Managing patients with heart failure David Fitchett, MD · 2016-06-16 · MERIT-HF, CIBIS II,...
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Managing patients with heart failure David Fitchett, MD University of Toronto, Canada Asian Cardio Diabetes Forum April 23 – 24, 2016 – Kuala Lumpur, Malaysia
Transcript of Managing patients with heart failure David Fitchett, MD · 2016-06-16 · MERIT-HF, CIBIS II,...
Managing patients with
heart failure
David Fitchett, MDUniversity of Toronto,
Canada
Asian Cardio Diabetes ForumApril 23 – 24, 2016 – Kuala Lumpur, Malaysia
Proportion of Population Living with Heart Failure
Ponikowski et al ESC Heart Fail 2014;1:4
Challenges in Heart Failure
• High mortality
• High readmission rate
• Poor quality of life
• Expensive to health care system
• Frequently associated with comorbidities
Clinical manifestations
• Increasing frequency of acute events with disease progression leads to high rates of
hospitalization and increased risk of mortality
• With each acute event, myocardial injury may contribute to progressive LV
dysfunction
A progressive condition with high mortality
LV: left ventricular
Gheorghiade et al. Am J Cardiol 2005;96:11G–17G; Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73
Chronic decline
Mortality
Acute episodes
Disease progression
Function
& quality
of life
(QoL)
Risks of Systolic/Diastolic HF
Reduced EF or Syst HF
HFrEF
HTN
DM
Preserved EF or Diast HF
HFpEF
Bhatia S, et al., N Engl J Med 2006; 55:260-9
Heart Failure in Patients with DiabetesIncidence and Prevalence
Incidence Prevalence
Nicholls et al Diabetes Care 2001;24:1614
Patients with DM 2 -5 times more likely to develop CHF than non-diabetics
Age at baseline
Impaired LV
Diastolic Function in
Diabetes
Impact of Diabetes on CV Mortality in Patients
with Left Ventricular Systolic Dysfunction
65% greater risk of HF
SAVE Arch Int Med 2004;164:2273
HR 1.49 (95% CI 1.28-1.74) HR 1.39 (95% CI 1.14-1.68)
Adverse CV Outcomes Mortality
Survival of Patients with
Acute Decompensated Heart Failure
Burger et al
Am J Cardiol 2005;95:1117-9
Independent Predictors of 6 month Mortality
6/12 mortality 22.7%
Heart Failure with Reduced Ejection Fraction
The Building Blocks of Therapy
Transplant
VAD
CRT
ICD
Beta Blocker ACE Inhibitor
ARBMRA
Hydralazine / IDN
Digoxin
CABG
LCZ 696
Ivabradine
IV Iron
Betablocker
Mineralocorticoidreceptor
antagonist
Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction
ACEinhibitor
Angiotensinreceptorblocker
Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS,
MERIT-HF, CIBIS II, RALES, EMPHASIS-HF and PARADIGM
10%
20%
30%
40%
0%
% D
ecre
ase in
Mo
rtality
Neprilysin
Inhibitor
0
16
32
40
24
8
Enalapril(n=4212)
360 720 10800 180 540 900 1260
Days After Randomization
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236
LCZ696
Enalapril
Patients at Risk
1117
Kap
lan
-Meie
r E
sti
mate
of
Cu
mu
lati
ve
Rate
s (
%)
914
LCZ696(n=4187)
HR = 0.80 (0.73-0.87)
P = 0.0000002
Number needed to treat = 21
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
PARADIGM HF Subgroups
PARADIGM
Glucose Lowering: Impact on Heart Failure
Glycemic Agent / Control + benefit 0 neutral - harm
Intensive vs less intensive 0 / ?+
Insulin 0 / ?-
Metformin ?+
Sulphonylurea / Glinide ?-
TZD ---
DPP4 i 0 / -
GLP1 agonist 0
SGLT2 inhibitor +++
Lack of Intensive Glycemic Control on Heart Failure Admission or Death
Control et al Diabetalogia 2009
Glycemic Controland LV Function
• 105 patients with DM and poor control• Baseline A1C 10.3%• LV function by echo global longditudinal strain• FU 12 months
LV diastolic function also improved: e’ increased 24%
Leung et al Circ Card Imag 2016;9:e003643
Insulin and Increased Heart Failure Mortality
Independent Predictors of Mortality• Insulin treatment HR 4.3 (95% CI 1.69-10.9)• Non insulin DM HR 0.95 (95% CI 0.31-2.93)
Smooke et al Am Heart J 2005;149:168
Months
Pioglitazone: Diabetes + CVD
Incidence of Heart Failure
Dormandy et al Lancet 2005;366:1279 PROACTIVE
RECORD• Open label: Rosiglitazone vs no rosiglitazone
• No difference in CV death / CV hospitalisation
• More patients needed loop diuretics
• Fatal and non fatal HF events more frequent– 2.7% vs 1.3% HR 2.1 (95% CI 1.35-2.7)
• More HF deaths (10 vs 2)
• High mortality in survivors of HF hospitalisation– 30% vs 28%
Home et al Lancet 2009;373:2125-35
SAVOR TIMI 53Primary Endpoint (CV death, MI, Stroke)
Scirica et al N Engl J Med 2013 DOI: 10.1056/NEJMoa1307684
T2 DM + High risk for CVD
Known CVDMultiple risk ff
Heart failure hospitalisationSaxa 3.5% Placebo 2.8%
HR 1.27 (95% CI 1.07-1.58)NNH =142
Risk of Heart Failure with
Saxagliptin Occurs Early
SAVOR TIMI 53 Scirica et al Circulation 2014;130:1579-88
Heart Failure and Saxagliptin
- Risk increased
• Prior heart failure
• Elevated BNP
- Risk similar across range of renal function
- No weight gain or peripheral oedema
- No increase of NT Pro BNP
- Similar incidence of HF death (0.5% vs 0.5%)
SAVOR TIMI 53 Scirica et al Circulation 2014;130:1579-88
EXAMINE Alogliptin in Patients with diabetes and Recent Acute coronary Syndrome
On treatmentA1C difference 0.36
Heart failure hospitalisation Alogliptin 3.9% Placebo 3.3%HR 1.19 (95% CI 0.90-1.58) p=0.22
DM on treatmentACS in past 15-90dAlogliptin vs placeboBaseline A1c 8.0%
CV death, MI , Stroke
.White et al N Engl J Med 2013. DOI: 10.1056/NEJMoa1305889
• Sitagliptin vs placebo
• DM and established CVD
• 1o EP 4P MACE 1300 events
• 71% male, age 66 + 8 yrs
• DM duration 11 + 8 yrs
• BMI 29.5 A1C 6.5 – 8.0%
• Insulin 23%
TECOSTrial Evaluating Cardiovascular Outcomes with Sitagliptin
N = 14723
months
CV death, MI, CVA, UA %
Heart failure hospitalisation Sitagliptin 3.1% Placebo 3.1%HR 1.00 (95% CI 0.83-1.20)
Green et al NEJM June 2015
Lixisenatide in High CVD Risk
ELIXA Pfeffer et al N Engl J Med 2015;373:2247
N= 6068ACS in past 180 daysA1C < 11%
Age 60 yrsMale 69.5 %Duration DM 9.3 yrsMean A1C 7.6%25% N America + Europe22.5% prior CHF
Median FU 25 monthsA1C difference 0.4%Less serious hypoglycemia
No increased HF risk
Baseline Characteristics (n= 7034)
• Age 63.1 (9% > 75 yrs)
• Male 72%
• Current / ex smoker 46%
• Diabetes > 10yrs 57%
• eGFR 74 ml/min/1.73m2
– 26 % 30-60 ml/min/1.73m2
• Coronary disease 75%
• Prior MI 47%
•Multivessel CAD 47%
• CABG 25%
• Stroke 23%
•Heart failure 10.5%
Zinman et al N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720
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Baseline Characteristics (n= 7034)
• ACE inhibitor 81%
• Beta blockers 65%
• MRA 6%
• Loop diuretic 15%
• Insulin 49%
• Metformin 74%
• SU 43%
• TZD 4.2%
Zinman et al N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720
Hospitalisation for heart failure
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HR 0.65(95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
Heart failure Hospitalisation
and Cardiovascular Mortality
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Early and Sustained Reduction of Heart failure
Hospitalisation and Cardiovascular Mortality
Ho
spit
alis
atio
n f
or
he
art
failu
re /
CV
Mo
rtal
ity
Patients with event (%) Empagliflozin
(n=4687)
Placebo(n=2333)
HR (95% CI)
CV death 172 (3.7%) 137 (5.9%) 0.62 (0.49, 0.77)
Sudden death 53 (1.1%) 38 (1.6%) 0.69 (0.45, 1.04)
Worsening of heart failure or cardiogenic shock
14 (0.3%) 22 (0.9%) 0.32 (0.16, 0.62)
Acute MI 15 (0.3%) 11 (0.5%) 0.68 (0.31, 1.48)
Stroke 16 (0.3%) 11 (0.5%) 0.72 (0.33, 1.55)
Other* 74 (1.6%) 55 (2.4%) 0.66 (0.47, 0.94)
0,13 0,25 0,50 1,00 2,00
Categories of CV death
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Favors empagliflozin Favors placebo
Cox regression analysis.
*1.5% on empagliflozin and 2.3% on placebo were presumed CV death (insufficient data for the
adjudication committee to categorize cause of death).
HR, hazard ratio; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.
Patients with event/analyzed
Empagliflozin Placebo HR (95% CI) p-value
Investigator-reported heart failure*
204/4687 143/2333 0.70 (0.56, 0.87) 0.001
Investigator-reported serious heart failure*†
192/4687 136/2333 0.69 (0.55, 0.86) 0.001
Investigator-reported heart failure
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Cox regression analysis.
*Based on narrow standardized MedDRA query “cardiac failure”.†Reported as serious adverse events by investigator.
HR, hazard ratio; CI, confidence interval.
Favors empagliflozin Favors placebo
Treatment of Patients with and without Baseline
Heart Failure
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Prior HF No Prior HF
Empa Placebo Empa Placebo
Patients hospitalized
for heart failure
(%)
Hospitalization for HF in patients with HF vs without
HF at baseline
HR 0.75
(95% CI 0.48, 1.19)
HR 0.59
(95% CI 0.43, 0.82)
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Cox regression analysis. CI, confidence interval; HR, hazard ratio
Inzucchi SE. AHA 2015. Oral presentation
Outcomes in Patients with and without Heart Failure at Baseline
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Loop diuretics at baseline
Yes 53/725 (7.3%) 44/364 (12.1%) 0.60 (0.40, 0.90)
No 119/3962 (3.0%) 93/1969 (4.7%) 0.63 (0.48, 0.82)
CV death in patients with and without heart
failure* at baseline and on Loop Diuretics
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Cox regression analysis.
CV death: adjudicated outcome.
*Based on narrow standardized MedDRA query (SMQ) “cardiac failure”.
HR, hazard ratio; CI, confidence interval; CV, cardiovascular.
Favors empagliflozin Favors placebo
Patients with event/patients analysed (%)
Empagliflozin Placebo HR (95% CI)
Heart failure at baseline*
Yes 38/462 (8.2%) 27/244 (11.1%) 0.71 (0.43, 1.16)
No 134/4225 (3.2%) 110/2089 (5.3%) 0.60 (0.47, 0.77)
0,25 0,50 1,00 2,00
Cardiovascular Death in Patients with and
without Heart Failure at Baseline
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Time to first introduction of loop diuretics, hospitalisation
for heart failure or cardiovascular death
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CV and all-cause death in patients with
hospitalization for heart failure during the trial
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Cox regression analysis.
CV death and hospitalization for heart failure: adjudicated outcomes
HR, hazard ratio; CI, confidence interval; CV, cardiovascular.
Patients with event (%) Empagliflozin
(n=126)Placebo(n=95)
HR (95% CI)
CV death 18 (14.3%) 23 (24.2%) 0.65 (0.35, 1.22)
All-cause mortality 27 (21.4%) 29 (30.5%) 0.74 (0.43, 1.26)
0,25 0,50 1,00 2,00
Favors empagliflozin Favors placebo
Adverse events in patients with and without
heart failure at baseline
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The Impact of Glucose Lowering Drugs on
Heart Failure Outcomes
-3.00
-2.50
-2.00
-1.50
-1.00
-0.50
0.00
0.50
1.00
1.50
PROACTIVE
RECORD
ORIGIN
EMPAREG
Differen
ceinHeartFailureEventRates% * ** * **
SAVOR
*p<0.05**p<0.001
EXAMINE
Heart Failure and Diabetes
• All standard treatments for heart failure
appear to be effective in patients with
diabetes
• Metformin safe to use in HF
• SU uncertain: probably avoid
• Avoid TZDs and Saxaglipin in patients at
risk or with HF
• GLP1 agonists likely no harm in HF
