Cardiology Review (One Hour or its Free!) Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Bruyere FHT, Ottawa, ON Dept of Family Medicie, Univ of Ottawa.

Cardiology Review(One Hour or its Free!)

Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Bruyere FHT, Ottawa, ONDept of Family Medicie, Univ of Ottawa

Jan 2015

Objectives

• Review treatment options for common issues in cardiology, including:– Hypertension (HTN)– Dyslipidemia – Coronary Artery Disease (CAD)

• Acute coronary syndromes (ACS)– Heart failure (CHF)– Stroke (cerebrovascular accident)(CVA)– Chronic kidney disease (CKD)– Peripheral vascular disease (PVD)

• Rationalize choices of pharmacotherapy in cardiology

Vascular disease

Hypertension

CAD / ACS

CHF

PVD

CKD

CVA

Rational Prescribing Needs a Process to Provide Structure

• First, lay out your options: – Drug A– Drug B– Drug C– Non-drug options D, E, & F– No treatment

• (Always an option!)

Rational Prescribing Needs a Process to Provide Structure

1. Efficacy

2. Toxicity

3. Cost

4. Convenience

1. What’s good is it?

2. What’s the catch?

3. How much is this going to cost me?

4. How much work is this going to be?

1. Efficacy

• If there is no efficacy, why waste your time on the potential toxicity, cost and inconvenience of a drug?

• If there is proven efficacy at the population level, then balance this against the potential toxicity to the individual.• N.B. If there is poor evidence for efficacy,

remember: DO NO HARM.

2. Toxicity – Ask About…

Bothersome Severe

Common Not legal

Rare Who cares

2. Toxicity

• N.B. RCTs are usually powered to show differences in efficacy, not always toxicity. – Efficacy endpoint: ~ 1 in 5000 – Toxicity endpoint: ~ 1 in 20,000

• So, might need > 4 RCTs to see statistical signals of toxicity after a drug reaches market.

• Age is important: • Newer agents = Less Safety Data• Older agents = More Safety Data

3. Cost – Ask About…

• Patient cost vs Societal cost

• Covered by provincial drug plan? – By private plans?

4. Convenience – Ask About…

• What is the likelihood of compliance?1. Frequency of administration?

– Daily vs QID?

2. Special restrictions? – PO vs IV? – Home vs Office vs Hospital therapy?

3. Many interactions?4. Special monitoring requirements?

HYPERTENSION

Essential HypertensionA A B C D

ACEinh ARB(B-bl) beta-

blockersDHP-CCB

(dihydropyridine) Thiazide Diuretic

"-pril" "-sartan" "-olol" "-dipine"  

enalapril valsartan bisoprolol nifedipine hydrochlorothiazidelisinopril irbesartan metoprolol amlodipine chlorthalidoneramipril candesartan propranolol felodipine indapamide

Blocks conversion of AT1 to ATII (ACEinh) or blocks ATII receptors

(ARB) = Inhibition of vasoconstriction,

aldosterone, catecholamine, and arginine vasopressin release, water intake, and hypertrophic responses

Reduces sympathetic

outflow & heart rate & renal

AT2 production

Relaxes peripheral

smooth muscle

Reduction in systemic vascular

resistance (not diuresis)

1st line 1st line1st line (if < 60y.o.)

1st line 1st line

Essential HypertensionEfficacy 1st line 1st line 1st line

(< 60yo)1st line 1st line

Hypotension Hypotension Hypotension Hypotension Hypotension

hyperK+ hyperK+ Bradycardia Orthostatic hypotension hypoK+, hypoNa+

Acute renal failure (ARF)

ARF

Bronchoconstriction in brittle asthmatics

(esp high dose, esp non-cardio-

selective)

Edema ARF

Monitor BP, SCr, K+ BP, SCr, K+ BP, HR, RR BP, OH, edema BP, SCr, K+, Na+

Cost

cheap, generic (except Coversyl

& Mavik), ODB covered

still expensive, new generics, ODB covered

Cheap & generic,

ODB covered

expensive, generics,

ODB covered

VERY cheap, generic,

ODB covered

Convenience(eg.)

QD Ramipril

2.5mg - 10mg

QD Losartan

25mg - 100mg

QDBisoprolol

2.5mg - 10mg

QDAmlodipine

2.5mg - 10mg

QAMChlorthalidone

25mg

Toxicity

A (ACEinh) A (ARB) B C D

Choosing Therapy• If efficacy (#1), cost (#3) and convenience (#4) are all

more or less equivalent:– Choose based on potential Toxicities (#2)– Tailor the meds to the individual patient!

• Efficacy is population based• Toxicities are individual.

• Additive versus synergistic in BP lowering– Can choose between groups A or B plus C or D

(synergistic)– But, rarely clinically relevant

• N.B. Choice will also be guided by various comorbidites

Hypertension with ComorbiditiesA (ACEinh) A (ARB) B C D

HTN

MI

CHF

DM2

CVA

PVD

Angina

        (ALLHAT)

(HOPE) (VALIANT) (CAPRICORN, BHAT)    

(CONSENSUS, SOLVD, ATLAS)

(MERIT-HF, CIBIS II,

COPERNICUS)   

(HOPE) (IDNT, IRMA-2, RENAAL)      

(HOPE, PROGRESS)

(LIFE, SCOPE, MOSES)     (ALLHAT,

PROGRESS)

(HOPE)      

Second Line Therapy

• What if you have used all available 1st line options?

• 2nd line options: – Alpha blockers– Spironolactone– Hydralazine– Nitrates – Clonidine– Beta-blockers (> 60 y.o.)– etc.

• ~ Equivalent efficacy – choose based on potential toxicity, cost or convenience factors.

• Ensure that you balance these factors in their order of importance.

Second Line Therapy• Alpha blockers

– Eg. Terazosin, Prazosin, Doxazosin– Toxicity: Risk of orthostatic

hypotension– Cost: cheap, generic– Convenience: only QD

• Good 1st choice of 2nd line tx • Dual treatment of BPH & BP if also

needed in male patients

• Spironolactone – Efficacy: mortality benefit in late

stage CHF (NYHA class III or IV)

– Toxicity: risk of hyperK+ • esp with ARBs or ACEinh’s

– Cost: cheap generic– Convenience: only QD

• Hydralazine– MOA: direct vasodilation of

arteries– Toxicity: orthostatic hypotension– Cost: cheap, generic– Convenience: QID dosing

• Nitrates– eg. ISDN, ISMN, NTG– MOA: smooth muscle

vasodilation of vasculature (veins > arteries);

– Toxicity: headache, orthostatic hypotension, dizziness

– Cost: cheap/ generic– Convenience: BID- QID dosing;

Process

1. Start first drug2. Increase to moderate

dose3. Monitor for efficacy

(BP) and toxicity• If close to target:

– increase dose

• If far from target: – start new drug

• Dose response curves– Flatten at top half– Less bang for your buck

mg

BP

Questions?

DYSLIPIDEMIA

Dyslipidemia

• Never forget your 4 Steps of Rational Prescribing!

It will save you a LOT of time.

Dyslipidemia Options

• Statins• Fibrates• Niacin• Ezetimibe• Cholestyramine

1. Efficacy: 1. Mortality Benefit

• (reduction in mortality)

2. Morbidity Benefit• (reduction in non-fatal

MI, CVA, hospitalizations etc)

3. Reduction in Surrogate Markers

• Eg. LDL

Bottom Line: Statins.Only(*) statins have clear reduction in mortality.

• High Risk Framingham patients:– Primary prevention – morbidity reduction– Secondary prevention – mortality reduction

• Moderate Risk Framingham patients:– Tiny absolute risk reduction– Not usually clinically relevant

(*) Some evidence with Gemfibrozil (VA-HIT, HHS trials) but ++ GI side effects

The End.

Exceptions• Gemfibrozil

– Two trials that show reduction in CVD events• Helsinki Heart Study (HHS)• Veterans Administration HDL Intervention Trial (VA-HIT)

– Performed before widespread adoption of ACEinh, statins, etc– Never combine it with statins

• Serious risk of rhabdomyolysis

• N.B. Fenofibrate– No effect on CVD events

• Fibrates for high TGs – risk of pancreatitis– ?inferior to statins in outcomes? – See: David Preiss, et al. Lipid-Modifying Therapies and Risk of Pancreatitis: A Meta-analysis. JAMA. 2012;308(8):804-811. (see:

http://jama.jamanetwork.com/article.aspx?articleid=1352090 )

• Fibrates for high TGs – treatment of gout risk factors

Why statins?

• Lipid lowering effectsvs• Pleiotrophic effects

– Plaque stabilizing– Anti-inflammatory– Improved endothelial cell function– Inhibition of thrombogenic response

Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694580/?tool=pubmed Accessed Apr 25/12.

Bottom Line• Being on any statin at any dose is the priority.• Being on the highest dose of statin that a

patient can tolerate is secondary.– Pushing the statin dose to levels that result in side

effects is just not worth it. Non-compliance will result.

– Doubling the statin dose only lowers LDL by 6%• The LDL target is just your guide

– A marker of the statin’s pleiotrophic effects

Questions?

CORONARY ARTERY DISEASE

&

Acute Coronary Syndrome (ACS)

CAD / ACS

• All on a spectrum of ischemic damage:

• Stable Angina• Unstable Angina• NSTEMI• STEMI

• Basic Principles:1. BP control2. Plaque

stabilization3. Clot prevention

CAD / ACS

1) BP controlMortality benefit with:– ACEinh or ARB

plus

– Beta-blocker

(see: HTN section)

2) Plaque ControlMortality benefit with:

– Statin

(see: Dyslipidemia section)

CAD / ACS 3) Clot PreventionAnti-Thrombotics – lots!

From: http://en.wikipedia.org/wiki/Direct_thrombin_inhibitor

AntiplateletsIndications

• Primary prevention ACS– ASA– Clopidogrel – Ticlopidine

• Primary prevention CVA– ASA– Clopidogrel – Ticlopidine

• Secondary prevention ACS– ASA– Clopidogrel– Ticlopidine

+– Prasugrel– Ticagrelor

• Secondary prevention CVA– ASA– Clopidogrel – Ticlopidine

+– ASA + Dipyridamole MR

Mechanisms of ActionASA

• Irreversible inh of COX-1– (thromboxane reduction)– Platelet lifespan: 7-10 days

Dipyridamole MR• inhibits the uptake of

adenosine & breakdown of cGMP

Ticagrelor• Reversible inhibition of

ADP platelet receptor subtype P2Y12

Thienopyridines• Clopidogrel & Ticlopidine

– Prodrugs activated by P450-2C19– N.B. 2% - 14% of population are

poor metabolizers

• Prasugrel– Prodrug activated by ester bond

hydrolysis

via:• Irreversible inhibition of

ADP platelet receptor subtype P2Y12

How to Choose?(if only there was a process…)

1. Efficacy2. Toxicity3. Cost4. Convenience

Primary Prevention – ACS & CVA

1) Efficacy (all ~ equivalent)– ASA (+/- evidence)

• 75mg = 325mg daily• “For older patients with risk

factors”• CHEST’12: >50yrs consider risk vs benefit • CCS’11: not recommended • AHA’10: if 10yr CAD risk ≥10% • USPSTF’09: men 45 79 yrs if low bleed risk‐• Diabetes: men≥45yr/women≥50yr; & ≥1 risk

factor (smoking,↑BP, ↑ lipids, history of young parenteral MI, albuminuria)

– Clopidogrel & Ticlopidine• Little direct evidence• Only for ASA allergic or

intolerant

2) Toxicity (bleeding ~ same)• ASA

– NNH 125; major bleeds (WHS trial)– Any GI bleed ~ 2.7% (severe 0.7%)– Dyspepsia ~ 5%

• Clopidogrel (C) & Ticlopidine (T)– Bleed:

• Any GI bleed 2% (severe 0.5%) (C)– Rash:

• 6% (C) / 12% (3% severe) (T)– TTP:

• >20/3 million (C) / >1/5000 (T)

– Neutropenia: • <1% (C) / 2.4% (T) !!

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

Primary Prevention – ACS & CVA

3) Cost– ASA

• Pennies! ($4/mo)• 81mg costs > 325mg

– Can cut 325mg in 1/4th

– Clopidogrel• ~ $40/mo

– Ticlopidine• ~ $39/mo

4) Convenience– ASA

• 75-325mg once daily – Clopidogrel

• 75mg once daily– Ticlopidine

• 250mg BID po• Requires regular

monitoring of CBC, LFTs

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2015

Bottom Line: 1o Prevention ACS & CVA• ASA.

– Most evidence, well tolerated, cheap cheap!, QD• Ongoing efficacy studies for primary prevention

– http://www.aspree.org/usa/aspree-content/aspirin/other-aspirin-studies.aspx

– Consider bleed risks, even with “baby” ASA (81mg)• RISK FACTORS FOR BLEEDING:

– Age >75 yrs, DM, elevated INR warfarin, female, ↓ hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt.

– Clopidogrel only if ASA allergic / severe intolerance– Ignore ticlopidine:

• Little evidence, serious toxicities, BID dosing plus regular blood work!

– No evidence for Aggrenox® in primary preventionFrom: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

Secondary Prevention – ACSEfficacy

Agent Monotherapy Combo w/ ASA

ASAExcellent evidence for

NSTEMI, STEMI, CABG, PCI (low NNTs)

--

Clopidogrel~ equivalent to ASA

(small absolute improvement per CAPRIE trial)

Clopidogrel + ASA > ASA x3-12 mo

(CURE trial) (ACS, PCI various durations)

Prasugrel untestedPrasugrel + ASA > Clop + ASA

(ACS + PCI) x12 mo (TRITON-TIMI 38 trial)

Ticagrelor untestedTicagrelor + ASA > Clop + ASA

(ACS + PCI +/- CABG) x12mo (PLATO trial)

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.

Secondary Prevention – ACSToxicity

Agent Monotherapy Combo w/ ASA

ASAw/ ASA: rate of hemorrhagic events = 5.58

(95% CI, 5.39-5.77) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, 3.48-3.72)

Incidence rate ratio: 1.55; (95% CI, 1.48-1.63)

--

Clopidogrel~ equivalent in absolute senseSlightly less GI bleed & GI events except diarrhea; More Rash

More major bleeding vs ASA alone

Prasugrel untestedMore fatal & life-threatening bleeds vs Clopid + ASA

Ticagrelor untested

More major & minor bleeds vs Clopid + ASAMore dyspnea & increased urate

Secondary Prevention – ACSToxicity

Agent Monotherapy Combo w/ ASA

ASAw/ ASA: rate of hemorrhagic events = 5.58 (95% CI,

5.39-5.77) / 1000 pt-yrs VS. w/o ASA: 3.60 (95% CI, 3.48-3.72)

Incidence rate ratio: 1.55; (95% CI, 1.48-1.63)

--

Clopidogrel

Less GI bleeding: Clopidogrel < ASA (1.99% vs 2.66% p < 0.002) (Less severe GI bleed - 0.49 vs 0.71%; p < 0.05)Less GI events - clopidogrel < ASA (27.1 vs 29.8%; p < 0.001) More Diarrhea clopidogrel > ASA (4.46 vs 3.36%; p < 0.001)More Rash – clopidogrel > ASA (6.0% vs 4.6% p < 0.001)No difference in: Early D/C, Neutropenia, Thrombocytopenia & Intracranial bleed. (per CAPRIE)

Major bleeding – clop + ASA > ASA (3.7% vs. 2.7%; RR = 1.38; P=0.001),

Life-threatening bleeding - no diff (2.1 percent vs. 1.8 percent, P=0.13) Hemorrhagic strokes – no diff (per CURE trial)

Prasugrel untestedMore fatal and life-threatening bleeds vs clopid + ASA

Ticagrelor untested

More major and minor bleeds vs clopid + ASAMore dyspnea, & incr UA

Secondary Prevention – ACS3) Cost

– ASA • Pennies! (only 325mg covered)

– Clopidogrel• ~ $40/mo• LU code for ACS

– Prasugrel• ~ $100/mo;covered w/ LU code

– Ticagrelor• ~ $108/mo; covered w/ LU code

4) Convenience– ASA

• 75-325mg once daily – Clopidogrel

• 75mg once daily– Prasugrel

• 10mg once daily– Tigagrelor

• 90mg BID

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2015

Bottom Line: 2o Prevention ACS

• ASA + Clopidogrel x 3- 12 mo, then ASA alone– Clopidogrel alone if ASA allergy– Prasugrel only in cardiac centres post ACS + PCI &

if no excess bleed risks

Always assess risk of clotting vs risk of bleeding!

Secondary Prevention – CVAEfficacy

Agent Monotherapy Combo w/ ASA

ASAASA ~23% RRR > placebo

NNT ~ 50-100 x1 year to prevent any vascular event. (50-325mg)

(CAST, IST, SALT, Dutch-TIA trials)

--

Ticlopidine Superior to ASA (CATS & TASS trials)

unknown

ClopidogrelEquivalent to ASA

(extremely small absolute improvement per CAPRIE trial)

Possible improvement for 1st 21 days post CVA (CHANCE

trial)No benefit long term

(CHARISMA, MATCH trials)

Aggrenox®Superior to ASA (ESPRIT & ESPS2

trials), but Equivalent to Clopidogrel (PRoFESS trial) whaaa…??

--

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.

Secondary Prevention – CVAToxicity

Agent Monotherapy Combo w/ ASA

ASA

Low, but look at additive bleeding risk factors: (Age >75 yrs, DM, elevated INR warfarin, female, ↓

hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g. anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke

noncardioembolic, ↑Scr, ↓ wt.)

--

Clopidogrel~ equivalent in absolute senseSlightly less GI bleed & GI events except diarrhea; More Rash

More bleeding vs ASA alone(CHARISMA & MATCH trials)

Aggrenox®

More headache, diarrhea, GI upset, dizziness, & early D/C vs ASA or

ClopidogrelMore intracranial bleed vs Clopidogrel

--

Secondary Prevention – CVA

3) Cost– ASA

• Pennies! ($4/mo)– Clopidogrel

• ~ $40/mo• LU code for ASA

intolerance only– Aggrenox®

• ~ $66/mo• LU code for CVA

4) Convenience– ASA

• 75-325mg once daily – Clopidogrel

• 75mg once daily– Aggrenox®

• 200/25mg BID po

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Jan 2015

Bottom Line 2o Prevention CVA

• ASA or Clopidogrel or Aggrenox®– Any will do, until tie breaker trial between these

agents. – Aggrenox® might be more efficacious, but with

more side effects and less convenience.

Summary – CAD / ACS

• N.B. Remember which modifiable risk factors need management– Remember which medications offer a mortality

benefit in treated those risk factors; Use them 1st!

• BP control with ACEinh (or ARB) + b-blocker• LDL control with statin• Clot prevention with ASA (+/- Clopidogrel)

Questions?

(CONGESTIVE) HEART FAILURE (CHF)

Heart Failure

• Several types: – Left vs Right sided– Systolic vs Diastolic– Preserved ejection

fraction vs not

• Basic Principles:1. BP control2. Plaque

stabilization3. Clot prevention

CHF – Systolic, Poor LVEF

1) BP controlMortality benefit with:– ACEinh or ARB

plus

– Beta-blocker

(see: HTN section)

2) Plaque ControlMortality benefit with:

– Statin

(see: Dyslipidemia section)

CHF – Systolic, Poor LVEF

3) Clot Prevention• Mortality Benefit with:

– ASA 81mg qd– If ASA allergic:

• Clopidogrel 75mg qd

(see: Primary prevention of ACS & CVA section)

• Other forms of CHF less well studied.

• Benefits of these interventions are not as clear– But offered anyway.– Pay closer attention to

benefit/risk ratio since benefit is smaller / unknown

CHF – other interventions• Spironolactone

– Mortality benefit in NYHA Class III & IV

– N.B. Increased harm in NYHA Class I or II• Risk of hyperK+ !

• Digoxin– Morbidity benefit– (See DIG trial, PROVED trial)

– Reduction in hospitalizations due to CHF• Not seen with preserved

ejection fraction

• Furosemide– Reduction in CHF

symptoms– No morbidity nor

mortality benefit.

Questions?

CKD & PVD

Chronic Kidney Disease (CKD)

• Vascular damage to renal beds– Is BP control required?

• If so, what is the best agent? • ACEinh or ARB first!

– Is prevention of atherosclerosis required?• If so, what is the best agent? • Statin at any dose tolerated

– Is CKD a vascular risk? • If so, are anti-platelets required? • ASA (low dose, every day)

Peripheral Vascular Disease (PVD)

• Vascular damage to peripheral beds– Is BP control required?

• If so, what is the best agent?

– Is prevention of atherosclerosis required?• If so, what is the best agent?

– Is PVD a vascular risk? • If so, are anti-platelets required?

(Same)

Overall Summary• Vascular problems throughout the body require similar

approaches to management. • Understanding the pathophysiology and pharmacology

of preferred agents will inform your therapeutics.– ACEinh

• Anti-inflammatory and modulation of RAAS– Statin

• Anti-inflammatory and other pleiotrophic effects– ASA

• Anti-inflammatory and anti-platelet– Beta-blocker

• (If cardiac involvement) – to reduce MVO2

Questions?