Transcript Slide 1

GUIDELINES FOR THE
MANAGEMENT OF
CHRONIC STABLE ANGINA
American College of Cardiology,
Puerto Rico Chapter,
February 6, 2007
GAP
The Goals of Therapy in CAD
To improve quality of life (symptoms)
To reduce mortality
To reduce morbidity
To reduce progression of disease and
induce regression.
Treatment of Chronic Stable Angina
Medical
Revascularization
PCI
ACBG
MEDICAL THERAPY
ANTIPLATELETS
BETA BLOCKERS
NITRATES
CALCIUM ANTAGONIST
ACEI
STATINS
NEW THERAPIES
ANTIPLATELET AGENTS
ASA
– Physicians’ Health Study
– Swedish Angina Pectoris Trial
TICLOPIDINE
CLOPIDOGREL
– CAPRI
– CURE
Receptor GP IIb-IIIa: The Final Common Pathway to
Platelet Aggregation
High-dose heparin stimulates
PAF which activates platelets
• GP IIb-IIIa inhibitors displace fibrinogen in existing thrombi to
disaggregate thrombus and prevent further platelet crosslinking and thrombosis
• GP IIb-IIIa inhibitors prevent platelet
activation by blocking GP IIb-IIa (outsidein signaling)
White HD. Am J Cardiol 1997; 80:2B-10B.
Schafer A. J Clin Invest 1986; 78:73-79.
DeJong MJ, et al. Critical Care Nursing Clin of N Am 1999; 11:355-371.
Moser M, et al. J Cardiovasc Pharmacol 2003;41:586-592.
Phillips DR, Scarborough RM. Am J Cardiol 1997;80(4A):11B-20B.
PHYSICIANS' HEALTH STUDY
A randomized, double-blind, placebo controlled trial
designed to test the effects of low-dose aspirin and
beta-carotene in the primary prevention of CVD and
cancer among 22,071 US male physicians, aged 40
to 84 at baseline in 1982. Baseline blood specimens
were collected and frozen for later analyses from
14,916 participants.
Using a 2x2 factorial design:
• 325 mg of aspirin (Bufferin, supplied by
Bristol-Myers Products on alternate days)
• 50 mg of beta-carotene (Lurotin, supplied by
BASF AG on alternate days)
PHYSICIANS' HEALTH STUDY
Primary Endpoints
• Total cancer
• Prostate cancer
• Cardiovascular disease
• Eye disease
 Cataract
 Macular
degeneration
PHYSICIANS' HEALTH STUDY
The trial's Data and Safety Monitoring Board
stopped the aspirin arm of the PHS several
years ahead of schedule because it was clear
that aspirin had a significant effect on the risk of
a first myocardial infarction. As reported in the
July 20, 1989 New England Journal of
Medicine, aspirin reduced the risk of first
myocardial infarction by 44% (P less than
0.00001). There were too few strokes or deaths
upon which to base sound clinical judgment
regarding aspirin and stroke or mortality
Pharmacotherapy for Chronic
Stable Angina (class I)
1. Aspirin in the absence of contraindications A
2. Beta-blockers as initial therapy in the absence of
contraindications in patients with prior myocardial infarction or
without prior myocardial infarction A,B
3. ACE inhibitor in all patients with CAD who also have diabetes
and/or LV systolic dysfunction A
4. LDL-lowering therapy in patients with documented or suspected
CAD and LDL cholesterol >130 mg/dl, with a target LDL of <100
mg/dl A
5. Sublingual nitroglycerin or nitroglycerin spray for the immediate
relief of angina B
6. Calcium antagonists † or long-acting nitrates as initial therapy for
reduction of symptoms when beta blockers are contraindicated B
7. Calcium antagonists † or long-acting nitrates in combination with
beta blockers when initial treatment with beta blockers is not
successful B
8. Calcium antagonists † and long-acting nitrates as a substitute for
beta blockers if initial treatment with beta blockers leads to
unacceptable side effects
Pharmacotherapy for Chronic
Stable Angina (class IIa)
1. Clopidogrel when aspirin is absolutely contraindicated
2. Long-acting non-dihydropyridine calcium antagonists
† instead of beta blockers as initial therapy B
3. In patients with documented or suspected CAD and
LDL cholesterol 100–129 mg/dl, several therapeutic
options are available: B
– a. Lifestyle and/or drug therapies to lower LDL to
<100 mg/dl
– b. Weight reduction and increased physical activity
in persons with the metabolic syndrome
– c. Institution of treatment of other lipid or non-lipid
risk factors; consider use of nicotinic acid or fibric acid
for elevated triglycerides or low HDL cholesterol
4. ACE inhibitor in patients with CAD or other vascular
disease
Pharmacotherapy for Chronic
Stable Angina
IIb (weak supportive evidence)
– Low-intensity anticoagulation with warfarin in
addition to aspirin B
III (not indicated)
– 1. Dipyridamole B
– 2. Chelation therapy B
CURE
Approach to the treatment of chest pain
OXYGEN DEMAND
Double product = (Heart Rate) (systolic blood pressure)
BETA BLOCKERS
Effects of β-blockade on ischemic heart
Printed from: Drugs for the Heart © 2007 Elsevier
Cardiac effects of β-adrenergic blocking drugs at the levels of the SA
node, AV node, conduction system, and myocardium
Printed from: Drugs for the Heart © 2007 Elsevier
Contraindications to β-blockade
Printed from: Drugs for the Heart © 2007 Elsevier
BETA BLOCKERS STUDIES
TIBET (Total Ischemic Burden European
Trial)
APSIS (The Angina Prognosis Study In
Stockholm)
ASIST (Atenolol Silent Ischemia Trial)
TIBBS (Total Ischemic Burden Bisoprolol
Study)
IMAGE (International Multicenter Angina
Exercise Study)
BB for clinical use
ACC/AHA 2002 Guideline Update for the Management of Patients With
Chronic Stable Angina
Comparison of hemodynamic
effects of β-blockers and of CCBs
Printed from: Drugs for the Heart © 2007 Elsevier
CARDIAC VS. VASCULAR
Printed from: Drugs for the Heart © 2007 Elsevier
Mechanisms of anti-ischemic effects of
calcium channel blockers
Printed from: Drugs for the Heart © 2007 Elsevier
Verapamil and diltiazem have a broad
spectrum of therapeutic effects.
Printed from: Drugs for the Heart © 2007 Elsevier
Contraindications to verapamil or
diltiazem
Printed from: Drugs for the Heart © 2007 Elsevier
Contraindications to
dihydropyridines
Printed from: Drugs for the Heart © 2007 Elsevier
Properties of CCB in clinical use
Schematic diagram of effects of
nitrate on the circulation
Printed from: Drugs for the Heart © 2007 Elsevier
Effects of nitrates in generating NO• and
stimulating guanylate cyclase to cause
vasodilation
Printed from: Drugs for the Heart © 2007 Elsevier
Current proposals for therapy of
nitrate tolerance.
Printed from: Drugs for the Heart © 2007 Elsevier
A serious nitrate drug interaction
Printed from: Drugs for the Heart © 2007 Elsevier
Nitrates in Angina
Effect of simvastatin on cardiovascular events
among patients with and without coronary heart
disease (CHD) in the Heart Protection Study
Dual role of ACE inhibitors, both
preventing and treating cardiovascular
disease
Printed from: Drugs for the Heart © 2007 Elsevier
Post-infarction remodeling
Printed from: Drugs for the Heart © 2007 Elsevier
ACC/AHA Guidelines for Treatment of Risk Factors
(class I)
1. Treatment of hypertension according to Joint National
Conference VI guidelines A
2. Smoking cessation therapy B
3. Management of diabetes C
4. Comprehensive cardiac rehabilitation program
(including exercise) B
5. LDL-lowering therapy in patients with documented or
suspected CAD and LDL cholesterol ≥130 mg/dl, with a
target LDL of <100 mg/dl A
6. Weight reduction in obese patients in the presence of
hypertension, hyperlipidemia, or diabetes mellitus C
ACC/AHA Guidelines for Treatment of Risk Factors
(class IIa)
1. In patients with documented or suspected CAD and LDL
cholesterol 100–129 mg/dl, several therapeutic options are
available: B
–
–
a. Lifestyle and/or drug therapies to lower LDL to <100 mg/dl B
b. Weight reduction and increased physical activity in persons with
the metabolic syndrome B
–
c. Institution of treatment of other lipid or nonlipid risk factors;
consider use of nicotinic acid or fibric acid for elevated triglycerides or
low HDL cholesterol B
2. Therapy to lower non-HDL cholesterol in patients with
documented or suspected CAD and triglycerides >200 mg/dl, with a
target non-HDL cholesterol <130 mg/dl B
3. Weight reduction in obese patients in the absence of
hypertension, hyperlipidemia, or diabetes mellitus C
ACC/AHA Guidelines for Treatment of Risk Factors
(class IIb)
1. Folate therapy in patients with elevated
homocysteine levels C
2. Identification and appropriate treatment
of clinical depression to improve CAD
outcomes C
3. Intervention directed at psychosocial
stress reduction C
ACC/AHA Guidelines for Treatment
of Risk Factors (class III)
1. Initiation of hormone replacement therapy in
postmenopausal women for the purpose of
reducing cardiovascular risk A
2. Vitamins C and E supplementation A
3. Chelation therapy C
4. Garlic C
5. Acupuncture C
6. Coenzyme Q C
Specific Goals for Risk Reduction Strategies
in Patients with Chronic Stable Angina
Smoking Complete cessation
Blood pressure <140/90 or 130/85 mm Hg if
heart failure or renal insufficiency; <130/85 mm
Hg if diabetes
Lipid management Primary goal: LDL <100
mg/dl Secondary goal: If triglycerides ≥200
mg/dl, then non-HDL should be <130 mg/dl
Physical activity Minimum goal: 30 min 3 or 4
d/w Optimal goal: daily
Weight management BMI 18.5–24.9 kg/m2
Diabetes management HbA1c <7%
Specific Goals for Risk Reduction Strategies
in Patients with Chronic Stable Angina
Antiplatelet agents/anticoagulants : All patients: indefinite use of aspirin 75–
325 mg per day if not contraindicated. Consider clopidogrel as an
alternative if aspirin is contraindicated. Manage warfarin to international
normalized ratio = 2.0 to 3.0 in patients after myocardial infarction when
clinically indicated or for those not able to take aspirin or clopidogrel
ACE inhibitors: Treat all patients indefinitely after myocardial infarction; start
early in stable high-risk patients (anterior myocardial infarction, previous
myocardial infarction, Killip class II [S3 gallop, rales, radiographic CHF]).
Consider chronic therapy for all other patients with coronary or other
vascular disease unless contraindicated. Use as needed to manage blood
pressure or symptoms in all other patients
Beta blockers: Start in all post-myocardial infarction and acute patients
(arrhythmia, LV dysfunction, inducible ischemia) at 5–28 days. Continue 6
mo minimum. Observe usual contraindications. Use as needed to manage
angina, rhythm, or blood pressure in all patients
ACC/AHA Guidelines for Echocardiography, Treadmill
Exercise Testing, Stress Radionuclide Imaging, Stress
Echocardiography Studies, and Coronary Angiography
During Patient Follow-Up
1. Chest radiograph for patients with evidence of new or
worsening CHF C
2. Assessment of LV ejection fraction and segmental
wall motion by echocardiography or radionuclide imaging
in patients with new or worsening CHF or evidence of
intervening myocardial infarction by history or ECG C
3. Echocardiography for evidence of new or worsening
valvular heart disease C
4. Treadmill exercise test for patients without prior
revascularization who have a significant change in
clinical status, are able to exercise, and do not have any
of the ECG abnormalities listed in No. 5
ACC/AHA Guidelines for Echocardiography, Treadmill
Exercise Testing, Stress Radionuclide Imaging, Stress
Echocardiography Studies, and Coronary Angiography
During Patient Follow-Up
5. Stress radionuclide imaging or stress echocardiography procedures for
patients without prior revascularization who have a significant change in
clinical status and are unable to exercise or have one of the following ECG
abnormalities: C
–
–
–
–
a. Preexcitation (Wolff-Parkinson-White) syndrome
b. Electronically paced ventricular rhythm
c. More than 1 mm of rest ST depression
d. Complete left bundle branch block
6. Stress radionuclide imaging or stress echocardiography procedures for
patients who have a significant change in clinical status and required a
stress imaging procedure on their initial evaluation because of equivocal or
intermediate-risk treadmill results C
7. Stress radionuclide imaging or stress echocardiography procedures for
patients with prior revascularization who have a significant change in clinical
status C
8. Coronary angiography in patients with marked limitation of ordinary
activity (CCS class III) despite maximal medical therapy
Chronic stable angina
NEW THERAPIES
Myocardial ischemia:
Sites of action of anti-ischemia
medication
Development of ischemia
Consequences of ischemia
↑ O2 demand
•
•
•
•
Heart rate
Blood pressure
Preload
Contractility
Ischemia
(Ca2+ overload)
↓ O2 supply
Conventional
anti-ischemic
medications
 ß blockers
 Nitrates
 Ca++ blockers
• Electrical instability
• Myocardial dysfunction
(↓ systolic function/
↑ diastolic stiffness)
Ranolazine
Compression
of nutritive
blood vessels
(Stone, 2004)
Consequences associated with
dysfunction of late sodium current
• Diseases
(eg, ischemia, heart
failure)
Na+ channel
• Pathological milieu
(reactive O2 species, (Gating
mechanism
ischemic metabolites)
malfunction)
• Toxins
and drugs
(eg, ATX-II, etc.)
Mechanical
dysfunction
Oxygen supply
and demand
• Abnormal contraction • Increase ATP
and relaxation
• ↑ diastolic tension
(↑LV wall stiffness)
consumption
• Decrease ATP
formation
Electrical
instability
• Early after potentials
• Beat-to-beat ΔAPD
• Arrhythmias (VT)
Diastolic relaxation failure increases
oxygen consumption and reduces oxygen
supply
Increased myocardial tension
during diastole:
– Increases myocardial O2
consumption
– Compresses intramural small
vessels
Reduces myocardial blood flow
– Worsens ischemia and
angina
Ranolazine: Mechanism of action
Ischemia
↑ Late INa
Ranolazine
inhibits the late inward
Na current
Na+ overload
Ca2+ overload
Diastolic relaxation failure
(increased diastolic tension)
Extravascular compression
Monotherapy with ranolazine increases exercise
performance at trough and peak: MARISA
Placebo
500 mg bid
1000 mg bid
1500 mg bid
Peak
Time, sec
Trough
560
520
480
440
400
**
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Exercise
duration
Time
to angina
Time to 1mm
ST
depression
n=175,
**p <0.01 vs placebo; ***p <0.001 vs. placebo
Exercise
duration
Time
to angina
Time to 1mm
ST
depression
Chaitman et al JACC 2004;43:1375
Combination regimen of ranolazine with:
► Atenolol 50 mg qd, or
► Diltiazem 120 mg qd, or
(CARISA)
► Amlodipine 5 mg qd
Change from baseline, sec
Placebo
150
Trough
* *
750 mg bid
1000 mg bid
Peak
** **
*
*
***
***
*
**
100
50
Exercise
duration
Time
to angina
Time to 1-mm
ST depression
n=791
*p <0.05; **p ≤0.01; ***p ≤0.001 vs placebo.
Exercise
duration
Time
to angina
Time to 1-mm
ST depression
Chaitman et al. JAMA 2004;291:309
Effect of ranolazine in patients with
refractory angina despite
maximum amlodipine therapy: ERICA
p=0.48
p=0.028
6
5
4
3
2
1
0
Amlodipine
p=0.18
5.5
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Amlodipine
+
+
Ranolazine
Baseline
p=0.014
5.0
Amlodipine
+
Placebo
NTG consumption/week
Number of NTGs consumed/week
Number of angina episodes/week
Angina episodes/week
Placebo
On placebo
Amlodipine
+
Ranolazine
On ranolazine
Stone et al. Circulation 2005;112:II-748
TMR
Surgical
surgeons use the laser to make between
20 and 40 tiny (one-millimeter-wide)
Percutaneous TMR
Percutaneous
Rationale
improved perfusion by stimulation of
angiogenesis
potential placebo effect
anesthetic effect mediated by the
destruction of sympathetic nerves carrying
pain-sensitive afferent fibers
Peri-procedural infarction.
EECP
EECP
Increases arterial blood pressure and
retrograde aortic blood flow during diastole
(diastolic augmentation).
Cuffs are wrapped around the patients
legs and sequential pressure (300mmHg)
is applied in early diastole.
Patient selection
Angina class III/IV
– Refractory to medical therapy
– Reversible ischemia of the free wall
– not amenable for revascularization
Excluded if LVEF<20% or had current
major illness
ACC/AHA Guidelines for Revascularization with
PCI and CABG in Patients with Stable Angina
(class I)
1. CABG for patients with significant left main coronary
disease A
2. CABG for patients with triple-vessel disease. The
survival benefit is greater in patients with abnormal LV
function (ejection fraction <0.50)A
3. CABG for patients with double-vessel disease with
significant proximal LAD CAD and either abnormal LV
function (ejection fraction less than 50%) or
demonstrable ischemia on noninvasive testing A
4. Percutaneous coronary intervention for patients with
double-or triple-vessel disease with significant proximal
LAD CAD, who have anatomy suitable for catheterbased therapy and normal LV function and who do not
have treated diabetes B
ACC/AHA Guidelines for Revascularization with
PCI and CABG in Patients with Stable Angina
(class I)
5. PCI or CABG for patients with single- or doublevessel CAD without significant proximal LAD CAD but
with a large area of viable myocardium and high-risk
criteria on noninvasive testing B
6. CABG for patients with single- or double-vessel CAD
without significant proximal LAD CAD who have survived
sudden cardiac death or sustained ventricular
tachycardia C
7. In patients with prior PCI, CABG or PCI for recurrent
stenosis associated with a large area of viable
myocardium or high-risk criteria on noninvasive testing C
8. PCI or CABG for patients who have not been
successfully treated by medical therapy and can undergo
revascularization with acceptable risk B
QUESTIONS??