Transcript Cardiology Review: Pharmacotherapy in Cardiology

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
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
Hypertension
CVA
CAD / ACS
Vascular
disease
CKD
CHF
PVD
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
1. What’s good is it?
2. Toxicity
2. What’s the catch?
3. Cost
3. How much is this
going to cost me?
4. Convenience
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
Common
Rare
Severe
Not legal
Who cares
2. Toxicity
• Age is important:
• Newer agents =
• Older agents =
Less Safety Data
More Safety Data
• 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.
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 Hypertension
A
A
B
C
ACEinh
ARB
(B-bl) betablockers
DHP-CCB
(dihydropyridine)
"-pril"
"-sartan"
"-olol"
"-dipine"
enalapril
lisinopril
ramipril
valsartan
irbesartan
candesartan
bisoprolol
metoprolol
propranolol
nifedipine
amlodipine
felodipine
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
1st line
1st line
D
Thiazide Diuretic
hydrochlorothiazide
chlorthalidone
indapamide
Reduces
Reduction in
sympathetic
Relaxes
systemic vascular
outflow & heart
peripheral
resistance (not
rate & renal smooth muscle
diuresis)
AT2 production
1st line
(if < 60y.o.)
1st line
1st line
Essential Hypertension
Efficacy
Toxicity
Monitor
Cost
Convenience
(eg.)
A (ACEinh)
A (ARB)
B
C
D
1st line
1st line
1st line
1st line
1st line
Hypotension
Hypotension
hyperK+
hyperK+
(< 60yo)
Hypotension Hypotension
Hypotension
Orthostatic
Bradycardia
hypoK+, hypoNa+
hypotension
Acute renal
failure
(ARF)
ARF
Bronchoconstric
tion in brittle
asthmatics
(esp high dose,
esp non-cardioselective)
BP, SCr, K+
BP, SCr, K+
BP, HR, RR
Edema
ARF
BP, OH,
edema
BP, SCr, K+, Na+
cheap, generic
still expensive,
Cheap &
expensive,
(except Coversyl
new generics,
generic,
generics,
& Mavik),
ODB covered ODB covered ODB covered
ODB covered
QD
Ramipril
2.5mg - 10mg
QD
Losartan
25mg - 100mg
QD
Bisoprolol
2.5mg - 10mg
QD
Amlodipine
2.5mg - 10mg
VERY cheap,
generic,
ODB covered
QAM
Chlorthalidone
25mg
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 Comorbidities
A (ACEinh)
A (ARB)
B
D
(ALLHAT)
HTN
MI
(HOPE)
CHF
(CONSENSUS,
SOLVD, ATLAS)
DM2
(HOPE)
(IDNT, IRMA-2,
RENAAL)
CVA
(HOPE,
PROGRESS)
(LIFE, SCOPE,
MOSES)
PVD
(HOPE)
Angina
C
(VALIANT)
(CAPRICORN,
BHAT)
(MERIT-HF,
CIBIS II,
COPERNICUS)
(ALLHAT,
PROGRESS)
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 drug
2. Increase to moderate
dose
3. Monitor for efficacy
(BP) and toxicity
• If close to target:
• Dose response curves
– Flatten at top half
– Less bang for your buck
BP
– increase dose
• If far from target:
– start new drug
mg
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 effects
vs
• 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 control
2. Plaque
stabilization
3. Clot prevention
CAD / ACS
1) BP control
Mortality benefit with:
– ACEinh or ARB
2) Plaque Control
Mortality benefit with:
– Statin
plus
– Beta-blocker
(see: HTN section)
(see: Dyslipidemia section)
CAD / ACS 3) Clot Prevention
Anti-Thrombotics – lots!
From: http://en.wikipedia.org/wiki/Direct_thrombin_inhibitor
Antiplatelets
Indications
• Primary prevention ACS
• Primary prevention CVA
– ASA
– Clopidogrel
– Ticlopidine
– ASA
– Clopidogrel
– Ticlopidine
• Secondary prevention ACS • Secondary prevention CVA
– ASA
– Clopidogrel
– Ticlopidine
+
– ASA
– Clopidogrel
– Ticlopidine
+
– Prasugrel
– Ticagrelor
– ASA + Dipyridamole MR
Mechanisms of Action
ASA
• 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.
2.
3.
4.
Efficacy
Toxicity
Cost
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)
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)
– Clopidogrel & Ticlopidine
• Little direct evidence
• Only for ASA allergic or
intolerant
– 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
4) Convenience
– ASA
– ASA
• Pennies! ($4/mo)
• 81mg costs > 325mg
– Can cut 325mg in
1/4th
– Clopidogrel
• ~ $40/mo
– Ticlopidine
• ~ $39/mo
• 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 prevention
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
Secondary Prevention – ACS
Efficacy
Agent
Monotherapy
Combo w/ ASA
ASA
Excellent evidence for
NSTEMI, STEMI, CABG,
PCI (low NNTs)
--
Clopidogrel
~ equivalent to ASA
(small absolute improvement
per CAPRIE trial)
Clopidogrel + ASA > ASA
x3-12 mo
Prasugrel
untested
(CURE trial) (ACS, PCI various durations)
Prasugrel + ASA > Clop + ASA
(ACS + PCI) x12 mo
(TRITON-TIMI 38 trial)
Ticagrelor
Ticagrelor + ASA > Clop + ASA
untested
(ACS + PCI +/- CABG) x12mo
(PLATO trial)
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13
From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.
Secondary Prevention – ACS
Toxicity
Agent
Monotherapy
Combo w/ ASA
ASA
w/ 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 sense
Slightly less GI bleed & GI events except
diarrhea; More Rash
Prasugrel
Ticagrelor
More major
bleeding vs ASA
alone
untested
More fatal & lifethreatening bleeds
vs Clopid + ASA
untested
More major & minor
bleeds vs Clopid +
ASA
More dyspnea &
increased urate
Secondary Prevention – ACS
Toxicity
Agent
ASA
Clopidogrel
Prasugrel
Ticagrelor
Monotherapy
Combo w/ ASA
w/ 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)
--
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 <
Major bleeding – clop + ASA >
ASA (3.7% vs. 2.7%; RR = 1.38;
0.001)
Life-threatening bleeding - no
diff
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)
P=0.001),
(2.1 percent vs. 1.8 percent, P=0.13)
Hemorrhagic strokes – no diff
(per CURE trial)
untested
More fatal and lifethreatening bleeds vs
clopid + ASA
untested
More major and minor
bleeds vs clopid + ASA
More dyspnea, & incr
UA
Secondary Prevention – ACS
3) Cost
– ASA
• Pennies! (only 325mg
covered)
– Clopidogrel
• ~ $40/mo
• LU code for ACS
– Prasugrel
• ~ $100/mo;covered w/ LU code
– Ticagrelor
4) Convenience
– ASA
• 75-325mg once daily
– Clopidogrel
• 75mg once daily
– Prasugrel
• 10mg once daily
– Tigagrelor
• 90mg BID
• ~ $108/mo; covered w/ LU code
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 – CVA
Efficacy
Agent
ASA
Monotherapy
Combo w/ ASA
ASA ~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)
Equivalent to ASA
Clopidogrel
Aggrenox®
(extremely small absolute improvement per
CAPRIE trial)
unknown
Possible improvement for 1st
21 days post CVA (CHANCE
trial)
No benefit long term
(CHARISMA, MATCH trials)
Superior to ASA (ESPRIT & ESPS2
trials), but Equivalent to Clopidogrel
(PRoFESS trial) whaaa…??
From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013
From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13
From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.
--
Secondary Prevention – CVA
Toxicity
Agent
Monotherapy
Combo w/ ASA
Low, but look at additive bleeding risk factors:
(Age >75 yrs, DM, elevated INR warfarin, female, ↓
ASA
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 sense
Slightly less GI bleed & GI events except
diarrhea; More Rash
Aggrenox®
More headache, diarrhea, GI upset,
dizziness, & early D/C vs ASA or
Clopidogrel
More intracranial bleed vs Clopidogrel
-More bleeding vs
ASA alone
(CHARISMA &
MATCH trials)
--
Secondary Prevention – CVA
3) Cost
– ASA
• Pennies! ($4/mo)
– Clopidogrel
• ~ $40/mo
• LU code for ASA
intolerance only
4) Convenience
– ASA
• 75-325mg once daily
– Clopidogrel
• 75mg once daily
– Aggrenox®
• 200/25mg BID po
– Aggrenox®
• ~ $66/mo
• LU code for CVA
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 control
2. Plaque
stabilization
3. Clot prevention
CHF – Systolic, Poor LVEF
1) BP control
Mortality benefit with:
– ACEinh or ARB
2) Plaque Control
Mortality benefit with:
– Statin
plus
– Beta-blocker
(see: HTN section)
(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?