8th Annual Cardiovascular Update eBook by Nathan Bugden

CARDIOVASCULAR UPDATE Faculty:

Peter Mitoff, MD, FRCPC Richard Choi, MD, FRCPC, Chair Mark Fisher, MD, FRCPC, Chief Lukasz Drzymala, MD, FRCPC Giridhar Logsetty, MD, FRCPC

Handout Package

Wednesday February 25, 2015 St. Josephâ&#x20AC;&#x2122;s Health Centre Education Centres A&B

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 More Peter Mitoff, MD

p. 23

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

p. 28

The Good, the Bad and the Ugly: Cardiac Test Results to Ignore and to Recall Lukasz 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 Logsetty Division of Cardiology, St. Josephâ&#x20AC;&#x2122;s Health Centre

Conflict Disclosure Information Speaker:

Mitigating Potential Bias

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

Objectives

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

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

 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/Pearls 5. 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

Why Do We Treat Hypertension?

Janeway, 1913 • CHF • Stroke • MI

Janeway TC. Arch of Intern Med, 1913

50% 30-40% 20-25%

Blood Pressure Lowering Treatment Trialists' Collaboration, BMJ 2008

Take Home Point

Prevalence of Hypertension in Canada

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

3.3%*

of those age 18 to 39

21.8%

of those age 40 to 59

52.4%

of those age 60 to 70

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.

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

Impact of health behaviours on blood pressure

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 managementespecially in regards to dietary sodium intake

Intervention

Systolic BP (mmHg)

Diet and weight control

‐6.0

Diastolic BP (mmHg) ‐4.8

Reduced salt/sodium intake

‐ 5.4

‐ 2.8

Reduced alcohol intake (heavy drinkers)

‐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

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 is recommended.

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/Pearls 5. What is the cost to my patients?

I. Accurate Measure of Blood Pressure Assess 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 is appropriate 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 analogous to 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 is registering 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

Not all Patients are Suited to Home 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)

• 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

• Improved adherence to drug therapy Most patients can be trained to measure blood pressure Periodic reassessment of technique and retraining is desirable

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

VII. Suggested Protocol for Home Measurement of Blood Pressure for 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 readings should be averaged. • Average BP equal to or over 135/85 mmHg should be considered elevated (for those patients whose clinic BP target is less than 140/90 mmHg).

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.

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

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

Home Measurement: Doing it Right

Preparation

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

VII. Home Measurement of BP: Confirm Contradictory Home Measurement Readings

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

VIII. Ambulatory BP Monitoring Beyond the diagnosis of hypertension, ABPM measurement may also be considered for selected patients for the management of HTN

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

Repeat home monitoring or perform 24-hour ambulatory blood pressure monitoring

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.

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

VIII. Ambulatory BP Monitoring

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

How to? • Use validated devices • How to interpret?

Description

– Mean daytime ambulatory blood pressure >135/85 mmHg is considered elevated. – Mean 24 h ambulatory blood pressure >130/80 mmHg is considered elevated.

Blood Pressure mmHg

Home pressure average

135 / 85

Daytime average ABP

135 / 85

24-hour average ABP

130 / 80

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

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

24-h ABPM

Awake BP

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

Awake BP < 135/85 and 24-hour < 130/80

>135 SBP or >85 DBP

or 24-hour

• Some patients with white coat hypertension develop sustained hypertension.

>130 SBP or >80 DBP

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

Consistent with HTN

Patients with high normal blood pressure should be followed annually.

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

Objectives

BP: 140-179 / 90-109

 Back to basics: Clinic BPM

ABPM (If available)

Home BPM

Hypertension visit 3 >160 SBP or >100 DBP <160 / 100

Diagnosis of HTN

ABPM or HBPM

Awake BP <135/85 and 24-hour <130/80

Hypertension visit 4-5 >140 SBP or >90 DBP

Diagnosis of HTN

< 140 / 90

Continue to follow-up

Awake BP >135 SBP or >85 DBP or 24-hour >130 SBP or >80 DBP

Diagnosis of HTN

< 135/85

>135 SBP or >85 DBP

Repeat Home BPM If < 135/85 Continue to follow-up

Diagnosis of HTN

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

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/Pearls 5. What is the cost to my patients?

II. Indications for Pharmacotherapy

II. Indications for Pharmacotherapy Recommended Treatment Targets

Usual blood pressure threshold values for initiation of pharmacological treatment Population

SBP

DBP

Diabetes

130

High risk (TOD or CV risk factors)

140

Low risk (no TOD or CV risk factors) Very elderly

160 160

100 NA

Treatment consists of health behaviour ±pharmacological management

TOD=target organ damage

Population

SBP

Diabetes

<130

DBP <80

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

<140

<90

Very elderly (≥ 80 years)

<150*

*This higher treatment target for the very elderly reflects current evidence and heightened 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

Take Home Point

TARGET <140/90 mmHg INITIAL TREATMENT AND MONOTHERAPY Lifestyle modification therapy

Thiazide

ACEI

ARB

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

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

Betablocker*

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

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

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?

Case 1 - Elevated Cr with ACEi/ARB  An increase of sCr of 10-20% above baseline, is normally 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

Case 1 - Elevated Cr with ACEi/ARB

Case 2 - ACEi/ARB and Hyper K

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

 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)

• If increase in Cr > 30%:  What should you do? – reduce ACEi/ARB dosage or stop – Assess for volume depletion, esp. if also on diuretic.

Case 2 - ACEi/ARB and Hyper K

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

 Develops in 10% of outpatients within 1 year of initiation  At risk: DM and pre-existing impaired renal function

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.

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

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

Palmer BF. N Engl J Med 2004;351:585592.

Case 2 - ACEi/ARB and Hyper K • In our patient with K >5.5 • Approach: Dietary Hx OTC and herbal supplements ?salt substitute  After dietary advice, repeat K level, 1 week later 5.0

Case 3 - HTN and Gout

Case 2 - ACEi/ARB and Hyper K 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.       

What effect does thiazide have on uric acid levels?

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

• HPDF Study, increases in uric acid levels were seen • However, gout was rare, occurring in 18 of 3693 patients over 5 years (0.5%)

You wonder if Thiazide is safe...

• Health Professionals FU study (multivariate risks)

1. Gout 2. Blood Sugar

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

What effect does thiazide have on uric acid levels? • Rise in serum uric acid is small and dose related

• Uric acid 2mg/dl = 119umol/L

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

• Uric acid 6 mg/dl = 357 umol/L • HCT not absolutely contraindicated in patients at risk for or with gout

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

What effect does thiazide have on uric acid levels?

What About Blood Sugar With Thiazides?

• 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)

Case 4– NSAIDs and Antihypertensive Rx

Case 4 – NSAIDs and Antihypertensive Rx

• 62 yr old man with well controlled hypertension

• NSAIDs inhibit prostaglandin-mediated Vasodilatation, and promote Na and H20 retention – This works against BP medication • Vasodilating CCBs are least affected by this mechanism • E.g. Indomethacin reduced efficacy of Enalapril by nearly 50%, with almost had no effect on nifedipine • (Aspirin also has little effect on antihypertensives)

• Develops significant OA of the hip, requiring chronic NSAID therapy • Rx: Naproxen 250mg PO BID, Ramipril 10mg daily • BP becomes poorly controlled >160/90 mmHg

Figure 1. Effects of rofecoxib and celecoxib on clinic systolic BP in

Objectives

patients given ACE inhibitors, β-blockers, and calcium antagonists.

 Back to basics:

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

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/Pearls 5. What is the cost to my patients?

Costs of Various Common Antihypertensives ACE Inhibitors Ramipril 2.5/5/10 Perindopril 2/4/8 Trandolapril 1/2/4 Lisinopril 5/10/20

Cost 0.15/0.15/0.19 0.65/0.82/1.13 0.69/0.79/0.98 0.14/0.16/0.29

ARB Candesartan 4/16/32 Irbesartan 150/300 Losartan 50/100 Valsartan 160/320 Olmesartan 20/40

0.17/0.29/0.29 0.30/0.30 0.31/0.31 0.28/0.28 1.08/1.08 www.healthinfo.moh.gov.on.ca

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 can be useful in identifying patients with true hypertension • BP reduction is the major determinant of reducing CV risk, not the choice of agent

Costs of Various Common Antihypertensives BB/Diuretic

Cost

Bisoprolol 5/10

0.10/0.15

Metoprolol 50/100

0.06/0.14

Atenolol 50/100

0.14/0.24

HCTZ 25/50

0.02/0.02

Chlorthalidone 50

0.12

Indapamide 1.25/2.5

0.07/0.12

CCB

Cost

Felodipine

0.52./0.56/0.84

Amlodipine Nifedipine 20/30/60

0.24/0.36 1.27/0.62/0.94

Verapamil 120/180/240

n/a/0.52/0.51

Diltiazem 120/180/240/300

0.36/0.48/0.64/0.80

CV Update 2015 Lipids and Cardiovascular Risk: Is there anything new for 2015? Richard Choi, MD, FRCP(C) Staff Cardiologist, St. Josephâ&#x20AC;&#x2122;s Toronto February 25, 2015

Conflict Disclosure Information 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, Merck and 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

Take Home Messages

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

 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 for treatment 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-on therapy with cholesterol absorption inhibitors represent the current treatment approach to get to target

2. To understand the key changes from the updated Canadian Lipid Guidelines. 3. To apply the updated risk assessment tools, treatment thresholds and treatment targets

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

Why did outpatient lab reports change? Nonfasting samples, nonHDL cholesterol and the elimination of Tc:HDL

 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 treatment decisions 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?

Why did outpatient lab reports change? What is nonHDLc?

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

 Non-HDLc is the ‘sum of all bad cholesterol’

− 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)

Non‐HDLc (or apoB) represent total atherogenic particles

− 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 total circulating atherogenic particles

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

Initiate Therapy If

Primary Target 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)

≤ 2 mmol/L or ≥ 50% decrease in LDL-C (Strong, Moderate)

• ApoB ≤ 0.8 g/L • Non HDL-C ≤ 2.6 mmol/L (Strong, Moderate)

Intermediate FRS 10%-19%

Low FRS < 10%

• 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) • LDL-C ≥ 5.0 mmol/L • Familial hypercholesterolemia (Strong, Moderate)

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

Strong, High: Strong Recommendation, High-quality Evidence Strong, 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.

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

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

Low FRS < 10%

Initiate Therapy If • LDL-C ≥ 5.0 mmol/L • Familial hypercholesterolemia (Strong, Moderate)

Primary Target LDL-C

Alternate Target

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

 Very high lipids (like very high BP) should be treated 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 Strong, High: Strong Recommendation, High-quality Evidence Strong, 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.

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

− 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

Homozygous FH 12.5 Years

Heterozygous FH 35 - Years

200

THRESHOLD FOR CHD Cumulative LDL-C (mmoL)

 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

‘Cumulative LDL Burden’ - Higher LDL-C Burden in FH Patient Results in Earlier Onset of CHD Heterozygous FH Heterozygous 48 - Years FH 53 - Years

Female Sex

150 START HIGH DOSE STATIN

100

Without FH 55 - Years

START LOW DOSE STATIN

Smoking Hypertension Diabetes Triglycerides HDL-C Lipoprotein(a)

0 0

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

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.

Diagnostic Criteria for Familial Hypercholesterolemia: Simon Broome Register

So a POSSIBLE diagnosis of FH can come from:

Familial hypercholesterolemia is defined as:

 Adult LDL of 5 or more PLUS

 Early positive family history of clinical CAD

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 pretreatment 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.

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

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 •

− < 50 years of age in 2nd degree relative − < 60 years of age 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

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

Case Study #1 – low risk, high LDL

FH More Common than Previously Thought FH Heterozygote

FH Homozygote

•

1 in 200 to 500

•

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

 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

1 in 1 million

 Audience question – statin + lifestyle vs lifestyle alone?  Raw FRS is 2.3% - double for early positive FHx CAD

FH is One of the Most Common of Inherited Diseases

− Modified FRS (corrected for FHx) is 4.6%  still low risk

Heterozygous FH Dominant ostosclerosis

 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…

Adult polycstic kidney disease Huntington’s disease Cystic fibrosis Duchenne muscular dystrophy Sickle cell anemia Phenylketonuria Haemophilia 0

Frequency per 1,000 births 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.

− 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

2012 CCS Lipid Guidelines – Who to Screen

 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 any plausible 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 or are high risk, it needs to be lowered

 And anyone with clinical CV disease (CAD, CVD, PAD) Figure 1. Approach on who and how to screen for dyslipidemia Anderson TJ, Grégoire J, et al. 2012 Update of CCS Dyslipidemia Guidelines. Can J Cardiol. 2013;29:151–167.

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

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

 45M - no RF/FHx of CVD, no clinical CVD, SBP < 120 mmHg  Tc 5.6, tg 2.4, LDL 3.4, HDL 1.05, non-HDL 4.5  FRS is 5.6% with vascular age of 45 – low risk but >5%

Risk Level

 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

Initiate Therapy If

Intermediate FRS 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)

Primary Target LDL-C

Alternate Target

≤ 2 mmol/L or ≥ 50% decrease in LDL-C (Strong, Moderate)

• ApoB ≤ 0.8 g/L • Non HDL-C ≤ 2.6 mmol/L (Strong, Moderate)

 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 Strong, High: Strong Recommendation, High-quality Evidence Strong, 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.

Case Study #3 – intermediate risk (#2 + 10 yrs)  55M - no RF/FHx of CVD, no CVD, SBP < 120 mmHg  Tc 5.6, tg 2.4, LDL 3.4, HDL 1.05, non-HDL 4.5  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%* 0%

10%

20%

30%

40%

50%

Rosuvastatin

10 mg 5 mg

20 mg

10 mg 20 mg

Atorvastatin

10 mg

20 mg

40 mg 80 mg

Simvastatin

10 mg

Pravastatin

10 mg

Lovastatin

20 mg

Fluvastatin

20 mg

60% 40 mg

40 mg

Doubling the statin dose results in a further 6% LDL reduction

40 mg

80 mg

40 mg

*As per Canadian Product Monographs 1. Crestor (rosuvastatin) Product Monograph. AstraZeneca. May 1, 2013 2. 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.

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.

Lessons from WOSCOPS 20 year followup How 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 Tx benefit through 20+ years  No adverse safety signal  New concepts of:

− ‘Legacy effect’ − ‘Gain in event free years’

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

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

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

Initiate Therapy If

Primary Target 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)

High Risk Primary prevention and Secondary prevention

Case Study- #4, high risk – 2o prevention  55M - prior MI – high risk with known/established CVD  Tc 5.6, tg 2.4, LDL 3.4, HDL 1.05, non-HDL 4.5  Initiated Atorvastatin 80 mg od - treated lipid profile:  Tc 4.0, tg 2.4, LDL 1.8, HDL 1.11, non-HDL 2.9  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 Add-On Therapy

Ezetimibe1

Niacin3-5

LDL-C Lowering

Other Lipid Effects

15 – 25%

20%

Fibrates8,9

5 – 20%

Bile Acid Sequestrants10

15 – 20%

↑ HDL by 30% ↓ TG by 40%

Outcome Data (Add-on to statin)

Side Effects2

IMPROVE-IT study

URTI, headache, myalgia

No benefit as add-on to statin6,7

Flushing/pruritus, GI side effects

↑ HDL-C (10-50%) No benefit as ↓ TG (20-50%) add-on to statin

Limited

GI side effects, myalgia

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 Opin Cardiol. 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.

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 Patients stabilized post-ACS < 10 days LDL ≤ 3.24 mmol/L (or ≤ 2.6 mmol/L if prior statin) ASA + standard medical therapy

N = 18,141

Double blind

Simvastatin 40 mg*

Ezetimibe/simvastatin 10 mg/40 mg*

Follow-up visit day 30, every 4 months Duration: Minimum of 5,250 primary end point events and 2.5 years follow-up 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? 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.

Ezetimibe Outcome Trial: IMPROVE-IT    

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

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 will have to decide ahead of guidelines  is it truly worth it?

Bile Acid Sequestrants

Summary of Treatment and Effect on LDL

 Cholestyramine

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

− 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%

− 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 statin intolerance will require non-statin options − Each add-on drug  LDL by up to 20% each

Biologic Drugs will soon be available in Cardiovascular Medicine  Biologics used extensively in other fields: − Autoimmune (Rheum, IBD), OP, oncology, nephrology

Future Directions in Lipid management

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

 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

 Polar bears diverged from their brown bear counterparts 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

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 for treatment 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-on therapy with cholesterol absorption inhibitors represent the current treatment approach to get to target

 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

Cases in Combined Oral Antithrombotics: When Less is More Peter Mitoff, MD FRCPC Cardiologist, St. Joseph’s Health Centre CV Update 2015 February 25, 2015

Conflict Disclosure Information

Case 1

Speaker:

68M PMH:

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

• Routine yearly physical • Note slightly irregular pulse

– 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

• 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 Atrial fibrillation

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 is good 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) to lower bleeding risk. Decide to initiate oral anticoagulation therapy (OAC)

D) Target INR 2‐3, but change from ASA 81mg daily to 81mg three times weekly. Canadian Journal of Cardiology 30 (2014) 1114e1130

ASA and OAC in stable CAD

Key Points:

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

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

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

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

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

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

1. N Engl J Med, Vol. 347, No. 13. Sept 2002 2. J Am Coll Cardiol. 2003 Feb;41(4 Suppl S):62S‐69S.

1. Arch Intern Med 1993; 153: 1557‐62. 2. Ann Intern Med 2003; 139: 893‐900.

Case 2 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 …

• Severe episode of retrosternal chest pain • Calls EMS

78M PMH: – – – – –

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

• Transferred by EMS on CODE STEMI with intention of performing primary PCI. • Coronary angiography demonstrates proximally occluded RCA with thrombus. • Receives one bare metal stent. • Anti‐thrombotics on discharge: – Aspirin 81mg od – Ticagrelor 90mg bid – Apixaban 5mg bid

Inferior STEMI

“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.

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 coronary disease and may require PCI • 5‐10% of patients undergoing PCI have an indication for oral anti‐coagulation

D) Some combination of the above

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 immediately following stenting

• Duration of DAPT following PCI – Bare metal stents re‐endothelialize faster than drug eluting stents, so require a shorter duration of DAPT to prevent ST – Ideally 12 months* for both, but minimum duration:

TOAT in 2005

TOAT in 2015

Aspirin 81/325 + Clopidogrel + Warfarin

Aspirin 81/325 + Clopidogrel or Prasugrel or Ticagrelor + Warfarin or Dabigatran 110/150 bid or Rivaroxaban 15/20 od or Apixaban 2.5/5 bid

• Bare Metal Stents = 4 weeks, Drug Eluting Stents = 6 months * Some advocate 18m of DAPT for DES given the risk of late ST

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 TOAT 1. 2.

Lancet 2009; 374:1967‐1974. Arch Intern Med. 2010;170(16):1433‐1441

Canadian Journal of Cardiology 28 (2012) 125‐136

WOEST Results

WOEST Trial

• Randomized (open label) to: – Clopidogrel + OAC (warfarin) versus – ASA + Clopidogrel + OAC (TOAT) – For 1m after BMS, 1y after DES

Cumulative incidence of bleeding

Bleeding at 1 year

• 570 pts with indication for OAC undergoing stenting

50 %

Mortality at 1 year

Triple therapy group Double therapy group

6.4% p=0.027

30 %

20 %

19.5% 10 %

p<0.001

2.6% 0%

0% 0

30 60 90 120

180

270

365

Days

•

• Direct Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) – Promising, but no prospective trials in AF + ACS/elective PCI – In general, avoid in patients receiving TOAT, or consider lower dose

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

30 60 90 120

180

270

365

Days

Lancet. 2013 (12)62177‐1.

What about Newer Anti‐thrombotics in TOAT?

– No evidence – Increased bleeding compared to clopidogrel in ACS trials – Avoid in patients receiving TOAT

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

Lancet. 2013 (12)62177‐1.

• Newer Antiplatelets (Prasugrel and Ticagrelor)

Triple therapy group Double therapy group

7.5 %

44.9%

40 %

Recommendations for PCI requiring OAC 1. 2. 3. 4. 5.

Limit the total duration of TOAT Individualize based on patient’s bleeding risk Avoid Ticagrelor and Prasugrel Provide gastric protection Choice of OAC: – Warfarin: target INR 2.0‐2.5 – If NOAC, use lower dose

6. Bare metal stents preferable

90 is the New 50 ! Cardiovascular disease in the very elderly CV Update 2015 Mark A Fisher MD FRCPC Cardiology Service Chief St Josephâ&#x20AC;&#x2122;s Health Centre

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

Outline • Review several cases involving treatment of the very elderly with cardiac disease

Grants/research support - Servier Speakers Honorarium - Bayer, Boehringer Ingelheim, Pfizer, Servier

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

Consulting Fees - BMS, Pfizer Patents/ other - None

Who is Elderly? • The term elderly has been used to describe a variety 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*

• Consider how treatment should be tailored in the setting of advanced age

Case 1 • Mrs. C.B. – 99yo female, very good for age, lives alone in supportive housing • Admitted with recurrent sudden syncope, quite bruised but fortunately 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

Brief syncope while lying in bed

• Admitted to telemetry and diltiazem stopped • Noted to have non-conducted PAC’s and pauses up to 2.5 seconds on telemetry • Physical exam unremarkable apart from extensive bruising. Cognition normal. • Discussion about possible pacemaker with patient and daughter…would you want more proof ? Should her age affect decision?

Case 1 • Moved to CCU for closer monitoring (and possible temporary pacemaker)

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

• Decision made to insert VVI permanent pacemaker

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

• She waited a few days and received perm pacer uneventfully. Discharged few days after with no further syncope.

• 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

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

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

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

• 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

• Meds – Atorvastatin 10mg od and allopurinol

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

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

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

• ECG sinus with left anterior hemiblock and otherwise normal

Case 2 - Questions

Hypertension in the Elderly

• Are lifestyle modifications worth pursuing at his age?

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

• Should we treat his BP pharmacologically?

• Individuals aged 55-65 years without HTN have a 90% lifetime risk of developing stage 1 HTN (140159/90-99mmHg) and a 40% lifetime risk of stage 2 HTN (160/100 mmHg or greater)

• Do we have trial evidence to treat someone at his age? • Which agents are preferred? • Any special considerations in treating his BP?

• 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

Low Diastolic Pressure and Risk

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

• 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.

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

• 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

HYVET Trial

• 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

• 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

• Multiple randomized trials provide clear evidence of benefit from treating HTN in elderly pts, including those <80 years (SHEP, Syst- Eur, MRC, HYVET)

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

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

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

• 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

Frailty

• Orthostatic hypotension (and postprandial hypotension) is relatively common (20% of elderly)

• 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

• 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

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

• 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

Recommendations

• 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

Case 3

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

• Mrs. Y.N. – 90yo female, very active and good for her age… still line dances !

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

• HTN and hypothyroidism

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

• Several months of typical exertional chest tightness and dyspnea

• 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

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

Case 3

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 distal left main/ostial LAD and ostial RCA…everything went well and discharged home the following day!

Coronary Care in the Elderly • CAD is still the leading cause of death worldwide • Cardiovascular morbidity and mortality rates rise rapidly past 75 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, postprocedural renal 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% of those > 84yo • However things are improving: a Canadian study of 30,000 pts 80yo 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 improves survival 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

Aortic Stenosis Natural History

• 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?

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

Thank You !

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 upon the pt’s wishes as well as their frailty and co morbidities

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

Objectives

• I do not have an affiliation (financial or otherwise) with a pharmaceutical, medical device or a communication company)

1. To distinguish between normal/benign abnormalities and their important mimickers

• I cannot identify any conflict of interest

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

ECG Case 1

Where is the ECG abnormality?

• 61 Lawyer with treated hypertension • Four weeks ago, developed new onset chest pains with regular exertion which has now resolved • Family MD referred for consultation and GXT regarding chest pain

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

Wellen’s

• 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.

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

Stress test ‐ Case 3

How to work up VPB’s • Ensure no syncope or family history of sudden death • 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

Case 1: Ben

• 67 year‐old cyclist • Exertional chest pressure and dyspnea

Low sensitivity of exercise ECG: false negatives Sensitivity

Men Women

Specificity

65%

85%

LR- 0.65

LR+ 3.0

61%

70%

LR-0.56

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.

Low sensitivity of exercise ECG: false negatives 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.

GXT Case 3 – Take Home Message • 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

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

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

– Stress MPI – CT coronary angiography – Conventional angiography

Anna

Stress perfusion imaging ‐ Case 4 • Test report: Discordant study • Exercise ECG: Chest pain POSITIVE and ECG POSITIVE • Myocardial perfusion: No ischemia or infarction • LV function: Normal LVEF

Discordant Perfusion Testing • The good ‐ Normal perfusion usually portends a good prognosis even when abnormal exercise ECG (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

Case 4 – Take home message • 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

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

Echo ‐ Case 5 • 34M with a murmur – Father had aortic dissection – Echo • Mild aortic 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.

• • • • • • •

Aortic sclerosis MAC Borderline/mild mitral valve prolapse Mild/Septal hypertrophy Mobile/aneurysmal inter‐atrial septum Trivial/mild pulmonary regurgitation Trivial/mild tricuspid regurgitation

Summary • Septal T inversions can run the gamut from life threatening (CAD/PE) to normal variants • Frequent VPB’s are concerning if they portend VT (syncope, FHX SD, abnormal echos, VT on GXT) 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

2015 CONTINUING MEDICAL EDUCATION ANNUAL CURRICULUM

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