chronic ischemic heart disease and comorbidities manejo
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Chronic ischemic heart disease and comorbidities
José López-Sendón
Hospital Universitario La Paz Madrid. Spain
Manejo clínico del paciente con
cardiopatía isquémica crónica y
comorbilidades asociadas
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Chronic ischemic heart disease and comorbidities
Starting Point
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Chronic ischemic heart disease and comorbidities
What is the risk of the patient?
1- Low
2- Middle
3- High
4- It is not that important
ESC Stable Angina Guidelines Eur Heart J 2006;27:1341
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Chronic ischemic heart disease and comorbidities
Contraindications
Intolerant / contraindications
Aspirin 75-150 mg
od
Statin
ACEI in proven CVD
β-blocker in post MI
Clopidogrel
Lower dose / alternative agent
Treatments aimed at Improving Prognosis
ESC Guidelines Stable Angina Eur Heart J. 2006; 27:1341
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Chronic ischemic heart disease and comorbidities
Intolerant or contraindication β-blockers
Calcium antagonist or long-
acting nitrate or K channel
opener or If inhibitor
Treatments aimed at Symptom / Ischemia Relief
Add calcium antagonist
or long-acting nitrate
Symptoms not controlled after dose optimisation
Consider suitability for
revascularization
Symptoms not controlled after dose optimisation
Symptoms not controlled on 2 drugs after dose optimization
Ca antagonist or long-acting nitrate
Combination of nitrate and Ca
antagonist or K-channel opener
Symptoms not controlled
after dose optimisation Intolerant
ESC Guidelines Stable Angina Eur Heart J. 2006; 27:1341
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Chronic ischemic heart disease and comorbidities
The problem of Comorbidities
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Chronic ischemic heart disease and comorbidities
Comorbidities in Chronic Ischemic Heart Disease
Steg G, ECC 2011
All Angina (22%) No angina
Hypertension, % 70.9 78.4 68.8
Diabetes, % 29.3 28.9 29.4
Dyslipidemia, % 74.9 78.6 73.9
PAD, % 9.8 12.9 8.9
History of stroke, % 4.0 5.3 3.6
History of TIA, % 3.1 4.9 2.5
HF 14.9 39.7 7.8
History of atrial fibrillation/flutter 7.0 7.4 6.9
Asthma, COPD, % 7.4 9.2 6.9
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Chronic ischemic heart disease and comorbidities
Common problems related with comorbidities
• Worse prognosis
• Diagnosis more difficult
• Need of specific treatment
• Worse compliance
• Limitation of effective antiischemic treatments
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Chronic ischemic heart disease and comorbidities
EHS Stable angina BMJ 2006;332:262
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Chronic ischemic heart disease and comorbidities
BICA Study Bacterial Infection in Culprit Artery in STEMI
• 101 STE-MI <24h in 2 Finnish hospitals
• Thrombus aspiration and DNA analysis to identify bacteria
• 78% common dental bacteria in 78%
• 98% viridans (mitis-group) streptococci
• 0% Bacteriemia
• Ortopantomography
• 47% Periapical lesions
• 50% vertical bone pockets
J Mikkelsson, FI, P-5688
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Chronic ischemic heart disease and comorbidities
Antidepressive Drugs after AMI
JK Jensen, DK, P-4204
Hazard Ratio
0,5 1,0 1,5 2,0 2,5 3,0 3,5
Citalopram
Escitalopram
Sertraline
Paroxetine
Imipramine
Amitriptyline
Nortriptyline
Venlafaxine
Mirtazapine
Mianserin
Denmark
1997-2006
1st AMI
N=60,131
Anti-
depressants
15.9%
FU: 4 y
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Chronic ischemic heart disease and comorbidities Comorbidities Importance
Bronchial disease BB Contraindicated
Peripheral vasc disease BB Contraindicated
Diabetes, hypercholesterolemia Prognosis, target for treatment
Heart failure Veramapil, Diltiazem contraindicated
Atrial Fib Antithrombotics, Bleeding
Renal failure Pharmacokinetics
Hypertension J curve response
Hypotension Most antiischemic drugs contraindicated
Bradicardia BB, verapamil, diltiazem contraindicated
Anemia Antithrombotics, Bleeding
Stroke Antithrombotics
Infections Physiopathology
Cancer Compliance, prognosis, bleeding
Dementia, cognitive disorders Compliance
Genotype Individual response to treatment
Constipation Ca antagonsts contraindicated
Depression Antidepresive drugs increase mortality
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Chronic ischemic heart disease and comorbidities
Comorbidities Importance
Bronchial disease BB Contraindicated
Heart failure Veramapil, Diltiazem contraindicated
Hypotension Most antiischemic drugs contraindicated
Bradicardia BB, verapamil, diltiazem contraindicated
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Chronic ischemic heart disease and comorbidities
Gislason G. Eur Heart J. 2006;27:1153-1158.
n=55.315
Beta-blocker
ACE-i
Statin
Gislason G. Eur Heart J. 2006;27:1153-1158.
Discontinuation of treatment
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Chronic ischemic heart disease and comorbidities
Change in Systolic Blood pressure and Incidence of AMI A
MI
/ 1000 p
ers
on/y
ears
Alderman et al JAMA 1989;261:920 N= 1765 BP ≥ 160/85 Follow-up 4,2y
Blood pressure reduction during treatment (mmHg)
Ischemic Heart Disease No ischemic Heart Disease
AM
I / 1000 p
ers
on/y
ears
≥18 ≥18 7-17 7-17 <6 <6
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Chronic ischemic heart disease and comorbidities
“J curve” between Blood Pressure and Coronary Artery Disease
Patients with revascularization
Patients without revascularization
DBP (mmHg)
Hazard
Rati
o
JACC
2009; 54:1827
JAMA
2003;290:2805
INVEST 22.500 pts
3y F-up
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Chronic ischemic heart disease and comorbidities
Euro Heart Survey Stable Angina C Daly et al. Postgrad Med J 2010;86212
Hospitalization for Heart Failure in Stable Angina
1y
F-up
0.7 0.7
1.4
2.5
4.8
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Chronic ischemic heart disease and comorbidities
New Drugs
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Chronic ischemic heart disease and comorbidities
Ivabradine in combination with Beta-Blockers
New indication
HR > 60 lpm
Ivabradine is indicated:
- in patients unable to tolerate or with a contraindication to beta-blockers
- or in combination with beta-blockers in patients inadequately controlled with
an optimal dose and whose heart rate is > 60
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Chronic ischemic heart disease and comorbidities
Ivabradine’s mechanism of action
Effects on sinus node diastolic depolarisation
DiFrancesco and Camm, Drugs 64: 1757-1765, 2004
Delay of diastolic depolarisation in the sinus node
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Chronic ischemic heart disease and comorbidities
Ivabradine associated with beta-blockers
Tardif, et al. Eur Heart J 2009;30:540
Ivabradine + atenolol
Placebo + atenolol
0
10
20
30
40
50
60
Total
Exercise Time
Time to
Limiting Angina
Time to
Angina Onset
Time to
1 mm ST
depression
P<0.001 P<0.001
P<0.001 P<0.001
Heart Rate > 60 bpm
(Basal Heart Rate 67 bpm)
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Chronic ischemic heart disease and comorbidities
Patients with angina (HR > 60 bpm)
CV Death, hospitalization for MI or heart failure
Fox K, et al. Eur Heart J. 2009;30:2337
%
Ivabradine Placebo
RR (95% IC), 0.76 (0.58–1.00), P=0.05
Years
0
5
10
15
20
25
30
0 0.5 1 1.5 2
24%
Placebo
Ivabradine
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Chronic ischemic heart disease and comorbidities
Ivabradine n=793 (14,5 %) Placebo n=937 (17,7 %)
HR = 0,82 p<0,0001
0 6 12 18 24 30
Meses
40
30
20
10
0
Ivabradine
Placebo
CV Death or Hospitalization for worsening HF
- 18 %
(%)
Lancet. Online 29-08-2010
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Chronic ischemic heart disease and comorbidities
4.1 Therapeutic indications
Ranexa is indicated as add-on therapy for the symptomatic treatment of patients
with stable angina pectoris who are inadequately controlled or intolerant to first-
line antianginal therapies (such as betablockers and/or calcium antagonists).
Authorisation valid through the European Union 9 July, 2008 2008
Ranolazine
Na channel inhibitor
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Chronic ischemic heart disease and comorbidities
Ranolazine: mechanism of action
Ischaemia
↑ Late INa
Na+ overload
Ranolazine
NCX
Hasenfuss G, et al Clin Res Cardiol 2008;97:22
Maier LS. Cardiol Clin 2008;26:603
Mechanical dysfunction ↑Diastolic tension
↓ Contractility
Electrical dysfunction
Arrhythmias
O2 supply & demand ↑ ATP consumption
↓ ATP formation
NCX: sodium-calcium exchanger
Ca++ overload
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Chronic ischemic heart disease and comorbidities
Ranolazine vs Placebo
in patients with maximal tolerated BB and Ca Channel blockers
CARISA subgroup
in press
Total
Exercise Time
Time to
Angina
Time to 1 mm ST
depression
Placebo
Ranolazine
140
120
100
80
60
40
20
0
Changes in Exercise test Parameters
at peak drug levels after 12 weeks of Treatment
se
co
nd
s
44
90
73
32
118
100
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Chronic ischemic heart disease and comorbidities
Ranolazine versus Amiodarone for AF Prophylaxis After CABG
Murdock D, et al. ACC 2011
•Retrospective cohort study
• 393 pts undergoing CABG
•Amiodarone (400 mg
preoperative followed by 200 mg
twice daily for 10-14 days)
•Ranolazine (1500 mg
preoperative followed by 1000
mg twice daily for 10-14 days)
•Mean age 65 ± 10 years,
72% men
Ranolazine associated independently with a reduction of post –op AF
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Chronic ischemic heart disease and comorbidities
MERLIN-TIMI 36:
Reduction in VT lasting ≥8 beats
0
2
4
6
8
10
0 24 48 72 96 120 144 168
Hours from randomization
Incid
en
ce (
%)
Ranolazine
n = 3,162
Placebo
n = 3,189
RR 0.63 (0.52-0.76)
P < 0.001
RR 0.67
P = 0.008
RR 0.65
P < 0.001
8.3%
5.3%
Scirica BM et al. Circulation. 2007;116: 1647-1652
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Chronic ischemic heart disease and comorbidities
Effect of Ranolazine on QTc interval in LQT3
QTc vs. [RAN] plasma r = 0.7 ± 0.22
slope = 24.1 msec/1,000 ng/ml (P = 0.008)
Values are mean ± SE from 5 patients
QTc (Fridericia) change from baseline
0 4 8 12 16 20 24
Time (hrs)
1000
2000
3000
- 10
- 20
- 30
- 40
- 50
* * *
§ ‡
§
‡ †
†
‡
*
*
‡
* p < 0.05
† p < 0.01
‡ p < 0.001
§ p < 0.0001
repeated measures ANOVA
Ch
an
ge i
n Q
Tc
(ms
ec
)
[Ran
ola
zin
e]
( n
g /m
l)
LQT3 due to KPQ mutation leading to increased SCN5A – activation of Late Na current
Moss A, et al. J Cardiovasc Electrophysiol 2008;19:1289-93
Therefore Ranolazine inhibits the
Late Sodium Current
On Ranolazine, IV Off
45 mg/hr 90 mg/hr
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Chronic ischemic heart disease and comorbidities
Merlin: Patients with prior angina
CV death, MI or recurrent Ischemia P
erc
en
tag
e (
%)
P = 0.017
Wilson S.R. et al. JACC 2009;53:1510
i.v. 1,000 mg b.i.d. p.o.
29.4
25.2
23
24
25
26
27
28
29
30
Placebo (n = 1,776) Ranolazine (n = 1,789)
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Chronic ischemic heart disease and comorbidities
Baseline BNP
and Effect of Ranolazine on Primary Endpoint
CV Death, MI, or Recurrent Ischemia (%)
Days from Randomization
0
5
10
15
20
25
30
0 180 360
BNP NEG
p = 0.009
BNP POS
Placebo
BNP POS
Ranolazine
P-interaction = 0.05
Morrow DA et al. AHA 2007, Orlando, FL
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Chronic ischemic heart disease and comorbidities
Ranolazine in Patients With Diabetes and CAD
Placebo
(n = 37)
Ranolazine 750 mg b.i.d.
(n = 47)
-0.02%
-0.50%
Absolute Reduction in HbA1c From Baseline to Week 12
Timmis AD, et al. Eur Heart J. 2006;27:42
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
in
Hb
A1
c (
%)
p = 0.008
Baseline, mean HbA1c Ranolazine 7.9% Placebo 7.5%
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Chronic ischemic heart disease and comorbidities
Effect of Ranolazine on Glucose Stimulated Insulin Secretion
(GSIS) in Pancreatic Islets
* p<0.05, ** P <0.01
Rat Islets
3mM
Glucose 0 100 nM 1 uM 0
200
400
600 n = 4 - 6 *
**
20 mM Glucose
Ranolazine Concentration
Ins
ulin
Re
lea
se
(%
of
Co
ntr
ol)
Human Islets
3mM
Glucose 0 100 nM 5 uM 0
150
300
450 n = 3 - 7 **
20 mM Glucose
Ranolazine Concentration
Ins
ulin
Re
lea
se
(% o
f C
on
tro
l)
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Chronic ischemic heart disease and comorbidities
Ranolazine for Angina with Non-obstructive CAD in Women
• Pilot randomized, double-blind, placebo-controlled, crossover trial
• 20 women with angina, no obstructive CAD, and 10% ischemic myocardium
• Ranolazine 1000 mg bid or placebo for 4 weeks / 2-week washout
• The Seattle Angina Questionnaire was evaluated after each treatment
Mehta PK, et al. JACC Cardiovasc Imaging 2011;4:514-22a
SAQ scores on ranolazine versus placebo
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Chronic ischemic heart disease and comorbidities
Treatments aimed at Symptom Relief
Betablockers, 1st line treatment
Ca antagonists: Amlodipine: Low heart rate, HT
Ivabradine:
Nitrate / Nicorandil:
Ranolazine:
Contraindication or intolerant Insuficient control of angina / ischaemia
Add Other option
Diltiacem, verapamil: Tach, HT
Heart rate > 60 b/m
General option
General option (diabetes, HF, arrhythmias)
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Chronic ischemic heart disease and comorbidities
B-Blockers Ca Ch Block Nitrates Ivabradine Ranolazine
General 1st Line 2nd Line
2nd Line
Current Efficacy
Unknown
2nd Line
HR > 60 2nd Line
Heart Failure OK Contraindicated OK OK OK
Atrial Fib OK OK OK No effect OK
Hypotension Limited Limitado Limited OK OK
AV-Block Contraindicated D & V
contraindicated OK OK OK
Bradicardia Limited Limited Limited Limited OK
COPD/Asthma Limited OK OK OK OK
Diabetes Difficult control OK OK OK OK
Treatment of Myocardial Ischemia and Comorbidities
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Chronic ischemic heart disease and comorbidities
Conclusions
1- Follow Guidelines
2- Identify and treat comorbidities
3- Ivabradine and Ranolazine new
drugs for treatment of ischemia
4- Revasc complementary to meds