013 Feb 26.; 8. Tenebaum A, Fishman EZ. Cardiovasc Diabetol. 2012 Oct 11;11:125.; 9. Moutzouri E, et al. Vasc Health Risk Manag. 2010;6:525-39.;10. Corsini A et al. Eur J Cardiovasc Prev Rehabil. 2009;16(1):1-9.

Add-On Therapy LDL-C LoweringOther Lipid

EffectsOutcome Data (Add-on to statin)

Side Effects2

Ezetimibe1 15 – 25% IMPROVE-IT studyURTI, headache, myalgia

Niacin3-5 20% ↑ HDL by 30%↓ TG by 40%

No benefit as add-on to statin6,7

Flushing/pruritus,GI side effects

Fibrates8,9 5 – 20%↑ HDL-C (10-50%)↓ TG (20-50%) No benefit as

add-on to statinGI side effects, myalgia

Bile Acid Sequestrants10 15 – 20% Limited

GI side effects, myalgia

Intestinal Cholesterol Absorption Inhibitor

Ezetimibe Genericized - still LU codes

− 380 – on a statin, not yet at target

− 381 – statin intolerant

One dose - 10 mg tablet once daily LDL by 20% in monotherapy or when added

to baseline therapy (usually statin) IMPROVE-IT trial (AHA Nov 2014) showed

benefit as add-on therapy to a statin

Ezetimibe Outcome Trial: IMPROVE-IT

IMPROVE-IT = IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; EZE = ezetimibe*Uptitrated to 80 mg/d if LDL-C > 2.05 mmol/L

1. Clinicaltrials.gov; 2. Cannon CP, et al. Am Heart J. 2008;156:826-32; 3.Califf RM, et al. Am Heart J. 2010;159(5):705-9.

N = 18,141

Double blind

Duration: Minimum of 5,250 primary end point events and 2.5 years follow-up

Follow-up visit day 30, every 4 months

Ezetimibe/simvastatin 10 mg/40 mg*Simvastatin 40 mg*

ASA + standard medical therapy

Patients stabilized post-ACS < 10 daysLDL ≤ 3.24 mmol/L (or ≤ 2.6 mmol/L if prior statin)

Primary end point: CV death, MI, hospital admission for unstable angina, revascularization (> 30 days after randomization), or stroke

Key Question: Will the event reduction attributable to EZE be consistent with what would be anticipated from similar absolute LDL-C reductions with statins?

Ezetimibe Outcome Trial: IMPROVE-IT

Baseline LDL - 2.4 mmol/L - both arms got Simva

Eze vs placebo – achieved LDL 1.8 vs 1.4 (further 0.4)

ARR of 2% (32.7% vs 34.7%), NNT of 50, RRR of 6%

It took 18K+ patients over 7 years but we got a positive trial out of it which told us the following:− The ‘LDL hypothesis’ is supported with a nonstatin add-on

(and not just with a statin)

− A lower LDL is better even if the LDL is already less than the traditional target of < 2 mmol/L

− Ezetimibe has a favorable safety profile

The benefits are real but small – we as physicians willhave to decide ahead of guidelines is it truly worth it?

Greater LDL reduction translates into greater event reduction (lesser gains when already low)

Bile Acid Sequestrants

Cholestyramine− Difficult - SFx, vitamin/drug malabsorption, QID

Colesevelam - LDL by 15%

− Easier - less SFx, vitamin/drug malabsorption, BID

− Different formulation to cholestyramine Hydrophilic side chains

− 625 mg capsules - 2 caps bid, best dose is 3 caps bid

− Full ODB coverage with no LU code

− Enhances secretion of GLP-1 (incretin) A1C by 0.5%

Summary of Treatment and Effect on LDL

Diet – 10% and Exercise – 10-15% each Highest potency statins to begin – 40-60%

− Rosuvastatin 5-40 or Atorvastatin 10-80 mg od

Statin intolerance− Best strategy is to reintroduce statin at very low dose

daily, or alternate days or once weekly

Most pts can LDL by 50% with lifestyle + statin

High baseline LDL’s and low targets or statinintolerance will require non-statin options− Each add-on drug LDL by up to 20% each

Future Directions in Lipid management

Biologic Drugs will soon be available in Cardiovascular Medicine

Biologics used extensively in other fields:− Autoimmune (Rheum, IBD), OP, oncology, nephrology

3 lipid lowering biologics in advanced development

− PCSK-9 inhibitors

− Alirocumab, Bococizumab, and Evolocumab

− Once or twice monthly injectable

Alone or in combination with statins

Studies on FH pts, statin-intolerant pts, 2o prevention pts

Lowers LDL by 50-60%

Not yet approved, may be available by late 2015

Lessons from Polar Bear physiology -What does this have to do with lipids?

Polar bears diverged from their brown bearcounterparts about 150,000 years ago Eat a VERY high fat diet

− Seal kill – eat only blubber and leave the meat

Survival requires insulation from the elements− 8 inches of fat under their fur coats

Yet they live their lives free of atherosclerosis Rapid genetic adaptations have altered lipid

metabolism so they can eat what they need without CV consequence

Lessons from Polar Bear physiology

Humans are not polar bears

We, our kids & our pts should diet, exercise & heed the ‘wake up call’

Doctors should apply best practice guidelines for lipid lowering

Take Home Messages

Fasting labs for treatment, nonfasting for targets

nonHDLc represent ‘total atherogenic particles’ and is an alternate treatment target

Screen patients you think may have an indication fortreatment and would benefit from knowing their risk

No one should have an LDL higher than 5 and if they do, consider a diagnosis of familial hypercholesterolemia

LDL continues to be the primary target for treatment and goals remain as < 2.0 mmol/L for high/intermediate risk

A healthy lifestyle, high potency statin and add-ontherapy with cholesterol absorption inhibitors representthe current treatment approach to get to target

Cases in Combined Oral Antithrombotics: When Less is More

Peter Mitoff, MD FRCPCCardiologist, St. Joseph’s Health Centre

CV Update 2015February 25, 2015


Speaker: Dr. Peter Mitoff

Title of Talk: Cases in Combined Oral Antithrombotics: When Less is More

Financial Disclosure None

Grants / Research Support None

Speakers Honorarium None

Consulting Fees None

Patents None

Other None

Case 1

68MPMH:

– Stable CAD • NSTEMI 4 y ago, PCI to RCA• Normal LV function

– DM2– HTN– GERD

Meds:– ASA 81mg od– Atorvastatin 40mg od– Perindopril 4mg od– Rabeprazole 20mg od– Metformin 1g bid

• Routine yearly physical

• Note slightly irregular pulse

Atrial fibrillation

• ECHO <2y ago normal, recent bloodwork shows normal TSH, no symptoms suggestive of sleep apnea

• Discuss diagnosis of atrial fibrillation

• Select rate control strategy

• Discuss stroke risk:– CHADS2 Score = 2 (HTN, DM)

– 4% annual risk of stroke

• New 2014 CCS Algorithm

Canadian Journal of Cardiology 30 (2014) 1114e1130

Decide to initiate oral anticoagulation therapy (OAC)

In addition to initiating warfarin (target INR of 2 ‐3), you decide to do the following about ASA:

A) Continue it. It is necessary for secondary prevention as the patient has known CAD.

B) Stop it. ASA is not needed anymore because warfarin isgood enough for secondary prevention in CAD, and the bleeding risk is too high.

C) Continue it, but use low dose warfarin (target INR 1.5‐2) tolower bleeding risk.

D) Target INR 2‐3, but change from ASA 81mg daily to 81mg three times weekly.

ASA and OAC in stable CAD

Key Points:

1. Warfarin is at least as effective as ASA in MI secondaryprevention but increases risk of major bleeding1

2. Aspirin is not as effective at reducing stroke in atrialfibrillation compared to warfarin

3. The combination of warfarin and ASA is slightly superior to ASA in preventing ischemic endpoints, BUT, comes at a cost of significantly higher (2X) rates of serious bleeding2

1. N Engl J Med, Vol. 347, No. 13. Sept 20022. J Am Coll Cardiol. 2003 Feb;41(4 Suppl S):62S‐69S.

ASA and OAC in stable CAD

Key Points:

4. Using “low dose” warfarin (INR <2) is not effective at reducing stroke risk, and just increases bleeding risk.

5. For patients on chronic warfarin therapy, the risk of major bleeding is typically 2‐4% per person year, but may be as high as 5% in the elderly, or those with multiple comorbidities.1

6. Major bleeding is fatal in 9‐10% of cases and is associated with increased risks of adverse cardiovascular outcomes.2

1. Arch Intern Med 1993; 153: 1557‐62.2. Ann Intern Med 2003; 139: 893‐900.

Bottom Line:‐ If you are starting oral an coagula on → stop ASA.

Exceptions to this rule:‐ Mechanical heart valves: strong evidence exists for benefit of

combined warfarin and ASA

‐ Recurrent ischemic events on OAC

‐ Acute coronary syndromes, and coronary stents …

Case 2

78MPMH:

– DM2 on insulin– HTN– Dyslipidemia– TIA Feb ‘12– Atrial fibrillation (CHADS 5) on oral anticoagulation

Meds:– Apixaban 5mg bid (GFR >60, body wt 80kg)– Atorvastatin 40mg od– Candesartan 4mg od– Insulin

• Severe episode of retrosternal chest pain

• Calls EMS

Inferior STEMI

• Transferred by EMS on CODE STEMI with intention ofperforming primary PCI.

• Coronary angiography demonstrates proximallyoccluded RCA with thrombus.

• Receives one bare metal stent.

• Anti‐thrombotics on discharge:– Aspirin 81mg od

– Ticagrelor 90mg bid

– Apixaban 5mg bid

“TRIPLE THERPY”

You see him in follow up 1 week post discharge. You decide to:

A) Discontinue Apixaban. His bleeding risk is too high on triple therapy. Continue ASA and Ticagrelor for 12 months as he has a coronary stent.

B) Switch Apixaban to warfarin. Continue triple therapy but add a PPI for gastric protection.

C) Switch Ticagrelor to Clopidogrel and Apixaban to Warfarin.Continue triple therapy for 4 weeks, then discontinue ASA.

D) Some combination of the above

Triple Oral Thrombotic Therapy (TOAT)

• Combination of:

– ASA PLUS another anti‐platelet (i.e.. dual anti‐platelet therapy, DAPT) PLUS oral anticoagulation

Magnitude of the Problem:

• 20‐30% of patient with atrial fibrillation also have coronarydisease and may require PCI

• 5‐10% of patients undergoing PCI have an indication for oralanti‐coagulation

TOAT• Rationale:

– DAPT is warranted after an acute coronary syndrome, and is mandated following coronary stenting to prevent acute stent thrombosis (ST), however does not provide as effective protection from stroke in high risk patients with AF.

– The risk of ST decreases over time and is highest immediatelyfollowing stenting

• Duration of DAPT following PCI

– Bare metal stents re‐endothelialize faster than drug elutingstents, so require a shorter duration of DAPT to prevent ST

– Ideally 12 months* for both, but minimum duration:

• Bare Metal Stents = 4 weeks, Drug Eluting Stents = 6 months

* Some advocate 18m of DAPT for DES given the risk of late ST

TOAT in 2005

Aspirin 81/325

+

Clopidogrel

+

Warfarin

TOAT in 2015

Aspirin 81/325+

Clopidogrel orPrasugrel orTicagrelor

+Warfarin or

Dabigatran 110/150 bid orRivaroxaban 15/20 od or

Apixaban 2.5/5 bid

TOAT and Bleeding Risk

• Annual bleeding risk on triple therapy 10‐15%1 , associated with ↑ mortality

• Triple therapy doubles the rate of major bleeding compared with DAPT,and essentially triples the rate of major bleeding compared with monotherapy with aspirin, clopidogrel, or warfarin

• Bottom Line: Avoid if possible, if unavoidable, limit the duration of TOAT1. Lancet 2009; 374:1967‐1974.2. Arch Intern Med. 2010;170(16):1433‐1441 Canadian Journal of Cardiology 28 (2012) 125‐136

WOEST Trial

• 570 pts with indication for OAC undergoing stenting

• Randomized (open label) to:

– Clopidogrel + OAC (warfarin) versus

– ASA + Clopidogrel + OAC (TOAT)

– For 1m after BMS, 1y after DES

Lancet. 2013 (12)62177‐1.

Days

Cu

mu

lativ

e in

cide

nce

of

ble

ed

ing

0 30 60 90 120 180 270 365

0 %

10 %

20 %

30 %

40 %

50 %Triple therapy groupDouble therapy group

44.9%

19.5%

p<0.001

Bleeding at 1 year Mortality at 1 year

p=0.027

Days

0 30 60 90 120 180 270 365

0 %

7.5 %

6.4%

2.6%

• No increased risk of ST or other ischemic events in Double therapy group

Triple therapy groupDouble therapy group

WOEST Results

Lancet. 2013 (12)62177‐1.

What about Newer Anti‐thrombotics in TOAT?

• Newer Antiplatelets (Prasugrel and Ticagrelor)

– No evidence

– Increased bleeding compared to clopidogrel in ACS trials

– Avoid in patients receiving TOAT

• Direct Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban)

– Promising, but no prospective trials in AF + ACS/elective PCI

– In general, avoid in patients receiving TOAT, or considerlower dose

Recommendations for PCI requiring OAC

1. Limit the total duration of TOAT

2. Individualize based on patient’s bleeding risk

3. Avoid Ticagrelor and Prasugrel

4. Provide gastric protection

5. Choice of OAC:– Warfarin: target INR 2.0‐2.5

– If NOAC, use lower dose

6. Bare metal stents preferable

Recommendations of TOAT & Recent PCI

If low or intermediate bleeding risk (HAS BLED 0‐2):• Bare metal stent

– TOAT (ASA, clopidogrel, warfarin) x 1 month

– Then warfarin plus clopidogrel for 11 months

– Then OAC alone (warfarin versus DOAC)

• Drug eluting stent– TOAT (ASA, clopidogrel, warfarin) x 6 months

– Then warfarin plus clopidogrel for 6 months

– Then OAC alone (warfarin versus DOAC)

If high bleeding risk (HAS BLED ≥3): – use BMS, TOAT x 2‐4wks, then OAC alone

European Heart Journal (2010) 31, 2369–2429

90 is the New 50 !

Cardiovascular disease in the very elderly

CV Update 2015Mark A Fisher MD FRCPC

Cardiology Service Chief

St Joseph’s Health Centre

Conflict disclosure information

Dr Mark A Fisher : 90 is the new 50…CV Disease in the Very Elderly

Grants/research support - Servier

Speakers Honorarium - Bayer, Boehringer Ingelheim, Pfizer, Servier

Consulting Fees - BMS, Pfizer

Patents/ other - None

Outline

• Review several cases involving treatment ofthe very elderly with cardiac disease

• Discuss the issues raised by each case andexplore treatment options for the very elderly

• Consider how treatment should be tailored inthe setting of advanced age

Who is Elderly?

• The term elderly has been used to describe avariety of age subgroups in the literature

• Most papers I came across used the following:

65-74 yo – young elderly

75-84 yo – medium elderly

*85+ – very elderly*

Case 1

• Mrs. C.B. – 99yo female, very good for age, lives alone in supportive housing

• Admitted with recurrent sudden syncope, quite bruised butfortunately no fractures nor head injury

• Had a stroke 5 months before but very mild deficit

• On diltiazem 180 mg for CCS class II angina and stable

• Labwork unremarkable

• ECG showed Sinus with 1st degree AV block, RBBB and LAHB

Case 1

• Admitted to telemetry and diltiazem stopped

• Noted to have non-conducted PAC’s and pauses upto 2.5 seconds on telemetry

• Physical exam unremarkable apart from extensivebruising. Cognition normal.

• Discussion about possible pacemaker with patientand daughter…would you want more proof ?Should her age affect decision?

Brief syncope while lying in bed

Case 1

• Moved to CCU for closer monitoring (and possible temporary pacemaker)

• Decision made to insert VVI permanent pacemaker

• She waited a few days and received perm paceruneventfully. Discharged few days after with nofurther syncope.

• *Question of being cautious vs ageist in a 99yo*

Are Elderly Patients at Increased Risk of Complications Following Pacer Implantation?

• Pacing Clinical Electrophysiology 2012 : Meta analysis of 3 randomized trials comparing single vs. dual chamber pacers, 4814 pts, mean age 76, 43% female

• Analyzed for complications in <75 vs. 75 and older

• Complication rate was somewhat higher in older group (5.1% vs. 3.4%) but still acceptable. Driven by slightly more pneumothorax (1.6% vs. 0.8%) and lead dislodgements (2.0 % vs. 1.1%)

• No difference in infection, hematoma, or death

Bottom Line

• Conduction system disease is common in the elderly and most pacemakers are implanted in the elderly

• Average age of pacemaker recipients is 75

• Although the risk of certain complications does increase with age, it is still quite reasonable and there is no age limit for inserting pacemakers if a clear indication exists, especially if the patient is symptomatic

• **If a patient does have evidence of conduction system disease on ECG or holter / loop, be cautious with rate slowing medications**

Case 2• Mr. B.P. – 86yo male, lives with wife in home. Mildly frail.

Mild osteoarthritis and infrequent episodes of gout.

• Has been monitored by GP for “borderline hypertension” which developed over last couple years. Not diabetic. No cardiac history

• Meds – Atorvastatin 10mg od and allopurinol

• BP is consistently 160-165/75 mmHg in office and by his home BP monitor

• BMI is 32 with normal HS, clear chest, no carotid bruits

• ECG sinus with left anterior hemiblock and otherwise normal

Case 2 - Questions

• Are lifestyle modifications worth pursuing at his age?

• Should we treat his BP pharmacologically?

• Do we have trial evidence to treat someone at his age?

• Which agents are preferred?

• Any special considerations in treating his BP?

Hypertension in the Elderly

• Very Common – prevalence as high as 60-80%

• Individuals aged 55-65 years without HTN have a90% lifetime risk of developing stage 1 HTN (140-159/90-99mmHg) and a 40% lifetime risk of stage 2 HTN (160/100 mmHg or greater)

• Isolated systolic HTN (ISH) accounts for 60-80% of HTN in the elderly. Defined as systolic >160 mmHg with diastolic <90 mmHg

Hypertension in the Elderly

• Diastolic pressure falls after age 60 in both normotensive and untreated hypertensive patients…primarily due todiminished arterial compliance

• Among elderly, coronary heart disease risk variesdirectly with the systolic and pulse pressures and inversely with the diastolic pressure

Low Diastolic Pressure and Risk

• This observation of worse outcomes in elderly with lower diastolic pressures came primarily from population studies or from baseline pressures in clinical trials, NOT after treatment in trials.

• In clinical trials, even though active treatment patients had lower diastolic pressures at the end of the trial, they had significantly better outcomes

• From analysis of SHEP and INVEST signal of increased stroke and MI at diastolic levels below 60-65mmHg

• Expert consensus: aim for diastolic BP >60 mmHg or if known CAD > 65 mmHg. Or higher if symptoms of hypoperfusion

Treatment• Lifestyle modification should still be attempted – dietary

sodium restriction (2.3-2.8 mg/day) may actually be more potent with increasing age. Weight loss if obese. TONE trial

• Multiple randomized trials provide clear evidence of benefit from treating HTN in elderly pts, including those <80 years

(SHEP, Syst- Eur, MRC, HYVET)

• Most of these trials involved pts with ISH, but minority had diastolic HTN as well

• All of the trials required a systolic pressure of at least 160 mmHg…No trials have been performed in elderly with systolic of 140-159mmHg

HYVET Trial • 3845 pts at least 80 years of age (mean age 84) with sustained

systolic of at least 160 mmHg (mean 173/91 mmHg). Randomized to indapamide vs placebo and perindopril or placebo was added if pt failed to meet target of 150/80 mmHg

• After 2 years, mean BP was 15/6 mmHg lower with active Rx(143/78 vs 158/84 mmHg)

• Primary endpoint of fatal and nonfatal stroke... Fatal stroke was significantly reduced (6.5% vs 10.7%) and total stroke almost significant ( 12.4% vs 17.7%, p<.06)

• All cause Death reduced from 59.6 per 1000 per year with placebo to 47.2 per 1000 per year with active Rx

Orthostatic Hypotension• Orthostatic hypotension (and postprandial hypotension) is

relatively common (20% of elderly)

• Definition: within 2-5min of quiet standing, one or more of the following present:

- at least a 20mmHg fall in SBP- at least a 10mmHg fall in DBP- symptoms of cerebral hypoperfusion, i.e. dizziness

• Hypertensive elderly with orthostatic hypotension are more likely to fall than those without. Increased risk of hip fracture during the first 2 months following initiation of Rx

• **Supine and standing pressures should be measure in elderly pts prior to the initiation of antihypertensive therapy

Frailty• Randomized trials that showed benefit for the treatment of HTN

in older adults enrolled relatively fit patients since frail pts often have difficulty participating in trials, and have more comorbidities

• Although there are no trials, older adults who are frail may be atmore risk for side effects and may not have the same benefit from treatment

• Observational study of 2340 adults over 65, relationship between BP and mortality examined according to whether pt was frail or fit (ability to walk 6m in less than 8s)

• Amongst the frail, no association between BP and mortality. In the most frail, higher BP was associated with lower mortality. Only amongst fit individuals was expected association present

Recommendations

• BP reduction should always be gradual in older adults(in absence of hypertensive emergency)

• Check for orthostatic hypotension before starting therapy and be extra cautious with frail patients

• Start with lower initial dose to minimize risk of side effects

• Low dose thiazide diuretic, ACE I / ARB or long acting ca++ channel blocker are all reasonable…If combination required, ACE I/ARB + ca++ channel blocker may be best option (ACCOMPLISH trial)

• Age 60-79 target BP <140/90mmHg. Age 80+ <150/90mmHg

Case 3• Mrs. Y.N. – 90yo female, very active and good for her age…

still line dances !

• HTN and hypothyroidism

• Several months of typical exertional chest tightness and dyspnea

• Presented to ER after episode at rest… Troponin peaked at 25,CK 630

• Initial ECG anterior ST depression which resolved

Initial ECG in ER

Should she have a coronary angiogram?

Case 3• Admitting Internist’s note: “Excellent functional status,

may benefit from cardiac cath”

• Admitted to CCU, settled with medical Rx

• Long discussion with pt and family about cardiac cathand they eventually agreed

• Severe CAD - Heavily calcified 95% left main extending into LAD, 80% ostial RCA and heavily calcified aorta

Case 3

• Kept at St Michael’s after cath for discussion about the best treatment option: CABG vs PCI

• Given her advanced age and heavily calcified aorta, CABG was felt to be too risky…also she was NOT interested in CABG

• PCI performed with drug eluting stents to the distalleft main/ostial LAD and ostial RCA…everything went well and discharged home the following day!

Case 3 Coronary Care in the Elderly• CAD is still the leading cause of death worldwide

• Cardiovascular morbidity and mortality rates rise rapidly past75 years of age, a group that accounts for only 6% of the population but 60% of MI related deaths

• Age is a powerful predictor of adverse events during acute coronary syndrome (ACS)

• Comorbidities are more prevalent in the elderly: CHF, prior stroke and renal dysfunction rise continuously with age

• The elderly are at higher risk of complications both from medical therapy and interventions…bleeding, postproceduralrenal failure, stroke, respiratory failure and infection

Treatment options• The elderly demonstrate greater absolute and relative benefits in

reducing death/MI with early invasive care, and long-term follow up suggests the superiority of revascularization for survival and symptom improvement

• TACTICS-TIMI 18 enrolled pts with ACS across 9 countries to an early invasive vs conservative strategy…relative risk reduction of 56% in death or MI in pts 75+ at 6 months in the invasive arm, which was significantly greater than in younger individuals

• The benefits coexist with an increase in major bleeding, occurred in 17% of the older pts treated with an invasive strategy

• Patient preferences are important in determining management;both invasive vs conservative and PCI vs CABG

What actually happens?• Registry data show the very elderly are less likely to receive cath

and PCI in comparison with younger patients and yet derive the greatest benefit in terms of survival and re-hospitalization rates

• From GRACE registry: 69% of pts <65yo got a cath vs only 18% ofthose > 84yo

• However things are improving: a Canadian study of 30,000 pts80yo and older admitted with AMI between 1996 and 2007 showed that PCI rate increased from 2 to 25%. …1 year mortality improved over time but was still high at 41%

• Age alone should not be a contraindication to cath someone… perhaps we need to tolerate some increased bleeding if it improvessurvival and symptoms… best way is to discuss options with the pt

Case 4• Mrs. A.S. – 88yo F. Quite active although thin and looks frail

• Elevated cholesterol and hypothyroidism only medical problems

• I followed her for severe aortic stenosis (A.S.) since 2009 (AVA 0.6 cm2)

• Cardiac cath showed only mild CAD

• Surgical referral for AS …Surgeon felt she was too frail and old for surgery but to consider TAVR…however patient was not keen on any procedure

Case 4• Exertional dyspnea remained stable for a while but in

2012 worsening exertional dyspnea (NYHA Class III)

• Admitted with recurrent sudden syncopal episodes

• Echo showed critical AS with valve area of 0.4 cm2

and peak/mean aortic gradient of 100/60 mmHg

• She now became interested in possible interventional treatment

• Can we help her?

Aortic Stenosis Natural History

What is TAVR ?(Transcatheter Aortic Valve Replacement)

Trial Details

Cohort B (Non- surgical group)

• Assessed by 1 cardiologist and 2 cardiac surgeons

• > 50% risk of death or serious irreversible complications with AVR ( i.e. considered inoperable)

Exclusions

• Unicuspid or bicuspid AV, severe AI or MR (>3+)

• Recent AMI, TIA or stroke, LVEF <20%, Severe untreated CAD

Partner B – TAVR in Non Surgical Cohort

Case 4 - Outcome

• Mrs. A.S. readmitted in Oct 2012 with syncope, MI and urosepsis

• Once infection cleared she underwent aortic balloon valvuloplasty as a test to see how much she’d improve

• She did improve, regained her strength and mobility

• So in June 2013 she underwent TAVR with excellent result

• October 2013: seen in follow up, more active and no further dyspnea nor syncope…almost 90 years old

Conclusion

• We are living longer (and better!)

• Cardiovascular disease is common in the very elderly and causes major morbidity and mortality

• Treatment is appropriate for patients in their 80’s and 90’s, including invasive procedures in some cases

• Very important to individualize therapy depending uponthe pt’s wishes as well as their frailty and co morbidities

Thank You !

The good, the bad and the ugly: Cardiac test results to ignore and

to recall

Dr. L. Drzymala

St. Joseph’s Cardiovascular Update

February 25, 2015

Disclosures

• I do not have an affiliation (financial orotherwise) with a pharmaceutical, medicaldevice or a communication company)

• I cannot identify any conflict of interest

Objectives

1. To distinguish between normal/benignabnormalities and their important mimickers

2. To review appropriate work‐up of commonECG, holter, stress test and echo findings.

ECG Case 1

• 61 Lawyer with treated hypertension

• Four weeks ago, developed new onset chestpains with regular exertion which has nowresolved

• Family MD referred for consultation and GXTregarding chest pain

Where is the ECG abnormality?

Septal T‐wave inversions

• The good– Juvenile T‐wave pattern

• V1‐V3 (up to V4‐6)

• Symmetric and shallow (< 3 mm)

• Normal variant in young adults

• Usually women < 40‐45 of age

• The bad– Large pulmonary embolus and RV strain

• The ugly– Anterior wall Ischemia

ECG Case 1 continued

• Exercise stress test was cancelled

• Patient was referred for angiography

• High grade LAD lesion was found

• Ad‐hoc angioplasty was performed

CAD ‐ ‘Wellen’s’ T‐waves

• Symmetrical T‐wave inversions

– Usually deep (>2 mm)

– Less common are biphasic T‐wave

• Precordial leads

• Proximal LAD lesion (“widow maker” lesion)

– 69% sensitive

– 89% specific

• Only other important DDx is ICH.

Wellen’s

ECG and Holter Case 2

• 45 F• Recurrent exertional syncope

– After vigorous running– ‘Banned’ from multiple gyms

• 12‐lead ECG– normal sinus rhythm, one PVC

• Holter monitor shows– <1% PACs– 3% Ventricular ectopic beats

• Isolated PVCs with rare couplets, occasional bigeminy

Ventricular Premature beats

• The good

– Occur at times of rest and suppress with exercise

– Infrequent

• Less than 10,000 PVCs per 24 hours on holter

• Less than 10% of total heart beats

– No ischemia or VT on exercise stress test

– Normal structure and function on echo

Ventricular Premature Beats

• The bad– Frequent (Not really clear how much is too much)

• >10,00‐20,000 PVC/day

• >10% total beats

– Can actually induce a cardiomyopathy in previously structurally normal hearts

• The ugly– Worse with exercise

– Polymorphic (multiple QRS morphologies)

– During emotional or physical stress

How to work up VPB’s

• Ensure no syncope or family history of suddendeath

• Order an echo, Holter and stress test

• Benign VPB’s should be associated with:

– Normal echo

– No VT on Holter or stress test

– Not overly frequent on Holter (< 10K/24 hours)

• Without all above benign markers refer

Stress test ‐ Case 3

• 67 year‐old cyclist

• Exertional chest pressure and dyspnea

Case 1: Ben

Low sensitivity of exercise ECG:false negatives

Sensitivity Specificity

Men 65%LR- 0.65

85%LR+ 3.0

Women 61%LR-0.56

70%LR+ 2.0

Sensitivity = SnNOUT – if it is negative, rule out the disease.This means that 35‐40% of all stress tests are going to be falsely negative.

1. Approximately 20% of ECG‐negative GXT will have at least single vessel CAD

2. Lateral wall ischemia not well represented by 12‐lead ECG ‐ often branch of Circumflex artery

3. Sick ventricles (i.e. after MI) also have variable ECG ischemia response.

Low sensitivity of exercise ECG:false negatives

• Sometimes the best case for CAD is the history

• The best history is the history taken by thephysician who knows the patient best– Most of the time this is the primary care MD

• Believe a compelling or persistent history and‘step up’ the testing for clarity– Stress MPI

– CT coronary angiography

– Conventional angiography

GXT Case 3 – Take Home Message Stress perfusion imaging ‐ Case 4

• 63 year‐old woman with dyspnea

• Smoker, hypertension

• Walked 4 minutes, stopped due to SOB

• Mild chest pain

• 2 mm ST depression

Anna

Stress perfusion imaging ‐ Case 4

• Test report: Discordant study• Exercise ECG: Chest pain POSITIVE andECG POSITIVE

• Myocardial perfusion: No ischemia orinfarction

• LV function: Normal LVEF

Discordant Perfusion Testing

• The good ‐ Normal perfusion usually portendsa good prognosis even when abnormal exerciseECG (or chest pains)

Discordant Perfusion Tests

• The bad and the ugly– Myocardial perfusion may look NORMAL if there are balanced perfusion defects from 3V CAD.

– ‘Balanced ischemia’• perfusion is reduced in all regions in heart

• perfusion defects are not evident

– Suspect when• Good story

• Strongly abnormal exercise ECG

• Low exercise tolerance

• Chest pains on the treadmill

• Sometimes the best case for CAD is the history• The best history is the history taken by the physician who knows the patient best– Most of the time this is the primary care MD

• Even fancy myocardial perfusion tests get it wrong– Sensitivity in 85‐90%

• Believe a compelling or persistent history and ‘step up’ the testing for clarity– CT coronary angiography– Conventional angiography

Case 4 – Take home message

Echo ‐ Case 5

• 34M with a murmur

– Father had aortic dissection

– Echo

• Mild aortic regurgitation

Echo findings which rarely require follow‐up/re‐assessment

• Aortic sclerosis

• MAC

• Borderline/mild mitral valve prolapse

• Mild/Septal hypertrophy

• Mobile/aneurysmal inter‐atrial septum

• Trivial/mild pulmonary regurgitation

• Trivial/mild tricuspid regurgitation

When to do repeat echo(as per CCN echo indications)

• The good (Re‐assessment in >2 years)• Mild aortic/mitral stenosis/regurgitation• Mild LV systolic dysfunction• Mild aortic root or ascending aorta dilatation• Mild pulmonary hypertension

• The bad (Re‐assessment in >1 year)• Any LV dilatation• Prosthetic valves• Moderate stenosis/regurgitation• Moderate LV systolic dysfunction• Moderate aortic root or ascending aorta dilatation

• The ugly (Re‐assessment in > 6 month)• Re‐assessment of new valve lesion• Severe stenosis/regurgitation• Severe LV systolic dysfunction• Severe aortic root and ascending aorta dilatation.

Summary

• Septal T inversions can run the gamut from lifethreatening (CAD/PE) to normal variants

• Frequent VPB’s are concerning if they portendVT (syncope, FHX SD, abnormal echos, VT onGXT) and not concerning if none of these seen

• Stress tests and stress MPI can miss some CAD– sometimes a cath is justified by history alone

• Much of the echo report can be ignored

Thank you … Questions?

Dr. L. Drzymala

St. Joseph’s Cardiovascular Update

February 25, 2015

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