Transcript 2014 HF Guidelines: Focus on Anemia, Biomarkers and Recent

CCS Heart Failure Guidelines: 2014
Update On New Therapies,
Biomarkers, Anemia Management,
And Complex Cases
October 2014
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Heart Failure Guidelines
Anemia in HF
Moe GW, Ezekowitz JA et al., Can J Cardiol
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Heart Failure Guidelines
How prevalent is anemia in heart failure?
• Rare?
• Occasional?
• Frequent?
It Depends:
-on the patient you are seeing (view next slide for range of anemia in patients)
-on oms criteria (hemoglobin levels-note difference between male vs female)
-characteristic of population; age, sex, race and degree of renal failure
-on NYHA class
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Anemia in patients with heart failure
Hb = hemoglobin
Hct = hematocrit
HF = heart failure
The prevalence of anemia in heart failure patients is approximately:
– 30% for Inpatients
– 20% for Outpatients
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The prevalence of anemia and the severity of
heart failure
70%
60%
56%
52%
60%
Patients
50%
44%
40%
40%
30%
19%
14%
8%
13%
6%
2%
29%
21%
20%
20%
10%
30%
29%
11%
12%
4%
2%
0%
I (n=158)
II (n=467)
III (n=340)
IV (n=25)
NYHA Class
Hb<10g/dL (n=32)
Hb<=11g/dL (n=97)
Hb<=11.5g/dL (n=165)
Hb<=12.0g/dL (n=244)
Hb<=12.5g/dL (n=337)
Source: STAMINA Registry – 45 General Cardiologist sites, n=673, 12 Academic sites (incl. HF Specialists), n=337
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Heart Failure Guidelines
What are the causes of anemia in HF
patients?
1.
2.
3.
4.
5.
Blood tests (too many)
Blood lost (anywhere in GI system)
Medications
CKD
Don’t know
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Figure 1 - Mechanism of the development
of anemia in heart failure
↓ Cardiac output
↓ Renal perfusion
Activation RAAS
Pro inflammatory Cytokines
CKD
Volume overload
ACEi / ARB
↓ EPO secretion
↓ Bone marrow (response)
Hemodilution
↓ Production
Anemia
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How important is anemia in your initial work
up of a patient with heart failure?
•
•
•
•
Limited
Moderate
Important
What?
Anemia is important because it has been
linked to the prognosis of patients with
HF: refer to following slides
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Anemia is associated with increased risk
for hospitalization in heart failure patients
Study
Design
Alexander1
Retrospective cohort
study of a population
based HF database
Polanczyk2
Prospective, single
center, observational
study
N
Anemia Risk Assessment
Limitations
90,316
Anemia was an independent risk factor
of 1-year rehospitalization (RR 1.162;
95% CI: 1.134 to 1.191)
no confirmation of the HF
diagnosis; undercounts of minorities
and biased results.
205
Anemia was an independent predictor
of 3-month rehospitalization (p=0.002)
Too small of a population to resolve
a small difference in readmission
rates; role of confounding variables
due to lack of control
906
Anemia was an independent predictor
of 60-day death or rehospitalization
(odds ratio of 0.89 per 1 g/dL increase
in hemoglobin; 95% CI: 0.82 to 0.97)
Anemia may have been caused by
hemodilution in hospitalized
patients
Lack of data on transfusions or
other treatments for anemia; study
generalizability to non-study
population
OPTIME-CHF3
Retrospective chart
review
Kosiborod4
Retrospective chart
review
2,281
Patients had 2% higher risk of 1-year
rehospitalization for every 1% lower
hematocrit (95% CI: 1.01 to 1.03;
p=0.0002)
COPERNICUS5
Randomized,
double blind,
placebo controlled
trial
2,286
Anemia was an independent risk factor
for 1-year morbidity (HF hospitalization)
and mortality outcomes
1Alexander
M, et al. Am Heart J. 1999;137:919-927
CA, et al. J Card Failure. 2001;7:289-298
3Felker GM, et al. Am J Cardiol. 2003;92:625-628
4Kosiborod M, et al. Am J Med. 2003;114:112-119
5Anker SD, et al. J Am Coll Cardiol. 2004;43(suppl A):Abstract 842-2
2Polanczyk
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-
Hemoglobin and mortality in heart failure
patients
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Hemoglobin and mortality
%
35
Hgb 11.3
30
All cause mortality
Hgb 12.8
25
Hgb 13.6
Hgb 15.7
20
Hgb 14.4
15
10
5
0
I
II
III
IV
V
Haemoglobin quintiles
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O’Meara et al. CHARM Investigators. Circulation 2006
What is the rationale for anemia correction?
Potential benefits and risks of treating anemia in HF:
Potential Benefits
• Improved oxygen delivery
• Improved exercise tolerance
• Attenuate adverse
remodeling
• Improved Quality of Life
• Antiapoptotic?
• Decrease in hosp./death?
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Potential Risks
• Increased thrombosis
• Platelet activation
• Hypertension
• Endothelial activation
Adapted from Felker and O’Connor J Am Coll Cardiol. 2004;44:959-966.
Randomized controlled trials play a critical role in
advancing patient care through guidelines
Clinical
Trials
Drug Discovery
Guidelines
Patient
Outcomes
Quality
Indicators
Caregiver
Performance
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Califf, R et al JACC 2002;40(11):1895-1901
Should I treat anemia in a patient with
heart failure?
1. Yes
2. No
3. Refer to
a)
b)
c)
d)
GP
GI
IM
Next cardiologist
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The decision to treat, not to
treat, or to refer the patient is
discussed in the 2014 Heart
Failure Guidelines.
Evidence to support treatment of anemia
Table 1 Randomized, controlled studies with intravenous iron in patients with heart failure
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van Veldhuisen, D. J. et al. (2011) Anemia and iron deficiency in heart failure:
mechanisms and therapeutic approaches
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2011.77
The FAIR-HF trial
Method
Study design: The FAIR-HF trial was a randomized, double-blind, multicenter
study.
Study population: A total of 495 patients were enrolled in this study.
Ambulatory patients who had chronic heart failure of NYHA class II or III, a
LVEF of 40–45% or less, a hemoglobin level between 95 and 135 g/L and iron
deficiency. Uncontrolled hypertension, other significant heart diseases and
inflammation were some of the excluding factors.
Treatment regimen: Ferric carboxymaltose or saline was administered to the
patients randomly as an intravenous bolus injection of 4 ml. Dosing was done
every week till repletion of iron was achieved and after that every 4 weeks as
maintenance therapy after 8th or 12th week of initiation of therapy.
End point: The primary end point was a self-reported Patient Global
Assessment (PGA) form and NYHA functional class in the 24th week. Safety
end points were serious and non-serious adverse effects, hospitalization and
death up to the 26th week of study.
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Noticed an improvement in intravenous iron, compared to placebo (note: scale is
between 30-35 metres). The 6-minute-walk test aims to improve exercise tolerance
and perception of symptomology.
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The administration of ferric carboxymaltose in patients with chronic heart failure
and iron deficiency with or without anemia was beneficial (seeing an improvement
in symptomology).
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The effect of intravenous iron
Figure 4 Effect of intravenous iron (ferric carboxymaltose) in patients with heart failure and iron
deficiency in various subgroups (including those with and without anemia). Seem to be responding to
improvement in iron storage.
Permission obtained from Massachusetts Medical Society © Anker, S. D. et al. Ferric carboxymaltose in patients with heart
failure and iron deficiency. N. Engl. J. Med. 361, 2436–2448 (2009)
van Veldhuisen, D. J. et al. (2011) Anemia and iron deficiency in heart failure:
mechanisms and therapeutic approaches
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2011.77
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Anemia recommendations
Recommendation
We suggest that for patients with documented iron deficiency, oral or
intravenous iron supplement be initiated to improve functional capacity (Weak
Recommendation, Low-Quality Evidence).
Values and Preferences:
The iron supplement recommendation was derived mostly from the experience
of clinicians, small clinical trials, and 2 large randomized controlled trials (RCTs).
Practical Tip: Symptomatic patients with low transferrin and/or ferritin levels
should be considered for supplementary iron therapy principally with a goal of
improving symptoms
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EPO therapy
Advantages of EPO Therapy
Disadvantages of EPO Therapy
1. Increase hemoglobin level
2. Increases peak O2 consumption
3. Improve functional class
4. Decreases ventricular
remodeling
5. Improve cardiac and renal
functions
6. Reduce diuretic dose
7. Reduce hospitalizations
8. Reduce mortality rate (small
study)
1. Increase hypertension
2. Increase thrombosis
3. Increase endothelin activation
4. Expensive
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RED-HF trial (Reduction of Events by
Darbepoetin Alfa in Heart Failure)
Available online at NEJM.org
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I was hoping
I’d be in the
active therapy
group.
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Well, I was
hoping I’d be
in the placebo
group.
RED-HF trial
Study Population
•Hemoglobin 9 to
12 g/dL
•LVEF ≤ 35%
•NYHA Class II to IV
Timelines
Darbepoetin alfa group (target hemoglobin 13.0 to 14.5 g/dL)
N = 1200
1:1 randomization
Placebo group
N = 1200
Follow-up
Site Evaluation &
Selection
Approximately 620 global sites
Began enrolling
June 2006
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Event driven: ~1150 events
Study End September 1 2012
KCCQ primary analysis:
Change from baseline to month 6
KCCQ Overall Summary Score
Mean Change From Baseline to Month 6
KCCQ Symptom Frequency Score
Mean Change From Baseline to Month 6
10
P = 0.005
9
8
6.68
7
6
5
4.48
4
3
2
1
0
Placebo
(n = 929)
Darbepoetin alfa
(n = 928)
2.46
95% CI: (0.90, 4.02)
Change from Baseline in KCCQ
Symptom Frequency Score
Change from Baseline in KCCQ
Overall Summary Score
2.20
95% CI: (0.65, 3.75)
10
P = 0.011
9
8
7
6.20
6
5
3.91
4
3
2
1
0
Placebo
(n = 927)
Darbepoetin alfa
(n = 925)
Mixed effects model estimating treatment effect adjusted for region, type of device, and baseline KCCQ score;
scale scores range from 0 to 100, with higher scores indicating better functioning.
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Data on file, Amgen.
Prop. of Subject With Event (%)
Primary outcome: All cause death or first
hospitalization for worsening heart failure
100
Placebo
Darbepoetin alfa
Stratified Log-rank, p = 0.87
80
60
40
20
0
0
1
Subjects at risk:
1142
956
1136
975
2
4
5
Years of Randomization
818
855
695
712
591
581
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497
473
395
385
290
281
211
212
154
161
92
101
Selected adverse events of interest
Darbepoetin alfa
(N = 1133)
n (%)
Ischaemic cerebrovascular
conditions
Embolic and thrombotic
events
Placebo Risk difference
(N = 1140)
(95% CI)
p-value
51 (4.5)
32 (2.8)
1.7 (0.2, 3.2)
0.031
153 (13.5)
114 (10.0)
3.5 (0.9, 6.1)
0.009
Hypertension
81 (7.1)
69 (6.1)
1.1 (-0.9, 3.1)
0.292
Malignancies
69 (6.1)
68 (6.0)
0.1 (-1.8, 2.1)
0.900
Hypersensitivity reactions
99 (8.7)
96 (8.4)
0.3 (-2.0, 2.6)
0.787
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EPO recommendation
Recommendation
We recommend erythropoiesis stimulating agents not be routinely used to treat
anemia in HF (Strong Recommendation, High-Quality Evidence).
Values and Preferences:
The recommendations against the use of erythropoiesis-stimulating agents
(ESAs) were derived from robust data from RCTs.
Practical Tip: Patients with severe chronic kidney disease and anemia should
be referred to a nephrologist to seek the optimal therapy for anemia.
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Conclusion
1. Identify anemia and potential causes; anemia is a
marker of the severity of the disease (HF)
2. Evaluate
3. Consider treatment options
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Biomarkers
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Optimal use of biomarkers
• Establishing diagnosis and selecting optimal therapy for any given
patient are current challenges, as costs associated with HF diagnostic
and therapeutic strategies continue to rise
• Biomarkers may help stratify risk and individualize therapy
• This update will review the role of circulating biomarkers for the
management of patients with HF with a focus on its role in the
monitoring for disease progression
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B-type natriuretic peptides
Increased myocardial wall stress due to volume or pressure overload
activates the B-type natriuretic peptide (BNP) gene in cardiac myocytes,
producing the intracellular precursor propeptide (proBNP).
Cleavage releases the biologically active BNP and biologically inert
amino-terminal fragment (NT-proBNP).
BNP stimulates natriuresis and vasodilation with consequent afterload
reduction, inhibits renin-angiotensin-aldosterone release and sympathetic
nervous activity, and reduces fibrosis.
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Diagnosis of heart failure
• A 74 y.o. lady presents to ER with increased shortness of breath on
exertion for 2 months, no chest pain
• Known for hypertension and diabetes but has never had angina or a
notion of coronary artery disease. No family history of CAD and
stopped smoking 15 years ago but smoked 30 cigarettes a day for 40
years
• Medications: Perindopril 4mg qd, Metformin 500mg bid, Calcium and
Vitamin D
• P/E: Pulse 82 bpm, BP 150/85mmHg, T 37.1, RR 16, JVP and
carotids normal, S4 but otherwise cardiac auscultation is normal, mild
bibasal crackles, unremarkable abdominal exam and no peripheral
oedema
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Optimal use of biomarkers
•
•
•
•
Chest X-Ray: COPD, no clear signs of HF
CBC normal
E+, BUN, creatinine: normal
High sensitivity troponin T: 21 µg/L (gives normal in your lab)
Do you believe BNP or NT-proBNP could help you make the proper
diagnosis?
A) I really do not see how
B) I know for sure what her diagnosis is
C) I would rather check procalcitonin, as this must be infectious
D) Yes, they could help me clarify whether or not this is HF
E) It’s really too expensive and does not really help
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Optimal use of biomarkers
• Her NT-proBNP levels: 1600 pg/mL
Recommendation
We recommend that B-type NP (BNP)/amino-terminal fragment of propeptide
BNP (NT-proBNP) levels be measured to help confirm or rule out a diagnosis of
HF in the acute or ambulatory care setting in patients in whom the clinical
diagnosis is in doubt (Strong Recommendation, High-Quality Evidence).
Values and Preferences:
These recommendations remain unchanged from previous CCS HF guidelines.
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Natriuretic peptides for HF diagnosis
Table 2. Natriuretic peptides cut points for the diagnosis of heart failure
Age (years)
HF is unlikely
HF is very likely
< 100 pg/ml
HF is possible but
other diagnoses
need to be
considered
100-500 pg/ml
BNP
All
NT-proBNP
< 50
< 300 pg/ml
300-450 pg/ml
> 450 pg/ml
50 - 75
< 300 pg/ml
450-900 pg/ml
> 900 pg/ml
> 75
< 300 pg/ml
900 - 1800 pg/ml
> 1800 pg/ml
HF, heart failure
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> 500 pg/ml
The troubling case of Mr. B
• Mr. B. is 70 y.o. and comes in your office in May 2012 for his follow-up
(q 4 months). He lives 7 hours from your hospital and is followed by his
GP and you, his cardiologist, for HF due to ischemic cardiomyopathy.
The last echo (4 months) showed and EF of 25%, severe functional
MR, Mild RV dysfunction, moderate to severe TR, PAPs 55mmHg
• He still smokes 10 cigarettes/day, has COPD, respects his water and
salt intake limits and takes his medications
• He has had prior myocardial infarctions and coronary bypasses in
2001, has no ischemia but a large scar on his nuclear scan done 4
months ago. His ICD was implanted in primary prevention in 2005, he
had a narrow QRS. He never had ICD therapies.
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The troubling case of Mr. B
• Current medications: ASA 80mg qd, Bisoprolol 10mg qd, Candesartan
16mg bid, Spironolactone 25mg qd, Furosemide 80mg bid
• Mr. B’s NYHA class often varies between 2 and 3. Today he reports
being more short of breath (definitely NYHA 3) for about 6 weeks but
he is stressed with financial and family issues. He seems depressed
and worried
• He did not cough more than usual and did not have fever
• On physical examination: well perfused, very thin, pulse 60 (NSR), BP
95/55mmHg (usual), JVP 12 (V wave nadir), S3+, holosystolic apical
murmur 3/6, clear lungs, mild peripheral oedema. ECG: SR, right
ventricular pacing
• His last labs were done with his GP 3 weeks ago and showed stable
Hb 125g/L and creatinine 120umol/L, K 4.0
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What would you do?
A) Increase furosemide to 120mg bid and send him back to his GP until
next time (4 months)
B) Ask for NP levels today at your hospital and then decide what to do
C) Add digitalis to his therapy
D) Refer him for Mitra-Clip evaluation
E) All of the above
Note: There is no HF clinic closer to where he lives and his GP seems him every
3-4 weeks
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What we did:
His NT-proBNP level was 7500 (prior was 3700) and his creatinine up to
142umoL/L. We did increase his diuretics but also reevaluated all potential
means of improving his outcome (was referred for Mitra-Clip evaluation).
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Recommendations
Recommendation
We recommend measurement of BNP/NT-proBNP levels be considered in
patients with an established diagnosis of HF for prognostic stratification (Strong
Recommendation, High-Quality Evidence).
We suggest, in ambulatory patients with HF due to systolic dysfunction,
measurement of BNP or NT-proBNP to guide management should be
considered to decrease HF-related hospitalizations and potentially reduce
mortality. The benefit is uncertain in individuals older than 75 years of age
(Weak Recommendation, Moderate-Quality Evidence).
Values and Preferences:
These recommendations are based on multiple small RCTs, most of which
demonstrated benefit, and 3 meta-analyses, which universally demonstrated
benefit. It is realized that there is still a large RCT ongoing that might modify the
conclusions.
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Evidence for NP-guided therapy
• In the available trials, 3 systematic reviews and meta-analyses (Figures)
synthesizing the RCT results, NP-guided therapy has been shown to
improve survival and reduce hospitalizations
• In these studies, NP-guided therapy had no benefits in 2 subgroups: age
>75 years and those with HFpEF
• Consequently, a larger multicenter trial of a single-target NP level (NTproBNP 1000 pg/ml) and the use of guideline-approved therapies in both
treatment arms is now underway, the Guiding Evidence Based Therapy
Using Biomarker Intensified Treatment (GUIDE-IT, NCT01685840)
• The ongoing single-centre EX-IMPROVE-CHF, NCT00601679) will also
help clarify the role of NP-guided therapy in HF management
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Effect of NP-guided management on
mortality: hazard ratios from meta-analysis
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Effect of NP-guided management on HF
hospitalizations: HRs from meta-analysis
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What’s a significant change in NP level?
• A change of 30% in NP level likely exceeds the day to day variation
and is in general considered relevant.
• For ambulatory patients with HF evaluated in the clinic, a NP level that
increases more than 30% should therefore call for more intensive follow
up and/or intensified medical treatments, even if they are not congested
clinically.
• The latter can include diuretic therapy or intensification of ACE
inhibitors, β-blockers and mineralocorticoid receptor antagonists if their
doses are not yet at the targets defined by clinical trials.
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Pre-discharge NP levels
• Besides predicting prognosis of patients in general, BNP level obtained
pre-discharge has been associated with mortality and rehospitalization.
• Indeed, predischarge NP in conjunction with change in NP has now
been incorporated into a risk score for death and readmission of HF in
patients admitted with HF.
Salah K, Kok WE, Eurlings LW et al. ELAN-HF Score. Heart 2014;100(2):115-125.
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Pre-discharge NP levels
Recommendation
We suggest that measurement of BNP or NT-proBNP in patients hospitalized for
HF should be considered before discharge, because of the prognostic value of
these biomarkers in predicting rehospitalization and mortality (Strong
Recommendation, Moderate-Quality Evidence).
Values and Preferences:
This recommendation is based on multiple small RCTs, all of which
demonstrated an association with clinical outcomes. Although the risk of
readmission is decreased with lower NP levels, clinicians should also consider
the limitations of delaying discharge from the hospital for this purpose.
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Preventing heart failure
• The preliminary results of STOP-HF and PONTIAC trials suggest that a
NP guided strategy for at-risk individuals may provide benefit in both
preventing and treating HF, leading to reductions in cardiac mortality
and hospitalizations.
• Asymptomatic individuals at high risk for the development of HF but
without established heart disease: Subjects with hypertension,
hypercholesterolemia, obesity, known vascular disease, diabetes,
arrhythmia requiring treatment, valvular abnormalities.
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Preventing heart failure
Practical Tip: We suggest that individuals with risk factors for the
development of HF, NP levels be used to implement strategies to prevent
HF. An increased level of NP of BNP > 100 pg/mL and NT-proBNP > 300
pg/mL, higher values than those used in the 2 trials discussed below to
avoid over screening, along with the presence of risk factors for HF, should
at least trigger more intensive follow up (See Prevention of HF in CJC
Published Article).
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Algorithm of the use of natriuretic peptides
Patient Population
Risk factors for
HF
Natriuretic Peptide Level
Actions
NT-proBNP > 300 g/mL
More frequent follow
up, consideration of
intensification of
existing therapy
BNP > 100 g/mL
Stable ambulatory
HF
> 30%  from clinic
baseline value
More frequent follow
up ± intensification
of HF therapy
Hospitalized for
HF and before
discharge
> 30%  from admission
value
Discharge if
relatively free from
congestion
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Other biomarkers ready for clinic?
Biomarkers
Pathophysiological
HF populations Advantages
targeted
pathways / comorbid
conditions with
prognostic implications
Potential benefits
Challenges before
implementation
NGAL
Renal Function
Acute HF
Early detection of renal
function deterioration
Adjusting therapy to improve
prognosis by avoiding acute
renal failure progression
Unclear if using NGAL in
acute HF to modify therapies
improves clinical outcomes
Cystatin C
Renal Function
Acute and chronic HF
More sensitive detection of
changes in renal function
Same as above
Unclear if using Cystatin C,
over using eGFR, to modify
clinical management provides
further clinical benefit
Cardiac hstroponins
Myocyte death
Acute and Chronic HF
Very sensitive marker
predicting higher risk of CV
events regardless of etiology
Optimization of therapy in
patients with elevated hs-cTn
should be more aggressive
Prognostication improves
only for mortality and use
to modify therapy has not
been tested
ST2
Fibrosis / inflammation /
immunity
Acute and chronic
HFrEF, HFpEF and
previously low EF
recovered
Additional prognostic value
beyond NPs suspected
Low week-to-week variations
Could provide additional
value for short and long term
prognostication, regardless of
LVEF
Unclear if using ST2 in acute
HF to modify therapies
improves clinical outcomes;
Galectin-3
Cardiac and vascular fibrosis
Incident HF, HFrEEF
and HFpEF
Early detection of risk and
long term prognostication in
HF
Preventive measures and
therapy optimization based
on levels could improve
outcomes
Recent study showed ST2
superior to Galectin-3 in a
multivariable prediction model
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Clinical trials that might influence
practice
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
HF – Preserved ejection fraction
• No therapy specifically recommended for HF-PEF with “strong”
• Complicated phenotype(s) and trial design(s)
• Different patient demographics
• Many pharmacologic and non-pharmacologic interventions have
been tried:
• ACE, ARB, BB, exercise, etc
• Recently: mineralocorticoid antagonists (TOPCAT)
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
TOPCAT
• International, multi-center, double-blind, placebo-controlled RCT
• NIH Sponsored
• Significant CAN involvement: Sites, Exec, Country Leaders
• Randomization, 1:1
– Spironolactone, 15, 30, 45 mg daily
– matching placebo
• Primary outcome: CV death, HF hosp, or aborted cardiac arrest
• Assumed: 3-year placebo rate of 17.4%
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Desai, Rationale and design, Am Heart J 2011
Pfeffer, TOPCAT NEJM 2013
TOPCAT: Eligibility criteria
• Inclusion:
–
–
–
–
Symptomatic Heart Failure
Age ≥ 50
LVEF ≥ 45%
stratified according to:
• HF Hospitalization within the
past year, or
• Elevated natriuretic peptides
• Major Exclusion:
– eGFR<30 mL/min/1.7m2
– potassium ≥5 mmol/L
– uncontrolled hypertension,
AF with rate > 90/min, recent
ACS, restrictive, infiltrative,
or hypertrophic
cardiomyopathy
– BNP ≥100 pg/mL
– NT-proBNP ≥360 pg/mL
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Desai, Rationale and design, Am Heart J 2011
Pfeffer, TOPCAT NEJM 2013
TOPCAT: Baseline characteristics
N=3445 pts
Age, median (IQR), years
67 (61-76)
Female, %
52
Ejection Fraction, median, %
56
Diabetes, %
33
Atrial Fibrillation, %
35
eGFR, median, IQR
65 (54, 79)
< 60 (ml/min/1.73m2)
39%
Eligibility Stratum, %
Hosp. for HF
Natriuretic Peptide
72
29
ACE-I or ARB
Beta-blocker
Diuretic
84
78
81
Medications, %
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
S. Shah Circ HF 2012
TOPCAT: Primary outcome
(CV Death, HF Hosp, or Resuscitated Cardiac Arrest)
351/1723 (20.4%)
Placebo
320/1722 (18.6%)
Placebo
Spironolactone
HR = 0.89 (0.77 – 1.04)
p=0.138
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Pfeffer, TOPCAT NEJM 2013
TOPCAT: Enrollment strata
• BNP/NT-proBNP:
• Prior HF hosp:
28.5%
71.5%
Spiro
event rate
Placebo
event rate
Hazard Ratio
(95% CI)
P-value
Natriuretic
peptide
15.9%
23.6%
0.65 (0.49-0.87)
0.003
Heart Failure
Hosp
19.6%
19.1%
1.01 (0.84-1.21)
0.923
Enrolled by:
*P=0.013 for interaction
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Pfeffer, TOPCAT NEJM 2013
TOPCAT: Placebo event rates
Placebo:
280/881 (31.8%)
US, Canada,
Argentina, Brazil
12.6 per 100 pt-yr
Russia, Rep Georgia
2.3 per 100 pt-yr
Moe GW, Ezekowitz JA et al., Can J Cardiol
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Heart Failure Guidelines
Placebo:
71/842 (8.4%)
Pfeffer, TOPCAT NEJM 2013
TOPCAT: Regional strata
Placebo:
280/881 (31.8%)
US, Canada, Argentina,
Brazil
HR=0.82 (0.69-0.98)
Interaction p=0.122
Placebo:
71/842 (8.4%)
Russia, Rep Georgia
HR=1.10 (0.79-1.51)
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Pfeffer, TOPCAT NEJM 2013
TOPCAT: Regional strata
• Fully adjusted model for primary endpoint including region and other
variables:
– HR 0.85, 95%CI 0.73 to 0.99, p=0.043
– “15% relative risk reduction for the primary endpoint in favor of
spironolactone”
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Pfeffer, TOPCAT NEJM 2013
TOPCAT: Safety
• Doubling in the rate of hyperkalemia:
• 9.1% in the placebo group
• 18.7% in the spironolactone group
– no deaths due to hyperkalemia
• Fewer events of hypokalemia
• No renal failure leading to dialysis
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
HF-PEF Recommendation
Recommendation
We suggest that in individuals with HFpEF, an increased NP level, serum
potassium < 5.0 mmol/L, and an estimated glomerular filtration rate (eGFR) ≥ 30
mL/min, a mineralocorticoid receptor antagonist like spironolactone should be
considered, with close surveillance of serum potassium and creatinine (Weak
Recommendation, Low-Quality Evidence).
Values and Preferences:
This recommendation is based on a prespecified subgroup analysis of the
Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone
Antagonist (TOPCAT) trial, which includes analysis of the predefined outcomes
according to admission NT-proBNP level, and the corroborating portion of the
trial conducted within North and South America.
Moe GW, Ezekowitz JA et al., Can J Cardiol
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Heart Failure Guidelines
HF – Reduced ejection fraction
• Current GDMT (ACE or ARB, BB and MRA) reduces the risk of
mortality, hospitalization and improves quality of life
• Multiple, adequately powered RCT
• Residual risk despite GDMT
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
HF – Reduced ejection fraction
• Cumulative reduction in the
odds of death over 2 years
compared with no treatment
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Fonarow G C et al. J Am Heart Assoc 2012;1:16-26
PARADIGM-HF
• International, multi-center, double-blind, placebo-controlled RCT
• Randomization, 1:1
– LCZ696 200 mg BID
– Enalapril 10 mg BID
• Primary: composite of CV death and/or hospitalization for HF
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
McMurray NEJM 2014
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Vardeny CPT 2013
PARADIGM-HF: Eligibility criteria
Inclusion:
•NYHA II-IV HF
•LVEF ≤40 % [≤35% amend]
•Elevated NPs
– BNP ≥150 pg/mL
– NT-proBNP ≥600 pg/mL
Inclusion (con’t)
Any ACEi or ARB, but able to
tolerate stable dose equivalent to at
least enalapril 10 mg daily for at
least 4 weeks
Major Exclusion:
•Guideline-recommended use of
beta-blockers and mineralocorticoid •SBP < 95 mmHg
receptor antagonists
•eGFR < 30 ml/min/1.73 m2
•K > 5.4 mEq/L
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
McMurray NEJM 2014
PARADIGM-HF: Design
Single-blind run-in period
Double-blind period
LCZ696 200 mg BID
Enalapril
LCZ696
Rand’n
10 mg
BID
100 mg
BID
200 mg
BID
Enalapril 10 mg BID
2 weeks
N=1102
1-2 weeks 2-4 weeks
N=977
N=8399 patients
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
McMurray NEJM 2014
PARADIGM-HF: Baseline chars.
Age (years)
Women (%)
Ischemic cardiomyopathy (%)
LV ejection fraction (%)
NYHA functional class II / III (%)
Systolic blood pressure (mm Hg)
Heart rate (beats/min)
N-terminal pro-BNP (pg/ml)
B-type natriuretic peptide (pg/ml)
History of diabetes
Beta-adrenergic blockers
Mineralocorticoid antagonists
ICD and/or CRT
LCZ696
(n=4187)
Enalapril
(n=4212)
63.8 ± 11.5
21.0%
59.9%
29.6 ± 6.1
71.6% / 23.1%
122 ± 15
72 ± 12
1631 (885-3154)
255 (155-474)
35%
93.1%
54.2%
16.5%
63.8 ± 11.3
22.6%
60.1%
29.4 ± 6.3
69.4% / 24.9%
121 ± 15
73 ± 12
1594 (886-3305)
251 (153-465)
35%
92.9%
57.0%
16.3%
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
McMurray NEJM 2014
PARADIGM-HF: Primary endpoint
Kaplan-Meier Estimate
of
Cumulative Rates (%)
4
0
3
2
Enalapril
1117
(n=4212)
914
2
4
LCZ696
(n=4187)
1
6
HR = 0.80 (0.73-0.87)
P = 0.0000002
Number needed to treat = 21
8
0
0
180
540
4187
4212
3922
3883
3663
3579
3018
2922
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
720
900
1080
1260
896
853
249
236
Days After Randomization
Patients at Risk
LCZ696
Enalapril
360
Heart Failure Guidelines
2257
2123
1544
1488
McMurray NEJM 2014
PARADIGM-HF: CV death
Kaplan-Meier Estimate of
Cumulative Rates (%)
32
Enalapril
HR = 0.80 (0.71-0.89)
P = 0.00004
Number need to treat = 32
24
(n=4212)
693
558
16
LCZ696
8
(n=4187)
0
0
180
540
4187
4212
4056
4051
3891
3860
3282
3231
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
720
900
1080
1260
1005
994
280
279
Days After Randomization
Patients at Risk
LCZ696
Enalapril
360
Heart Failure Guidelines
2478
2410
1716
1726
McMurray NEJM 2014
PARADIGM-HF: All cause mortality
Kaplan-Meier Estimate of
Cumulative Rates (%)
32
Enalapril
HR = 0.84 (0.76-0.93)
P<0.0001
835
(n=4212)
24
711
16
LCZ696
(n=4187)
8
0
0
180
540
4187
4212
4056
4051
3891
3860
3282
3231
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
720
900
1080
1260
1005
994
280
279
Days After Randomization
Patients at Risk
LCZ696
Enalapril
360
Heart Failure Guidelines
2478
2410
1716
1726
McMurray NEJM 2014
PARADIGM-HF: endpoints
LCZ696
(n=4187)
Enalapril
(n=4212)
Hazard
Ratio
(95% CI)
P
Value
Primary
endpoint
914
(21.8%)
1117
(26.5%)
0.80
(0.73-0.87)
0.0000002
Cardiovascular
death
558
(13.3%)
693
(16.5%)
0.80
(0.71-0.89)
0.00004
Hospitalization
for heart failure
537
(12.8%)
658
(15.6%)
0.79
(0.71- 0.89)
0.00004
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
McMurray NEJM 2014
PARADIGM-HF: Safety endpoints
Prospectively identified adverse events
Symptomatic hypotension
Serum potassium > 6.0 mmol/l
Serum creatinine ≥ 2.5 mg/dl
Cough
Discontinuation for adverse event
Discontinuation for hypotension
Discontinuation for hyperkalemia
Discontinuation for renal impairment
Angioedema (adjudicated)
Medications, no hospitalization
Hospitalized; no airway compromise
Airway compromise
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
LCZ696
(n=4187)
Enalapril
(n=4212)
P
Value
588
181
139
474
449
36
11
29
388
236
188
601
516
29
15
59
< 0.001
0.007
0.007
< 0.001
0.02
NS
NS
0.001
16
3
0
9
1
0
NS
NS
---McMurray NEJM 2014
Is 1 trial enough?
Do we need to do another trial to obtain regulatory
approval/change clinical practice?
Number of trials
with P < 0.05
showing
efficacy
P value required in a single
trial to provide same strength
of evidence
1
0.05
2
0.00125
3
0.00003125
4
0.00000078
5
0.0000000195
PARADIGM-HF:
Effect on primary
endpoint
PARADIGM-HF:
Effect on
cardiovascular
death
0.00008
0.0000004
Based on formula (0.025)n x2 (personal communication Stuart Pocock)
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Slide courtesy of J McMurray
HF – Reduced ejection fraction
Recommendation
We recommend that in patients with mild to moderate HF, an EF ≤ 40%, an
elevated NP level or hospitalization for HF in the past 12 months, a serum
potassium < 5.2 mmol/L and an eGFR ≥ 30 mL/min and treated with appropriate
doses of guideline-directed medical therapy should be treated with LCZ696 in
place of an ACE inhibitor or an angiotensin receptor blocker, with close
surveillance of serum potassium and creatinine (Conditional Recommendation,
High-Quality Evidence).
Values and Preferences:
This recommendation places high value on medications proven in large trials to
reduce mortality, HF rehospitalization, and symptoms. It also considers the
health economic implications of new medications. The recommendation is
conditional because the drug is not yet approved for clinical use in Canada and
the price is still not known.
Moe GW, Ezekowitz JA et al., Can J Cardiol
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Heart Failure Guidelines
Appendix: Useful CCS Heart
Failure Guideline Algorithms
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Algorithm for Prevention and Treatment of
Clinically Stable Heart Failure
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Referral Pathway for Device Therapy in
Patients with Chronic Heart Failure
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Acute Heart Failure – Diagnosis
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Acute Heart Failure – Acute
Management
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Approach to Assessment for CAD in
Patients with HF
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Decision Regarding Coronary
Revascularization in HF
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Algorithm for Management of Different
Stages of HF using Natriuretic Peptides
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Appendix:
CCS Heart Failure Guideline
Resources
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines
Looking for best practices in heart
failure diagnosis and management?
To access this tool, and to view all of our guideline
resources, please visit www.ccs.ca.
Moe GW, Ezekowitz JA et al., Can J Cardiol
www.ccs.ca
Heart Failure Guidelines