Download 3% annual mortality rate

‫بسم هللا الرحمن الرحيم‬
Current Treatment of
Stable Angina
By
Ahmed Shafea Ammar
MD, FACC
Definition of Angina
Definition
 Chronic stable angina (CSA) is defined as the
predictable occurrence with exertion or emotional
upset of pressure or a squeezing sensation in the
substernal area of the chest and adjacent areas,
due to transient myocardial ischemia.
 Angina equivalents (exertional breathlessness,
fatigue, and/or nausea) may also occur with
physical activity or emotional stress.
Clinical Classification of
Chest Pain
Atherosclerosis Timeline
Foam
Cells
Complicated
Lesion/
Fatty Intermediate
Fibrous
Rupture
Streak
Lesion Atheroma Plaque
Endothelial Dysfunction
From First
Decade
From Third
Decade
Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).
From Fourth
Decade
Which Plaque Ruptures???
Vulnerable vs Stable
Atherosclerotic Plaques
Vulnerable Plaque
Lumen
Fibrous Cap
Lipid
Core
• Thin fibrous cap
• Inflammatory cell infiltrates:
proteolytic activity
• Lipid-rich plaque
Stable Plaque
Lumen
Lipid
Core
Fibrous Cap
• Thick fibrous cap
• Smooth muscle cells:
more extracellular matrix
• Lipid-poor plaque
Libby P. Circulation. 1995;91:2844-2850.
Epidemiology of Chronic Angina
 AHA reports that at least 6.6 million Americans
suffer with angina pectoris
 Despite therapeutic advances
– > 13 million episodes of angina a week in the US
– > 1000 episodes of angina every minute
 Growing prevalence of chronic angina due to
reductions in cardiovascular mortality
 Improved treatment of angina is an important goal
Comorbid Conditions Complicate Therapy
Studies of VA patients with CAD demonstrate the
following comorbidity incidence rates
– Diabetes: 26% to 31%
– COPD: 13% to 22%
– Peripheral vascular disease: 16% to 28%
– Congestive heart failure: 20%
Rumsfeld, 1999.
Noninvasive Risk Stratification
High-Risk (>3% annual mortality rate)
1. Severe resting LV dysfunction (LVEF < 35%)
2. High-risk treadmill score (score  -11)
3. Severe exercise LV dysfunction (LVEF < 35%)
4. Stress-induced large perfusion defect (particularly if anterior)
5. Stress-induced multiple perfusion defects of moderate size
6. Large, fixed perfusion defect with LV dilation or increased lung uptake
(thallium-201)
7. Stress-induced moderate perfusion defect with LV dilation or
increased lung uptake (thallium-201)
8. Echocardiographic wall motion abnormality (involving > 2 segments)
developing at low dose of dobutamine ( 10 mg/kg/min) or at low heart
rate (< 120 beats/min)
9. Stress echocardiographic evidence of extensive ischemia
Intermediate-Risk (< 3% annual mortality rate)
1. Mild-moderate resting LV dysfunction (LVEF 35% to 49%)
2. Intermediate-risk treadmill score (-11 score
5)
3. Stress-induced moderate perfusion defect
without LV dilatation or increased lung uptake
(thallium-201)
4. Limited stress echocardiographic ischemia
with a wall motion abnormality only at higher
doses of dobutamine involving  two
Low-Risk (< 1% annual mortality rate)
1. Lowest treadmill score (score  5)???
2. Normal or small myocardial perfusion defect
at rest or with stress
3. Normal stress echocardiographic wall
motion or no change of limited resting wall
motion abnormality during stress ???
Prognostic Markers in Exercise Testing
The Duke Treadmill Score (risk calculation)
The Duke treadmill score =
– exercise time in minutes on Bruce Protocol
– minus 5x the ST-segment deviation
(during or after exercise, in millimeters)
– 4x the angina index
(“0” if there is no angina, “1” if angina occurs, and
"2" if angina is the reason for stopping the test).
 works well for both inpatients and outpatients, and equally well
for men and women
N Engl J Med 1991;325:849-53
Survival According to Risk Groups Based on Duke
Treadmill Score
Risk Group (Score)
Low ( +5)
Moderate (-10 to +4)
High (< -10)
Total
62%
34%
4%
Survival
99%
95%
79%
N Engl J Med 1991;325:849-53
4 –Year Annual
Mortality
0.25%
1.25%
5.00%
Use of Exercise Test Results in Patient Management
need for additional testing (i.e. stress imaging)
risk score
predicted average
annual mortality
recommended
treatment
low
<1% per year
medical therapy
intermediate
1% to 3%
cardiac catheterization
exercise imaging study
>3% per year
cardiac catheterization
high-risk score
* <5% pt with low-risk treadmill score will be identified as high risk after imaging
* those with known LV dysfunction should have cardiac catheterization
Therapy of Angina
Goals of Current Therapy of Angina
 Control of Anginal Symptoms
 Reduction of MACE
Drugs in angina and secondary prevention of
coronary heart disease
For chest pain
 Nitrates
 Beta-blockers
 Calcium antagonists
For prognosis
 Asprin
 Statin
 Beta-blockers (after
myocardial infarction)
 Calcium antagonists
 ACE inhibitor
Strategies to control Anginal Symptoms
Antianginal Medications
 ß-Blockers,
 Nitrates, and
 Calcium channel blockers (CCBs)
ALL are effective antianginal and anti-ischemic agents.
However
 There is no evidence that any of these drugs prolong
life or reduce the incidence of MI in patients with CSA
(J Cardiovasc Pharmacol Ther. 2004)
β-Blockers
Beta blockers
 Beta blockers decrease three major
determinants of myocardial oxygen demand
– Heart rate
– Contractility
– Systolic wall tension
 Beta blockers also allow improved perfusion of
the subendocardium by increasing diastolic
perfusion time
Rebound Phenomena
 Sudden cessation of beta blocker therapy
may precipitate myocardial infarction
 Those at risk include patients with angina
and men over 50 years.
Contraindications
 Asthma
 Peripheral Vascular Disease
– Relative contraindication
 Raynauds Syndrome
 Heart failure
– Those patients who are dependent on
sympathetic drive
 Bradycardia / Heart block
Adverse Drug Reactions




Tiredness /fatigue
Impotence
Bradycardia
Bronchospasm
Nitrates
Hemodynamic Effects of nitrates
Dilatation of vessels
Veins
Arterioles
Dilation of venous
capacitance
vessels
Pre-load reduction
PCP and
PAP
End diast. Ventricular
pressure
Coronary vessels
Dilation of peripheral
resistance vessels
Dilation of coronary
vessels
After-load reduction
Vasal resistance
Resistance against cardiac-output
Coronary/Venous
spasm
Coronary blood flow
Cardiac output
Diastolic wall tension
O2 consumption
O2 supply
Optimized O2 balance
PCP= pulmonary capillary pressure PAP= pulmonary arterial pressure
The Value of Nitrates as Excellent Combination
Partners
1.
2.
3.
4.
Nitrates are safe, with rare interactions with other
substances (no influence on hepatic metabolism
of other drugs).
Nitrates have no effect on plasma lipid & glucose
levels such as beta-blockers, & do not provoke
angina or peripheral edema such as calciumantagonists.
Nitrates have beneficial CV effects, which are
complementary to the effects of other CV drugs.
Nitrates are cost-effective.
Nitrates in management of stable angina
 For Immediate relief
Treatment with glyceryl trinitrate/ISDN that
can be given as a spray or sublingually.
 Long term Prophylaxis
Treatment with Isosorbide Mononitrate that
can be given either in a short-acting or a
sustained release formulation.
Different Available Nitrate Preparations
•Glyceryl Trinitrate
•Isosorbide Dinitrate
•Isosorbide
Mononitrate
“nitrate free interval”
 Tolerance may occur to nitrates.
 A nitrate free interval of at least 8 hours has
been recommended between doses.
 After overnight free period, sensitivity
returns the next day.
Adverse Drug Reactions
 Headache
– Increase dose slowly
 Hypotension
– GTN syncope
Calcium Channel Blockers
Anti-anginal Effects of CCBs
 CCBs reduce vascular tone and so produce
vasodilatation
– reduce after load and so myocardial work load
 Rate limiting CCBs reduce myocardial contractility
– reduce myocardial oxygen requirements
 Rate limiting CCBs reduce heart rate
– reduce myocardial oxygen requirement
 CCBS may also produce coronary vasodilatation
– Of little importance or even dangerous
Adverse Drug Reactions
 Ankle oedema
– Affects 15-20% of patients and does not
respond to diuretics
 Headache
 Flushing
 Palpitation
Contraindications
 Evidence that the use of short acting CCBs (nifedipine)
may precipitate acute MI or stroke
 Post MI
– May increase morbidity and mortality in patients
with impaired LV function
 Unstable angina
– Evidence that dihydropyridines may increase
infarction rate and death in the unstable patient
Beta-blockers vs. calcium antagonists: angina relief. Reproduced
from ACC/AHA 2002 guideline update for the management of
patients with chronic stable angina,3 with permission.
Beta-blockers vs. calcium antagonists: exercise time to 1 mm STdepression. Reproduced from ACC/AHA 2002 guideline update for the
management of patients with chronic stable angina,3 with permission.
New drugs for the treatment of angina
pectoris and mechanisms of action
Drug
Probable mechanism
TMZ
Metabolic switch
Ivabradine Slows heart rate; If channel inhibitor
Ranolazin New: slow sodium channel inhibitor; old: metabolic
e
switch
Nicorandil K-channel activator and nitrate like properties
Strategies to Reduce MACE
1- Risk Factors Management
2- Asprin
3- Statin
4- B- blocker
5- ACEI
6- Surgery
7- ?? DES
Risk Factor Management
1
(Level B), ↓1 year mortality by 50%
2
( Level A), ↓ CV mortality by 18-20%)
Level A = multiple RCTs Level B = single RCT or non RTs Level C= expert openion
Risk Factor Management
3
4
( Level B)
5
( Level C)
Risk Factor Management
6
LDL <100 mg/dl (Level A)
Risk Factor Management
Diabetes Melletis
7
Patients with angina should make efforts to
optimize glycemic control. (Level C)
ASPRIN
 Daily aspirin (81-325 mg) reduced CV mortality
and morbidity with an ARR of 12 /1000 patients
treated during a 15-month period.
(Lancet. 1992; 340: 1421–1425)
STATIN
 No specific trials with lipid-lowering agents have
been conducted in patients with CSA. However, in
the 4S trial, many patients had CSA and
experienced a reduction in angina as well as in
MACE
 Current guidelines recommend a target fasting
LDL cholesterol level of <100 mg/dL in patients
with CSA.
 The most recent NCEP-ATP III directive suggests
a target of LDL <70 mg/dL for high-risk CAD
patients.
Β-blockers
 ß-Blockers have been shown to improve survival and
reduce hospitalization in HF patients with an LVEF 40%
and in survivors of acute MI.
 BB should be used as first-line therapy in patients with
CSA who have reduced LV systolic function, provided that
such patients are on background treatment with ACEI.
 Practice guidelines recommend that ß-blockers are the first
choice of therapy for uncomplicated CSA.
(N Engl J Med. 2005; 352: 2524–2533)
ACEI
 ACEI should be used in all patients with CSA, who
have :
previous MI
diabetes,
hypertension,
proteinuria,
CKD
LVEF <40%
(Circulation. 2005;112:e255-e259.)
 In older patients with CAD, routine use of ACEI has
been recommended on the basis of the positive results
of the HOPE and EUROPA trials.
CABG & PCI
 PCI and CABG relieve angina in 80% to 90% of
patients.
 However, compared with medical therapy,
these procedures do not prolong life or reduce
the incidence of MI, except in patients with
LMC disease and in those with 2- or 3vessel disease with decreased LV function
(J Cardiovasc Pharmacol Ther. 2004)
(2001)
(2005)
Class I
Class IIa
Patients with 1 or more
significant lesions in 1 or
more coronary arteries
suitable for PCI with a high
likelihood of success and low
risk of morbidity or mortality.
 The vessel (s) to be dilated
must subtend a moderate or
large area of viable
myocardium and have high
risk. (Level of Evidence: B)
It is reasonable that PCI be
performed in patients with CCS
class III angina and single-vessel
or multivessel CAD who are
undergoing medical therapy and
who have 1 or more significant
lesions in 1 or more coronary
arteries suitable for PCI with a
high likelihood of success and
low risk of morbidity or mortality.
(Level of Evidence: B)

The recommendation class has
been changed to IIa to reflect
published data and Writing
Committee consensus.

Criteria regarding viable and
high-risk myocardium have been
deleted from this
recommendation.
CABG vs Medical TTT
Gr = Coronary anatomy severity groups (9) (J Thorac Cardiovasc Surg 1996)
95% = 95% prox. Stenosis Hazard ratio = MR
CABG vs PCI
(J Thorac Cardiovasc Surg 1996)
CABG vs PCI
Different trials
ARTS trial, repeat revascularization
Arts MR
CM-58
Percutaneous Coronary Angioplasty
Compared With Exercise Training in
Patients With Stable Coronary Artery
Disease
A Randomized Trial
(Circulation. 2004;109:1371-1378.)
 ACC/AHA/SCAI 2005 Guideline Update for Percutaneous
 Coronary Intervention—Summary Article
 A Report of the American College of Cardiology/American Heart
Association
 Task Force on Practice Guidelines (ACC/AHA/SCAI Writing
Committee to
 Update the 2001 Guidelines for Percutaneous Coronary
Intervention)
 WRITING COMMITTEE MEMBERS
 Sidney C. Smith, Jr, MD, FACC, FAHA, Chair; Ted E. Feldman, MD,
FACC, FSCAI*;
 John W. Hirshfeld, Jr, MD, FACC, FSCAI*; Alice K. Jacobs, MD, FACC,
FAHA, FSCAI;
 Morton J. Kern, MD, FACC, FAHA, FSCAI*; Spencer B. King, III, MD,
MACC, FSCAI;
 Douglass A. Morrison, MD, PhD, FACC, FAHA, FSCAI*; William W.
O’Neill, MD, FACC, FSCAI;
 Hartzell V. Schaff, MD, FACC, FAHA; Patrick L. Whitlow, MD, FACC,
FAHA;
 David O. Williams, MD, FACC, FAHA, FSCAI
PCI vs Medical TTT
Meta-analysis of randomised controlled trials
(BMJ 321:73-77, 2000)
PCI versus Exercise Training
Evolution of Therapy
PCI
TREATMENT
TMZ
Ivbradine
Ranolazine
Nicorandil
CCB
CABG
 block
Nitrates
Likely
mechanisms
 O2 demand
 O2 supply
 ATP/O2
1880
1965
+
+
+
1969
1975
1977
+
+
?
+
2004
+
Persistent Angina Despite
Current Drug Therapy
 Despite use of traditional anti-anginal agents
(-blockers, CCBs, and nitrates), patients still
reported an average of 2 anginal attacks/week†
 A significant percentage of patients have relative
intolerance to full doses of -blockers, CCBs, and
nitrates
 -blockers and many CCBs have similar depressive
effects on BP, HR and/or AV nodal conduction
 It would be desirable to develop an anti-anginal drug
without these limitations
†Pepine, 1994.
Persistent Angina Despite
Percutaneous Intervention (PCI)
1 yr after PCI for. . .
 Symptom relief
(N = 1403)
 Treatment of acute
myocardial infarction
(N = 352)
. . . the overall
prevalence of angina
was 26%
Angina at 1-yr follow-up by
events during or after initial PCI
Angina at
Events, n
follow-up, %
Events occurring after post-PCI
discharge only
MI
No
1576
25.2
Yes
44
38.6
CABG
No
1522
26.3
Yes
98
15.3
Repeat PCI
No
1370
24.1
Yes
250
34.0
Holubkov R, et al. NHLBI Dynamic Registry. Am Heart J. 2002;144:826-833.
Persistent Angina Despite
Optimal Revascularization
1 yr after optimal revascularization by stenting or surgery
for relief of ischemia (ie, not to prolong survival) …
TABLE 3. STATUS WITH RESPECT TO ANGINA AND MEDICATION USE AND QUALITY OF LIFE AMONG SURVIVING PATIENTS.*
VARIABLE
12 MO AFTER INTERVENTION
STENTING SURGERY
GROUP
GROUP
P
value
Free of angina (%)
78.9
89.5
<0.001
Free of antianginal medication (%)
21.1
41.5
<0.001
Free of angina and antianginal
medication (%)
19.1
38.4
<0.001
~ 60% to 80% are still taking anti-anginal medications
~ 10% to 20% still have angina
Serruys PW, et al. for the ARTS Study Group. N Engl J Med. 2001;344:1117-1124.
Unmet Need of Chronic Angina
 Angina continues in many patients despite
medical therapy and mechanical
revascularization
 The personal burden can deprive many
patients of their functional independence,
forcing them to downsize their lives
 The economic toll of angina places a huge
burden on patients, their families, the
healthcare system, and society
Unmet Need of Chronic Angina
When angina cannot be eliminated by current
drugs, it is often their additive effects on BP, HR,
AV conduction, and other important side effects
(depression, fatigue, sexual/sleep disorders,
etc.) that preclude complete relief.
Novel Therapies Needed for a Growing
Angina Burden
6
4
Patients,
millions
2
0
1900
2000
The 10 most
important
elements of
stable angina
management.
Ahmed Shafea
MD, FACC