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12/5/2013
Heart Failure Medication
Titration Protocols
Fadwa F. Al-Khuraisi, Bsc.Pharm, SCSCP
Clinical Pharmacist ,Prince Sultan Cardiac Center
Dec, 2013
Objectives
• Introduction
• Heart failure medication titration
protocols
• Heart Failure Medication Titration
Problem Solving
• PSCC heart failure clinic data
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Activation of the SNS;
Release of
catecholamines
Contractility
HR
Activation of Renin
angiotensin aldosterone
system
Antidiuretic hormone
circulatory
volume
Renal
perfusion
Vasoconstriction
+ = preload, SV, CO
Renin release
+ = Preload
- = After load
- = pulmonary
edema
Angiotensin II
- = cardiac oxygen demand
and work, co
- = cell death/ apoptosis
Aldosterone
level
Adaptive mechanisms in systolic heart failure
PHARMACOTHERAPY OF HEART FAILURE
Heart failure
Inotropic agents, Digoxin
X
Reduced cardiac
output
X Digoxin
Beta blockers
Renin
Sympathetic nervous
system activation
X
Angiotensin I
Vasodilators
X
ACEIs X
X
Vasoconstriction
Angiotensin II
X ARBs
X
Spironolactone
X
Aldosterone
Elevated cardiac filling
pressures
ARBs
X
Sodium and water
retention
X
Diuretics
Cardiac
Remodeling
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Stages, Phenotypes and Treatment of HF
At Risk for Heart Failure
Heart Failure
STAGE A
STAGE B
STAGE C
At high risk for HF but
without structural heart
disease or symptoms of HF
Structural heart disease
but without signs or
symptoms of HF
Structural heart disease
with prior or current
symptoms of HF
e.g., Patients with:
· HTN
· Atherosclerotic disease
· DM
· Obesity
· Metabolic syndrome
or
Patients
· Using cardiotoxins
· With family history of
cardiomyopathy
Structural heart
disease
THERAPY
e.g., Patients with:
· Previous MI
· LV remodeling including
LVH and low EF
· Asymptomatic valvular
disease
THERAPY
Goals
· Heart healthy lifestyle
· Prevent vascular,
coronary disease
· Prevent LV structural
abnormalities
Goals
· Prevent HF symptoms
· Prevent further cardiac
Drugs
· ACEI or ARB in
appropriate patients for
vascular disease or DM
· Statins as appropriate
appropriate
· Beta blockers as
appropriate
remodeling
Drugs
· ACEI or ARB as
In selected patients
· ICD
· Revascularization or
valvular surgery as
appropriate
ACC,AHA HF GUIDELINE 2013
Development of
symptoms of HF
STAGE D
Refractory HF
Refractory
symptoms of HF
at rest, despite
GDMT
e.g., Patients with:
· Known structural heart disease and
· HF signs and symptoms
HFpEF
HFrEF
THERAPY
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Prevent hospitalization
· Prevent mortality
Strategies
· Identification of comorbidities
Treatment
· Diuresis to relieve symptoms
of congestion
· Follow guideline driven
indications for comorbidities,
e.g., HTN, AF, CAD, DM
· Revascularization or valvular
surgery as appropriate
Goals
· Control symptoms
· Patient education
· Prevent hospitalization
· Prevent mortality
Drugs for routine use
· Diuretics for fluid retention
· ACEI or ARB
· Beta blockers
· Aldosterone antagonists
Drugs for use in selected patients
· Hydralazine/isosorbide dinitrate
· ACEI and ARB
· Digoxin
In selected patients
· CRT
· ICD
· Revascularization or valvular
surgery as appropriate
e.g., Patients with:
· Marked HF symptoms at
rest
· Recurrent hospitalizations
despite GDMT
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Reduce hospital
readmissions
· Establish patient’s endof-life goals
Options
· Advanced care
measures
· Heart transplant
· Chronic inotropes
· Temporary or permanent
MCS
· Experimental surgery or
drugs
· Palliative care and
hospice
· ICD deactivation
Pharmacologic Treatment for Stage C HFrEF
HFrEF Stage C
NYHA Class I – IV
Treatment:
Class I, LOE A
ACEI or ARB AND
Beta Blocker
For all volume overload,
NYHA class II-IV patients
For persistently symptomatic
African Americans,
NYHA class III-IV
For NYHA class II-IV patients.
Provided estimated creatinine
>30 mL/min and K+ <5.0 mEq/dL
Add
Add
Add
Class I, LOE C
Loop Diuretics
Class I, LOE A
Hydral-Nitrates
Class I, LOE A
Aldosterone
Antagonist
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Pharmacological Therapy for Management
of Stage C HFrEF
Recommendations
COR
LOE
I
C
I
A
I
A
IIa
A
IIb
A
III: Harm
C
Diuretics
Diuretics are recommended in patients with HFrEF with fluid retention
ACE Inhibitors
ACE inhibitors are recommended for all patients with HFrEF
ARBs
ARBs are recommended in patients with HFrEF who are ACE inhibitor
intolerant
ARBs are reasonable as alternatives to ACE inhibitor as first line therapy
in HFrEF
The addition of an ARB may be considered in persistently symptomatic
patients with HFrEF on GDMT
Routine combined use of an ACE inhibitor, ARB, and aldosterone
antagonist is potentially harmful
Pharmacological Therapy for Management of Stage C
HFrEF
Recommendations
COR
LOE
I
A
I
A
I
B
III: Harm
B
I
A
IIa
B
IIa
B
Beta Blockers
Use of 1 of the 3 beta blockers proven to reduce mortality is
recommended for all stable patients
Aldosterone Antagonists
Aldosterone receptor antagonists are recommended in patients with
NYHA class II-IV HF who have LVEF ≤35%
Aldosterone receptor antagonists are recommended in patients
following an acute MI who have LVEF ≤40% with symptoms of HF or DM
Inappropriate use of aldosterone receptor antagonists may be harmful
Hydralazine and Isosorbide Dinitrate
The combination of hydralazine and isosorbide dinitrate is recommended
for African-Americans, with NYHA class III–IV HFrEF on GDMT
A combination of hydralazine and isosorbide dinitrate can be useful in
patients with HFrEF who cannot be given ACE inhibitors or ARBs
Digoxin
Digoxin can be beneficial in patients with HFrEF
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Heart Failure Medication
Titration
• Heart failure (HF) guidelines recommend
timely titration of beta blockers , ACEIs and
other heart failure medications to doses
shown to be effective in clinical trials.
• Doses are often not optimized in clinical
practice because of difficulty in organizing
frequent clinic visits and greater risk of side
effects
Assessment of Treatment with
Lisinopril and Survival Trial (ATLAS)
• Lisinopril given to 3164 patients (NYHA II-IV) EF
< 30%
• lisinopril 2.5 to 5 mg was given for 2 weeks then
12.5 to 15 mg for an additional 2 weeks .
• If the initial doses were tolerated, subjects were
randomly assigned to daily therapy with
lisinopril 2.5 to 5 mg (low dose) or 32.5 to 35 mg
(high dose)
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Kaplan-Meier analysis showing time to death in the
low-dose and high-dose lisinopril groups.
All cause of mortality did not differ
significantly between the two groups (8%
lower in the highest dose group compared
with the lowest dose ; p=0.128)
Packer M et al. Circulation 1999;100:2312-2318
Kaplan-Meier analysis showing time to death or
hospitalization for any reason in the low-dose and
high-dose groups.
In high dose group ,hospitalization and the
combined end point of death and
hospitalization were reduced by 24%
(p=0.003) and 12% (p=0.002), respectively.
The higher dose was tolerated by 90% of
assigned patients
Packer M et al. Circulation 1999;100:2312-2318
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Heart Failure Clinic Role
• The goals for a heart failure clinic must be
– Verify diagnosis,
– Optimize medication,
– and provide comprehensive and intensive
medical education and counseling in
patients.
– increased safety and self-confidence in our
patients, creating highly motivated patients
with high compliance, increased quality of
life , and less need for hospitalization ,
leading to reduce cost for the heart failure
care
Clinical Pharmacist Role
•
•
•
•
•
•
•
Medication histories
Medication review
Assess the patient compliance
Optimizing dosing of key medications
Test and investigations
Tailoring therapy
Close monitoring of response to drug
therapy
• Dealing with adverse effects
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Heart Failure Score
Symptoms / sign
Value
Orthopnea
Score
0.5
PND
1
Reduction in exercise tolerance
0.5
Resting tachycardia > 100
0.5
JVP> 4 cm
0.5
HJR Positive
1
S3 present
1
Basal crackles
1
Hepatomegaly
0.5
Peripheral edema
0.5
Total
Patient status at the time of clinical review will be recorded in the form of a
“heart failure score ” . Derived by assigning a value to defined series of clinical
variables based on Framingham data for diagnosis of heart failure
Heart failure score <2
Initial visit
Beta Blocker, ACEIs and
diuretics
• Step 1: optimization of ACEIs doses
•
•
•
Patients do not need to be taking high doses
of ACE inhibitors before being considered for
Step
2: introduced
beta-blockers, for
treatment
with Beta Blocker.
The addition
of Beta
Blocker to patient
s
those
already
on beta-blocker,
the
taking
low
dose
ACEIs
produces
a
greater
dose will be titrated at 2 weekly
reduction in symptoms and in the risk of
intervals towards maximum goal
death than an increase in the dose of an ACEIs
based doses
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Heart failure score ≥ 2
Step 1: increase furosemide to 120 mg
/day or optimization of ACEIs
Step 2: add spironolactone (up to 50
mg/day) in patients with persistent class III
or IV symptoms
Step 3: addition of digoxin 0.25 mg/day
Step 4: increase furosemide with twice
daily doses up to maximum of 500 mg
twice daily with doubling the increments
Heart failure
score < 2 :
Titration of
beta blockade
Step 5: addition of Metolazone
Heart Failure Patients
Management Follow Up
• Patients intensified therapy will be
reviewed in approximately 2 weeks
with clinical assessment and
measurement of:
– ProBNP
– Plasma electrolytes and creatinine
– Postural hypotension, heart rate
– Intolerance of medication
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Heart Failure Patients
Management Follow Up
The over all aim is to:
– Establish a stable clinical status with a
heart failure score<2
– and maximum goal based doses of
ACEIs or ARBs and beta-blockers.
Medical Therapy for Stage C HFrEF:
Magnitude of Benefit Demonstrated in
RCTs
GDMT
ACE inhibitor or ARB
NNT for
Mortality
RR
Reduction in
Reduction
(Standardized
Mortality
to 36 mo)
RR Reduction
in HF
Hospitalizations
17%
26
31%
34%
9
41%
Aldosterone
antagonist
30%
6
35%
Hydralazine/nitrate
43%
7
33%
Beta blocker
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Should an Aldosterone
Antagonist Be the Next Step
After ACE Inhibitor + -Blocker?
Aldosterone
Antagonist
Angiotensin
Receptor Blocker
Effect on mortality
15%-30%
5%-10%
Effect on risk of death
or CHF hospitalization
15%-30%
10%-15%
Effect on blood
pressure
No change
Decrease
Renal
insufficiency
Hyperkalemia
Renal
insufficiency
Hyperkalemia
Other safety
Initiation strategies of ACEIs
Stop or
reduce dose Start low dose
of diuretics
ACEIs
for 24 hrs
those at higher risk of adverse events :
• higher doses of loop diuretics.
• severe heart failure or diabetes.
• Renal impairments
• Hypotension .
1 or 2 week
•
check BP
Double the ACEI dose until target
•
Renal function
dose achieved or not tolerated.
•
and k+ at baseline ,after
1-2 weeks, with any dose
increase and periodically
In acute HF, may increase dose more
rapidly e.g. q 1-2 days .
thereafter.
•
Expect some rise in BUN
,SCr and k+ .
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Drugs Commonly Used for HFrEF
(Stage C HF)
Initial Daily
Dose(s)
Drug
Maximum
Doses(s)
Mean Doses
Achieved in Clinical
Trials
ACE Inhibitors
Captopril
6.25 mg 3 times
122.7 mg/d (421)
Enalapril
16.6 mg/d (412)
Fosinopril
Lisinopril
Perindopril
Quinapril
Ramipril
Trandolapril
ARBs
Candesartan
Losartan
Valsartan
50 mg 3 times
10 to 20 mg
2.5 mg twice
twice
5 to 10 mg once
40 mg once
20 to 40 mg
2.5 to 5 mg once
once
8 to 16 mg
2 mg once
once
5 mg twice
20 mg twice
1.25 to 2.5 mg
10 mg once
once
1 mg once
4 mg once
4 to 8 mg once
32 mg once
50 to 150 mg
25 to 50 mg once
once
20 to 40 mg twice 160 mg twice
--------32.5 to 35.0 mg/d
(444)
--------------------------------24 mg/d (419)
129 mg/d (420)
254 mg/d (109)
Side Effects of ACE inhibitors
• Angioedema:
– Although rare, can occur at any time when using
ACE inhibitors. Stop ACE inhibitor immediately
and seek specialist advice. Trial of an ARBs
,possible cross-sensitivity.
• Cough :
– Pulmonary oedema should be excluded as a
cause if cough.
– If cough, that is likely to be caused by the ACE
Inhibitor, it is not always necessary to
discontinue the drug.
– If the cough is troublesome or interferes with
sleep, consider substituting ACE inhibitor with
an ARBs.
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Initiation strategies of Beta
Blockers
Start with low doses
Initiate only if stable
HF and euvolemic
Initial worsening of HF , hypotension and
bradycardia occur with high doses of loop
diuretics and those with severe HF .
Initial co-administration of diuretic useful
in limiting BB induce fluid retention
•Monitor clinical status,
•BP sitting & standing
•HR at rest & after 1 minute of walking
may be useful to assess adequacy of Bblockade dose.
Increase by 50 - 100% q 2-4 weeks
Beta Blockers in Heart Flaiure
Drug
Beta Blockers
Bisoprolol
Carvedilol
Carvedilol CR
Metoprolol
succinate
extended release
(metoprolol
CR/XL)
Initial Daily
Dose(s)
Maximum
Doses(s)
Mean Doses Achieved in
Clinical Trials
1.25 mg once
3.125 mg twice
10 mg once
10 mg once
50 mg twice
80 mg once
8.6 mg/d (118)
37 mg/d (446)
---------
12.5 to 25 mg
once
200 mg once
159 mg/d (447)
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Beta Blockers titration problem
solving
Beta Blocker
Therapy
Hypotension
Temporarily reduce
vasodilators therapy
If hypotension persist
decrease BB dose
Fluid Retention
Temporarily increase
diuretic dose
If fluid retension persist
decrease BB dose
Bradycardia
Reduce bb dose to
the highest tolerated
dose
If bradycardia persist
discontinue BB
Beta Blockers in Heart Flaiure
Stopping/Holding Beta Blockers :
BB should not be stopped abruptly:
• Taper over 1-2 weeks.
• If exacerbation of HF, may continue with or
decrease BB dose by half if not responsive to
increasing diuretics dose.
• COPD is not a contraindication of
cardioselective Betablockers
.
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Diuretics in Heart Failure
Diuretics are used to control fluid overload but the goal is
to use the minimum effective dose :
•
By using the minimum effective diuretic dose, it is
more likely that symptomatic hypotension and
unacceptable increases in Cr with ACE-I or BB can be
avoided
•
Effective diuretic dose reduction is more often
achieved after ACEIs and BB reach target doses.
Diuretics in Heart failure
Usual Starting Dose
Maximum Total
Daily Dose
Duration
Frusemide
20-40 mg daily or BID
600 mg
6-8 hours
Bumetinide
0.5-1 mg daily or BID
10 mg
4-6 hours
Ethacrynic acid
25-50 mg daily or BID
400 mg
6-8 hours
2.5 mg daily
20 mg
12-24 hours
25 mg daily or BID
200 mg
6-12 hours
K+-depleting diuretics
Metalazone
Hydrochlorothiazide
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Aldosterone Antagonists in Heart Failure
•
Use in stage II-IV HF and EF <30%
•
Monitir K+:
• Q 4-wks x3 , then
• Q 12-wks x3, then
• Q 6 -monthly
• Stop the therapy if:
• Renal insufficiency serum creatinine > 2.5 mg/dL in men or >
2.0 mg/dL in women (or estimated glomerular filtration rate
<30 mL/min/1.73m2),
• Potassium above 5.0 mEq/L.
Drug
Initial Daily Dose(s)
Maximum
Doses(s)
Mean Doses
Achieved in
Clinical Trials
Aldosterone Antagonists
Spironolactone
Eplerenone
12.5 to 25 mg once
25 mg once
25 mg once or
twice
50 mg once
26 mg/d (424)
42.6 mg/d (445)
Direct-acting Vasodilators in
Heart Failure
•
•
•
Hydralazine and nitrates in combination are effective at
reducing afterload and preload with a mortality benefit
May have greater benefit in patients of African-American
descent
Beneficial Subsets for ACE-I intolerant patients
Drug
Initial Daily Dose(s)
Maximum Doses(s)
Hydralazine & Isosorbide Dinitrate
37.5 mg hydralazine/
Fixed dose
75 mg hydralazine/
20 mg isosorbide
combination
40 mg isosorbide
dinitrate 3 times
(423)
dinitrate 3 times daily
daily
Hydralazine and Hydralazine: 25 to 50 Hydralazine: 300 mg
isosorbide
mg, 3 or 4 times
daily in divided doses
dinitrate (448)
daily and isorsorbide
and isosorbide
dinitrate:
dinitrate 120 mg daily
20 to 30 mg
in divided doses
3 or 4 times daily
Mean Doses
Achieved in Clinical
Trials
~175 mg
hydralazine/90 mg
isosorbide dinitrate
daily
---------
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Digoxin in Heart Failure
Is useful as add-on therapy for HF symptoms
especially if EF<30% despite optimal dose of
ACEI & BB
•
Useful For symptom relief ,
•
Shortening hospital length of stay,
•
and increased exercise tolerance.
•
Useful in HF patients who also have atrial fibrillation.
Digoxin target level in HF:
Between 0.6-1.3 nmol/L.
Routine levels not recommended in HF
Heart Failure Medication Titration
Problem Solving
• Hypotension
• Worsening Renal Function
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Heart Failure Medication Titration Problem
Solving
Hypotension
Asymptomatic
low BP
Symptomatic
low BP
Doesn't require any change
in therapy
If no symptoms of
congestion ,reduce diuretic.
If dizzy, confusion or falls :
• Reassess CCBs, diuretics,
ISDN/hydralazine
• Consider separating the
dosing of ACEI and BB .
• Take ACEIs and BB with
food.
Worsening Renal Function
• A rise in SCr of ≤30% above baseline is acceptable .
• A potassium of ≤ 5.6 is acceptable .
• Assess for non-essential vasodilators and k+
supplements/diet/ retaining agents (e.g. ARBs,
spironolactone) .
• Should receive standard therapy with an ACE-I , ARB or
spironolactone.
• Use digoxin with extreme caution.
• Reduce the ACEI , ARBs and dose by half if necessary .
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Worsening Renal Function
•If Cr increases by > 30% :
• Evaluate the patient's volume status
• if volume depleted : Consider reducing \holding
diuretic before reducing ACEI, ARB,
spironolactone or BB.
• Referral to a nephrologist is encouraged when
there is kidney impairment as defined by a Cr
increase by > 30% and eGFR < 30 mL\min .
Drugs That Adversely Affect Clinical
Status of Heart Failure
• The ACC/AHA guidelines advise to avoid:
• NSAIDs can cause sodium retention and peripheral
vasoconstriction and can attenuate the efficacy and
enhance the toxicity of diuretics and ACEIs.
• Antiarrhythmic agents can have cardiodepressant
effects and may promote arrhythmia; only
amiodarone and dofetilide have been shown not to
adversely affect survival.
•
Calcium channel blockers (verapamil and diltiazem)
can worsen heart failure and may increase the risk of
cardiovascular events.
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Data from Prince Sultan Cardiac Center
Heart Failure Clinic, 2013
Data from PSCC Heart Failure
Clinic, 2013
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12/5/2013
Data from PSCC Heart Failure
Clinic, 2013
72 patients ages
30-60 years
13 Patients < 29
years old
15 Patients > 60
years old
Data from PSCC Heart Failure
Clinic, 2013
60% EF < 30 %
35% EF 30-40
%
5% EF > 40 %
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Data from PSCC Heart Failure
Clinic, 2013
Data from PSCC Heart Failure
Clinic, 2013
Serum Creatinine
<100 Mmol/L
>200Mmol/L
65%
101-150 Mmol/L
151-200 MMol/L
ESRD
NA
21%
4%
4%
3%
3%
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Data from PSCC Heart Failure
Clinic, 2013
ACEIor.ARBs.agent * Sr.Potassium Crosstabulation
Sr.Potassium
<4
4.1-5.4
>= 5.5
NA
Total
Fosinopril
1
7
0
1
9
Perindopril
11
27
0
1
39
Captopril
1
0
0
1
2
Enalapril
2
9
1
0
12
Valsartan
3
10
0
0
13
Candesartan
5
9
0
1
15
Irbesartan
1
0
0
0
1
NONE
4
2
3
0
9
Total
28
64
4
4
100
Data from PSCC Heart Failure
Clinic, 2013
ACEI / ARBs and serum Potassium
45
40
35
30
25
20
15
10
5
0
NA
>=>= 5.5
5.5
4.1- 4.5
4.1-5.4
< 4> 4
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Data from PSCC Heart Failure
Clinic, 2013
On Beta Blockers maximum doses
Yes
No
30%
24%
76%
22%
12%
8%
21%
1%
Bisorprolol
Metoprolol
TOTAL
Carvedilol
Data from PSCC Heart Failure
Clinic, 2013
On ACEI or ARBs maximum doses
No
2%
12%
12%
13%
Valsartan
Enalapril
Captopril
Perindopril
Fosinopril
1%
ACEIor.ARBs.agent
11%
1%
4%
72%
19%
Irbesartan
26%
9%
Candesartan
Yes
Total
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Data from PSCC Heart Failure
Clinic, 2013
Patients on Vasodilators
8%
Yes
No
92%
Data from PSCC Heart Failure
Clinic, 2013
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Data from PSCC Heart Failure
Clinic, 2013
Pt on BB plus ACEI or ARBs plus Aldactone
29%
Yes
29%
71%
No
71%
Conclusion
• The goals of therapy for all heart failure patients are
to:
–
–
–
–
Abolishing the symptoms,
Avoid complications, arrhythmia,
Improve quality of life ,
and prolong survival .
• Clinical trials evidence indicated a relationship
between the degree of reduction in HF symptoms
and the dose of drug given.
• Larger doses are more likely to improve the patients
quality of life and reduce the incidence of hospital
stay, but the impact of larger doses on mortality is
less clear.
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