Download Summary: Although, dramatic advances in the prevention and

Stable angina pectoris: The medical management of symptomatic myocardial ischemia
Parker, J.D, Parker, J.O,
Canadian Journal of Cardiology 2012, 28(25), S70-80.
Prevalence of stable angina and summary: In Canada, 500,000 (2% of the population) people over the age of 12 report
1
2
exertional angina. Globally, stable angina is more prevalent in women and varies broadly country to country. Cumulative
3
post intervention studies confirm that many patients develop or continue to have angina following revascularization.
Exertional angina continues to be a problem, in particular. Although dramatic advances in the prevention and treatment of
CAD have been attributed to the development of effective surgical and percutaneous revascularization techniques, skilled
individualized medical management of symptomatic stable angina remains critical. Patients with stable angina have an
excellent prognosis; those who obtain relief from symptomatic myocardial ischemia may do well without invasive
intervention.
Medical Management: The pharmacological prevention of exertional symptoms of angina has involved the use of agents
which reduce myocardial oxygen demand and/or increase myocardial oxygen supply in response to exercise. Currently, the
classes of anti-anginal agents available in Canada are organic nitrates, β-adrenergic blocking agents, and calcium channel
antagonists.
Organic Nitrates are potent vasodilators that reduce preload, thereby reducing myocardial oxygen consumption and left
4
ventricular chamber size. In addition, when using dosing regimens that avoid tolerance, nitrates decrease myocardial oxygen
4
consumption by reducing blood pressure and increasing conduit artery distensibility. Table 1 presents pharmacologic
characteristics of commonly available organic nitrates, all of which have evidence of effectiveness in the therapy of exertional
angina.
Table 1. Pharmacologic characteristics of common organic nitrates
Half-life
Elimination
Heart rate
Vascular resistance
Usual dosage
SL NTG
6-9 min
Hepatic
↑
↓↓
0.4-0.6 mg
TD GTN
6-9 min
Hepatic
↔
↔
0.2-0.6mg/h (intermittent)
ISDN
1-2 (4-5) hrs*
Hepatic
↑
↓
5†-30mg TID (eccentric)
IS-5-MN (phasic release)
4-5hrs
Hepatic
↔
↔
60-240mg OD
GTN, glyceryl trinitrate; IS-5-MN, isosorbide-5-mononitrate; ISDN, isosorbide dinitrate; OD, once daily; SL, sublingual; TD, transdermal; TID, three times
daily. *Half-life of active metabolite isosorbide-5-mononitrate. †ISDN (5 mg) may be administered sublingually for prevention of angina.
Tolerance has been shown to develop with all types of organic nitrates when they are administered using dosing patterns or
5
preparations that lead to continuous nitrate concentrations in plasma over a 24-hour period. Tolerance is manifested by loss
of the hemodynamic and symptomatic effects of nitrates. To date, the only approach that has been applied clinically is the
use of ‘intermittent therapy’ where dosing regimens or nitrate formulations that yield low or nitrate-free concentrations in
plasma for 10-12 hours per day are employed.
Isosorbide dindrate is also available in 5 mg tablets that can be used sublingually; although not regularly used for the
treatment of acute episodes of angina it can be effective when taken prior to activity for those with refractory effort angina.
Sublingual nitroglycerin is prescribed for acute attacks of angina or pre-exertional activities. It is important to remember that
sublingual nitroglycerin can also be used prophylactically when patients with exertional symptoms embark on patterns of
activity that generally lead to the development of angina.
β-Adrenergic Blockers reduce myocardial oxygen demand in response to exercise by decreasing heart rate, blood pressure,
6-10
and myocardial inotropic responses. Via negative chronotropic effects, they can improve coronary blood flow by increasing
diastole time. Table 2 presents the pharmacologic characteristics of common β-1 selective β adrenergic blockers and
nonselective β-Adrenergic Blockers. Pharmacodynamic and pharmokinetic effects of these agents are based on the half-life,
β-1 receptor selectivity, sympathomimetic activity, lipophilicity and elimination to determine individual use. Agents with β-1
receptor selectivity can be used in patients with either chronic obstructive lung disease or diabetes. Clinically effective doses
are determined by resting heart rate, blood pressure, and side effect profile. The effect of β-adrenergic blockers on resting
heart rate can be a poor predictor of their effect on the heart rate response to exercise; it is strongly recommended that this
response be assessed with either a hallway walk or formal exercise testing for patients who exhibit poor responses to initial
dosing.
Stable angina pectoris: The medical management of symptomatic myocardial ischemia
Parker, J.D, Parker, J.O,
Canadian Journal of Cardiology 2012, 28(25), S70-80.
Table 2. Pharmacologic characteristics of common β-1 selective β adrenergic blockers and nonselective β-Adrenergic Blockers organic
nitrates
A.
β-1 selective β-adrenergic blockers
Atenolol
Half-life (hrs)
6-9
β-1 selectivity
+
Sympathomimetic activity
No
Lipophilicity
Low
Elimination
Renal
Usual dosage (mg)
50-100 OD
B. Nonselective β-adrenergic blockers
Propanolol
Half-life (hrs)
2-5
β-1 selectivity
0
Sympathomimetic
No
activity
Lipophilicity
High
Elimination
Hepatic
Usual dosage (mg)
40-60 BID
Metropolol
3-4
+
No
Moderate
Hepatic
50-100 BID
Bisoprolol
10-12
+
No
Moderate
Hepatic and renal
2.5-10 OD
Acebutalol
3-4*
+
Yes
Moderate
Hepatic and renal
200-600BID
Timolol
3-5
0
No
Nadolol
14-25
0
No
Pindolol
3-4
0
Yes
Moderate
Hepatic
10-20 BID
Low
Renal
40-160 OD
Moderate
Hepatic and renal
5-20 BID
BID, twice daily; hrs, hours, OD, once daily
*Active metabolite of acebutalol (diacetolol) has half-life of 8-12 hrs.
11-22
Calcium channel Blocking Agents are also effective anti-anginal agents and antihypertensive agents.
While their basic
mechanism of action is similar (i.e., blockade of the L-type calcium channel and reduction of intracellular calcium
concentrations), the three classes of calcium channel antagonists each have quite different chronotropic, hemodynamic and
inotropic effects. The dihydropyridines (the prototype is nifedipine) have little effect on heart rate or atrioventricular
conduction while having the most prominent effect on peripheral resistance. Although nifedipine was the first of this class to
be introduced, another effective dihydropyridine is amlodipine, a drug that has become very widely used in the therapy of
angina and hypertension. The benzothiazepines (the prototype is diltiazem) and the phenylalkylamines (the prototype is
verapamil) also reduce peripheral vascular resistance, although both these classes have prominent negative chronotropic
effects and impair atrioventricular conduction. All 4 calcium channel antagonists approved for angina in Canada are available
in once per day formulations (amlodipine, nifedipine GITS, diltiazem CD, and verapamil sustained release [SR]) (see Table 3).
Table 3. Pharmacologic characteristics of common calcium channel antagonists
Half-life (hrs)
Elimination
Heart rate
Vascular resistance
Usual dosage (mg)
Nifedipine
(GITS)
2-5
Hepatic
↑
↓↓
20-90 OD
Amlodipine
Diltiazem (CD)
Verapamil (SR)
30-50
Hepatic
↔
↓↓
2.5-10 OD
4-6
Hepatic
↓
↓
120-360 OD
5-12
Hepatic
↓
↓
180-360 BID
BID, twice daily; CD, controlled delivery; GITS, gastrointestinal therapeutic system; OD, once daily; SR, slow release.
Combination therapy: Combination therapy should be used with caution and consideration should be given to ensuring
maximally-tolerated doses single-drug therapy before the addition of another class of anti-anginal. Consistent benefit has
been demonstrated from the addition of a second agent when patients remain symptomatic on maximal monotherapy.
Choice of therapy: There remains no clear ‘first choice’ in the therapy of angina. β-adrenergic blockers currently are the main
stay for treatment of angina, particularly in the presence of prior infarction. Choice of therapy is often based on the presence
of associated clinical conditions such as concomitant hypertension (dihydropyridine calcium channel antagonist). Some may
prefer calcium channel antagonists as first line therapy, based on the assumption of a favourable side-effect profile. In the
absence of left ventricular systolic dysfunction or prior infarction there is no clear guidance to choose a β-adrenergic blocker
versus a calcium channel antagonist, although β-adrenergic blockade seems logical in the absence of contraindication or
striking hypertension.
Stable angina pectoris: The medical management of symptomatic myocardial ischemia
Parker, J.D, Parker, J.O,
Canadian Journal of Cardiology 2012, 28(25), S70-80.
Errata: Correction to
Parker, J.D, Parker, J.O. Stable angina pectoris: The medical management of symptomatic myocardial ischemia. Can
JCardiol 2012;28(25): S70-80.
The suggested dose ranges for nonselective β-adrenergic blockers, Table 2-B, should read as per this fact sheet. These
suggested dose ranges are incorrect in the published paper.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
C.M. Chow, L. Donovan, D. Manuel, H. Johansen, J.V. Tu. Regional variation in self-reported heart disease prevalence in Canada.
Can J Cardiol, 21 (2005), pp. 1265–1271
N. Payne, C. Saul. Variations in use of cardiology services in a health authority: comparison of coronary artery revascularisation
rates with prevalence of angina and coronary mortality. BMJ, 314 (1997), pp. 257–261
P.W. Serruys, F. Unger, J.E. Sousa et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of
multivessel disease. N Engl J Med, 344 (2001), pp. 1117–1124
J.D. Parker, J.O. Parker. Nitrate therapy for stable angina pectoris. N Engl J Med, 338 (1998), pp. 520–531
T. Munzel, A. Daiber, A. Mulsch. Explaining the phenomenon of nitrate tolerance. Circ Res, 97 (2005), pp. 618–628
J.O. Parker, A. Porter, J.D. Parker. Propranolol in angina pectorisComparison of long-acting and standard-formulation propranolol.
Circulation, 65 (1982), pp. 1351–1355
J.C. Tardif, I. Ford, M. Tendera, M.G. Bourassa, K. Fox. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol
in patients with chronic stable angina. Eur Heart J, 26 (2005), pp. 2529–2536
S. Savonitto, D. Ardissiono, K. Egstrup et al. Combination therapy with metoprolol and nifedipine versus monotherapy in patients
with stable angina pectorisResults of the International Multicenter Angina Exercise (IMAGE) Study. J Am Coll Cardiol, 27 (1996),
pp. 311–316
K.M. Fox, D. Mulcahy, I. Findlay, I. Ford, H.J. Dargie, The Total Ischaemic Burden European Trial (TIBET)
Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with
stable anginaThe TIBET Study Group. Eur Heart J, 17 (1996), pp. 96–103
D.T. Kawanishi, C.L. Reid, E.C. Morrison, S.H. Rahimtoola. Response of angina and ischemia to long-term treatment in patients
with chronic stable angina: a double-blind randomized individualized dosing trial of nifedipine, propranolol and their
combination. J Am Coll Cardiol, 19 (1992), pp. 409–417
S. Savonitto, D. Ardissiono, K. Egstrup et al. Combination therapy with metoprolol and nifedipine versus monotherapy in patients
with stable angina pectorisResults of the International Multicenter Angina Exercise (IMAGE) Study. J Am Coll Cardiol, 27 (1996),
pp. 311–316
K.M. Fox, D. Mulcahy, I. Findlay, I. Ford, H.J. Dargie, The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol,
nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable anginaThe
TIBET Study Group. Eur Heart J, 17 (1996), pp. 96–103
D.T. Kawanishi, C.L. Reid, E.C. Morrison, S.H. Rahimtoola. Response of angina and ischemia to long-term treatment in patients
with chronic stable angina: a double-blind randomized individualized dosing trial of nifedipine, propranolol and their
combination. J Am Coll Cardiol, 19 (1992), pp. 409–417
S.P. Glasser, T.J. Gana, L.G. Pascual, K.S. Albert. Efficacy and safety of a once-daily graded-release diltiazem formulation dosed at
bedtime compared to placebo and to morning dosing in chronic stable angina pectoris. Am Heart J, 149 (2005), pp. e1–e9
R.B. van Dijk, K.I. Lie, H.J. Crijns. Diltiazem in comparison with metoprolol in stable angina pectoris. Eur Heart J, 9 (1988), pp.
1194–1199
O. De Divitiis, V. Liguori, S. Di Somma et al. Bisoprolol in the treatment of angina pectoris: a double blind comparison with
verapamil. Eur Heart J, 8 (suppl M) (1987), pp. 43–54
W.H. Frishman, S. Glasser, P. Stone et al. Comparison of controlled-onset, extended-release verapamil with amlodipine and
amlodipine plus atenolol on exercise performance and ambulatory ischemia in patients with chronic stable angina pectoris. Am J
Cardiol, 83 (1999), pp. 507–514
W. Schneider, F.D. Maul, W.D. Bussmann et al. Comparison of the antianginal efficacy of isosorbide dinitrate (ISDN) 40 mg and
verapamil 120 mg three times daily in the acute trial and following two-week treatment. Eur Heart J, 9 (1988), pp. 149–158
R.S. Kohli, E.A. Rodrigues, L.O. Hughes, A. Lahiri, E.B. Raftery. Sustained release verapamil, a once daily preparation: objective
evaluation using exercise testing, ambulatory monitoring and blood levels in patients with stable angina. J Am Coll Cardiol, 9
(1987), pp. 615–621
G. Cocco, R. Alfiero. A double-blind dose-response study of amlodipine in patients with stable angina pectoris. Eur Heart J, 12
(1991), pp. 169–174
D.R. Kinnard, M. Harris, K.F. Hossack. Endurance testing for evaluation of antianginal therapy with amlodipine, a calcium channel
blocking agent. J Am Coll Cardiol, 12 (1988), pp. 791–796