optimal secondary prevention following acs in high risk ...€¦ · donohoe et al jama 2007;298:765...
TRANSCRIPT
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Optimal Secondary Prevention following ACS in High Risk Patients
Reducing Outcomes in your Diabetic Patient
David Fitchett MD
St Michael’s Hospital
Toronto
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David Fitchett MD Disclosures
• Received CME / consultation honoraria from
– Merck
– Boehringer Ingelheim
– Lilly
– Astra Zeneca
• Steering committee member for EMPA Reg
• DMC chair for SUSTAIN 6 and PIONEER
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Reducing Adverse Outcomes after ACS in Patients with Diabetes
Goals
To show:
• Diabetes increases risk of CV events
• Strategies to reduce adverse outcomes
• Changing landscape with new therapies
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Why Should Cardiologists Care About Diabetes?
• DM is present in 40-50% of patients with CHD
• 70% mortality in DM due to CVD
• DM worsens impact of other CV risk factors
• DM worsens outcome of all CV syndromes
• DM impacts all aspects of CV practice
• Treatments now available with large impact on CV outcomes
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Mortality following Myocardial Infarction in Patients with and without Diabetes
Donohoe et al JAMA 2007;298:765
DM STEMI
Non DM STEMI
DM STEMI
Non DM STEMI
62,000 Patients in TIMI trials
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Life Expectancy Is Reduced by ~12 Years in Diabetes Patients with Previous CVD
The Emerging Risk Factors Collaboration. JAMA 2015;314:52
60 End of lifeyrs
–6 yrs
–12yrs
No diabetes
Diabetes
Diabetes + MI
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Non Diabetic Patients Diabetic Patients
Diabetes has Major Impact on MI Recurrence
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Impact of Diabetes on Outcomes after ACS
Aguilar et al Circulation 2004;110;1572VALIANT
Diabetes
New Diabetes
No Diabetes
1 year outcomes
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In-Hospital Management of ACS in the DM Patients and Long-Term Outcomes
• Choice of revascularisation PCI vs CABG– Preference for CABG in multivessel CAD (FREEDOM)
• Anti-platelet agent– Preferential use of ticagrelor / prasugrel – Use of DAPT in patients managed without PCI
• Initiation / dose optimisation of – Statins, BP control, Use of ACEi /ARB, beta blocker
• Glycemic management– Glucose control– Need for referral?– Choice of drug with CV benefit / known safety
• Facilitate lifestyle change– Smoking cessation– Refer to Rehabilitation Clinic
Treatment strategies initiated during admission• Patient more likely to remain adherent• Value of structured orders (admission and discharge)
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Optimal Secondary Prevention on Patient with Type 2 Diabetes after ACS
• Vascular Protection
Prevention of vascular events
• Cardiac protection
Prevention of heart failure /
Sudden death
• Risk factor management
Limit CAD progression
Anti-platelet therapyLipid loweringACE inhibition /ARBLiraglutide
Beta blockersACE I / ARBMineralo corticoid inhibitionSaccubitril / ValsartanIvabradineICD and or CRTEmpagliflozin
Smoking cessationLipid and BP controlGlycemia control ?Rehabilitation and lifestyle
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Dysfunctional Platelets in Diabetes
Ferreiro J and Angiolillo D Circulation 2011;123:798
Diminished platelet inhibition in patients with DM
• ASA
• Clopidogrel
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Ticagrelor and ACS
Impact of Diabetes
James et al Eur Heart J (2010) 31, 3006
CV Death MI or stroke
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PEGASUS: Longer Term (up to 3yrs) Ticagrelor in
Patients with Diabetes
Diabetes
Bleeding
TIMI major HR 2.5 p<0.001
No increase in fata lbleeding , ICH or
Haemorhagic stroke
Bonaca et al N Engl J Med 2015
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Beta-blockers and Diabetes –
Implications in MI
Concerns• Masking hypoglycemia
• Impaired glycogenolysis
• Worse Glucose intolerance
• Hyperosmolar hyperglycemic coma
• Susceptibility to heart failure
Enhanced Treatment Benefit in Diabetes
% M
ort
alit
y R
edu
ctio
n
BHRT = Beta-blocker Heart Attack Trial
NMTS = Norwegian Multicentre Timolol Study
GMT = Goteburg Metoprolol Trial
0
10
20
30
40
50
60
70
BHRT NMTS GMT
Non-DM DM
Mortality reduction•Non DM 33%•DM 48%
% r
ed
uctio
n o
f m
ort
alit
y
Sawicki et al J Int Med 2001;250:11
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Mortality Reduced 26% by ACE Inhibtion
after MI in Patients with LVEF < 40%
Mortality 26%Readmission for CHF 27%Reinfarction 20%
Years
Flather et al Lancet 2000;355:1575
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TRAndolapril Cardiac Evaluation Study: Increased Survival in High-Risk Patients
Torp-Pedersen et al,. Lancet. 1999;354:9-12.
Me
dia
n L
ife
tim
e(m
on
ths
)
DiabetesN=237
CHFN=1025
AnginaN=795
HypertensionN=400
70
60
30
20
10
0
80
50
40
PlaceboTrandolapril
104%56%
97%
120%
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Association between Mean Blood
Glucose and In-Hospital Mortality.
Kosiborod et al Circulation 2008;117:1018
Reference Mean BG 100-<110
No diabetes
Diabetes
All
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Benefit of Tight Glycemic Control after Acute Myocardial Infarction
• STE and Non STE MI
• Blood glucose > 11 mmol/L
• N=1240
• Randomised to:– Intensive insulin for 24 h +
multi dose insulin for 3 months
– Early glucose target 7-10 mm/l
or
– Usual care
• Mean FU 3.4 years
DIGAMI Malmberg et al JACC 1995;26:57
NNT=9
Malmberg BMJ 1997;314:1512
RR 0.72 (95% CI 0.55-0.92)
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Benefit of Tight Glycemic Control after Acute Myocardial Infarction
• STE and Non STE MI
• Blood glucose > 11 mmol/L
• N=1240
• Randomised to:– Intensive insulin for 24 h +
multi dose insulin for 3 months
– Early glucose target 7-10 mm/l
or
– Usual care
• Mean FU 3.4 years
DIGAMI Malmberg et al JACC 1995;26:57
NNT=9
Malmberg BMJ 1997;314:1512
RR 0.72 (95% CI 0.55-0.92)
Patients with ACS and blood glucose > 11mmol/lmay receive glycemic control to 7-10mmol/l followed by strategies to achieve long-term glucose targets. Grade C level 2CDA Clinical Practice Guidelines 2013
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Early Incretin Trials and CVD Outcomes
R
R
R
Median Duration of Follow-upa
SAVOR-
TIMI2
TECOS3
EXAMINE1
6.5–8.0Non Inferior
CV death, MI,
stroke, or UA
Randomization Up to
Year 4
Year 3Year 2Year 1
Non InferiorCV death,
Nonfatal MI, or
Nonfatal stroke
Non InferiorCV death,
Nonfatal MI, or
Nonfatal stroke
Sitagliptin
Saxagliptin
Alogliptin
Placebo
Placebo
Placebo
6.5–12.0
6.5–11.0
HbA1c
Range, %
Primary
End pointDuration of Treatment (as part of usual care)
Heart failure hospitalizationSaxagliptin 3.5%; Placebo 2.8%HR 1.27 (95% CI 1.07–1.58)NNH = 142
Median Duration of Follow-upa
RELIXANon Inferior
CV death,
Nonfatal MI, or
Nonfatal stroke or
Hosp for Unstable Angina
Lixisenatide
Placebo
7.0–11.0
Post MI
Post MI
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EMPA-REG OUTCOME
Trial design
• T2DM (A1C >7-10%) + high CV risk (prior MI, CAD, CVA, PVD)
• Included patients 2 months post ACS
• Prior MI in 46.5%
• Study medication given in addition to standard of care
• Primary outcome: Triple MACE: CV death, nonfatal MI, non fatal stroke
• On treatment median 2.6 years Observation median 3.2 years
21
Randomised
and treated
(n=7020)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Placebo
(n=2333)
Screening
(n=11531)
590 Sites
42 Countries
Zinman et al N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720
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CV death
22
Cumulative incidence function.
CI, confidence interval; HR, hazard ratio.
Zinman et al. N Engl J Med 2015:373:2117-2128.
HR 0.62(95% CI 0.49, 0.77)
p<0.0001
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Hospitalisation for heart failure
23
HR 0.65(95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
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Empagliflozi
n
Placebo
n with event/
N analyzedHazard ratio
(95% CI) p-value
Incident or
worsening
nephropathy
525/4124 388/20610.61 (0.53,
0.70)<0.0001
New onset
macroalbuminuria459/4091 330/2033
0.62 (0.54,
0.72)<0.0001
Doubling of serum-
creatinine* 70/4645 60/23230.56 (0.39,
0.79)0.0009
Initiation of renal
replacement
therapy
13/4687 14/23330.45 (0.21,
0.97)0.0409
Incident or worsening nephropathy and its
components
24
*Accompanied by eGFR (MDRD) ≤45 mL/min/1.73m2.
Cox regression analyses.
0.13 0.25 0.50 1.00 2.00
Favors empagliflozin Favors placebo
1 20.5
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LEADER: Liraglutide in High Risk Patients with T2 DM
• Inclusion criteria
– Established CVD including prior MI after14 days (31%) • Included 17% patients with heart failure
– High risk for CVD
LEADER Marso et al N Engl J Med 2016 June 13 2016
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LEADER Liraglutide Cardiovascular Outcome Trial
CV death, MI, Stroke
Non-fatal MI HR 0.88 (95% CI 0.75-1.03)Non-fatal Stroke HR 0.89 (95% CI 0.72-.11)
Heart failure HR 0.87 (95% CI 0.73-1.05)
LEADER Marso et al N Engl J Med 2016 June 13 2016
Pati
ents
wit
h a
n e
ven
t %
Pati
ents
wit
h a
n e
ven
t %
CV Mortality
Months
Months
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SUSTAIN 6, LEADER and EMPA REG
Comparisons
27
Paitents
enrolled
FU Yrs 1o Outcome
ARR p
RRR
Mortality
ARR p
RRR
HFH Hosp
ARR p
RRR
SUSTAIN 6
T2 DM +
CVD or
High CV risk
2.1 2.3% 0.02
26%
-0.2% ns -0.3% ns
LEADER 3.8 1.9% 0.01
13%
1.4% 0.02
15%
0.6% ns
EMPA REG T2 DM +
CVD3 1.6% 0.04
14%
2.6% <0.001
32%
1.4% <0.002
35%
ARR Absolute risk reduction, RRR Relative risk reduction HFH Heart failure hospitalisation
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Meta-analysis of Clinical Trials with Statin
Treatment: Impact on Mortality in Diabetes
0.5 1.0 1.5
Diabetes
No diabetes
Any CHD death
Diabetes
No diabetes
Any death
436 (4.6%)
1112 (3.1%)
1548 (3.4%)
1031 (11.0%)
2801 (7.9%)
3832 (8.5%)
495 (5.3%)
1465 (4.1%)
1960 (4.4%)
1104 (11.9%)
3250 (9.1%)
4354 (9.7%)
0.88 (0.75-1.03)
0.78 (0.72-0.85)
0.81 (0.76-0.85)
0.91 (0.82-1.01)
0.87 (0.82-0.92)
0.88 (0.84-0.91)
Vascular causes:
CHD death
All causes:
Test for heterogeneity within subgroup: x21 = 2.8; p = 0.09
Test for heterogeneity within subgroup: x21 = 0.8; p = 0.04
Cause of death Treatment Control RR (CI)Events (%)
RR (99% CI)
RR (95% CI)
Kearney PM, et al. Lancet 2008; 371(9607):117-25.
Treatment better Control better
14 Trials
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Patients stabilized post ACS ≤ 10 days:LDL-C 1.29–3.2mM/l (or 1.29–2.6mMol/l if prior lipid-lowering Rx)
Standard Medical & Interventional Therapy
Ezetimibe / Simvastatin
10 / 40 mg
Simvastatin
40 mg
Follow-up Visit Day 30, every 4 months
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Uptitrated to
Simva 80 mg
if LDL-C > 2.0
(adapted per
FDA label 2011)
Study Design
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
90% power to detect
~9% difference
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Ezetimibe in Patients with Recent ACS
CV Events
On treatment analysis
Ez/simva 29.8% Simva 32.4%
HR 0.92 CI (0.87-0.98)
NNT 38
NNT 50
Years
CV
Eve
nts
%
HR 0.93 (95% CI 0.89-0.99)
NNT 50
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Simva† EZ/Simva†
Male 34.9 33.3
Female 34.0 31.0
Age < 65 years 30.8 29.9
Age ≥ 65 years 39.9 36.4
No diabetes 30.8 30.2
Diabetes 45.5 40.0
Prior LLT 43.4 40.7
No prior LLT 30.0 28.6
LDL-C >
2.5mmol/l
31.2 29.6
LDL-C ≤ 2.5 mg/dl
38.4 36.0
Major Pre-specified
Subgroups
Ezetimibe/Simva
Better
Simva
Better
0.7 1.0 1.3†7-year
event rates
*
*p-interaction = 0.023, otherwise > 0.05
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OSLER
Impact of Evolocumab on Cumulative CV events
Days
61% reduction of LDL
LDL on evolocumab 1.23mmol/l
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FOURIER Trial Meets Primary EndpointAMGEN Announcement February 2 2017
FOURIER trial with evolocumab met
• Primary composite endpoint – cardiovascular death, non-fatal myocardial infarction (MI),
non-fatal stroke, hospitalization for unstable angina
• Secondary composite endpoint– cardiovascular death, non-fatal MI or non-fatal stroke
• No new safety issues were observed.
Await full results and magnitude of benefit
American College of Cardiology, Washington, March 17
Diabetes in 9333 of the 27,564 patients (33.9%)
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Secondary Prevention in Patients
with Diabetes and ACS
• High risk group for CV events especially CHF
and CV death
• Need to identify patients with DM
• Need to optimise all aspects of risk reduction
including
– Lifestyle management, BP, Statins, RAASi
• New opportunities with additive and potentially
large benefit
– Glucose lowering agents with CV benefit
– Further LDL lowering with PCSK9 inhibitor