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The need to identify new targets for therapeutic intervention in angina
Luigi Tavazzi*
Cardiology Department, Policlinico S. Matteo, Institute of Care and Research, Pavia, Italy
* Corresponding author. E-mail address: l.tavazzi{at}smatteo.pv.it
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Abstract
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Therapy to reduce the occurrence and symptoms of angina have
been less well investigated than drugs to prevent myocardial
infarction and death. This article summarizes the current options
for anti-anginal and anti-ischaemic drugs and explains why new
therapeutic options are needed.
Key Words: Stable angina • Angina pectoris • Anti-anginal drugs • Nitrates • Beta-blockers • Calcium antagonists
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Does stable angina need to be treated?
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The Euro Heart Survey of Stable Angina analysed 3779 consecutive
outpatients with a new clinical diagnosis of stable angina.
1 At 1 year after diagnosis, percutaneous coronary intervention
had been performed in 22% of patients; among those with angiographically
determined coronary artery disease (CAD), the revascularization
rate was 69%. All patients with confirmed CAD were treated with
anti-anginal agents. In the Euro Heart Survey on Coronary Revascularization,
of 5619 consecutive patients with angiographically proven CAD,
53% had originally presented with stable angina.
2 These results
indicate that stable angina is a major medical and economic
problem and that pharmacological treatment is an important component
of management.
Pharmacological treatment of ischaemic heart disease has two main aims: to prevent myocardial infarction (MI) and death and to reduce the symptoms and occurrence of ischaemia. Anti-thrombotic agents, lipid-lowering drugs, and ACE-inhibitors fall into the first category, and their efficacy is well established. However, anti-ischaemic and anti-anginal therapies have been less well investigated. Beta-blockers, calcium antagonists, and nitrates are commonly used for this purpose. Other options include the potassium channel activator nicorandil and the newer agents ivabradine, trimetazidine, and ranolazine.
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Beta-blockers and calcium antagonists
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Evidence for the relative effectiveness of beta-blockers and
calcium antagonists in the treatment of stable angina is scanty.
Less than 2000 patients have been included in randomized trials
comparing both drug classes. In the follow-up of up to 3 years,
the endpoint of MI or death occurred with similar frequency,
58 vs. 62 events, giving an odds ratio of 1.06 (95% CI 0.7–1.5).
Meta-analysis showed a similar effect of beta-blockers and calcium
antagonists on both relief of angina and exercise time to 1 mm
ST-segment depression (
Figures 1 and
2).
3
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Figure 1 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.
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Figure 2 Beta-blockers vs. calcium antagonists: exercise time to 1 mm ST-depression. Reproduced from ACC/AHA 2002 guideline update for the management of patients with chronic stable angina,3 with permission.
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These anti-anginal agents tend to be under-prescribed and under-used,
possibly because of side effects. In the Euro Heart Survey of
Stable Angina, for example, atenolol was being prescribed for
521 of the 3779 patients, but it was being used at suboptimal
doses in many patients.
1 The mean dose prescribed was 38 mg/day
compared with a recommended dose of 100 mg/day in stable
angina. A quarter of patients were taking less than half the
recommended dose.
A meta-analysis of 23 studies comparing monotherapy with combined therapy found that the additive effect of beta-blockers and calcium antagonists is not great.4 Among 630 patients on a beta-blocker alone and 615 patients on a beta-blocker plus a calcium antagonist, the time to 1 mm ST-segment depression was 8% longer (33 s; P<0.001) with combined therapy. The exercise duration was 5% longer (23 s; P=0.002) in patients on combined therapy, and the time to onset of pain was 12% longer (42 s; P<0.001). Similarly, among 399 patients on a calcium antagonist alone and 388 on a calcium antagonist plus a beta-blocker, time to 1 mm ST-segment depression was 9% longer (41 s; P<0.001) with the combined therapy. Exercise duration was a non-significant 4% longer (17 s; P=0.35) in combined therapy patients, and the increase in time to onset of pain in these patients was of marginal significance (9%; 30 s; P=0.067). Thus the incremental anti-ischaemic effect of the two categories of drugs most used in patients with angina is rather limited.
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Nitrates
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Nitrates are commonly used drugs. For example, in the USA, 91%
of physicians treat congestive heart failure patients with organic
nitrates.
5 However, a meta-analysis of trials comparing long-acting
nitrates with beta-blockers and calcium antagonists in stable
angina had inconclusive results.
6 It included 12 trials comparing
nitrates with calcium antagonists and six trials comparing nitrates
with beta-blockers. There were no significant differences in
outcomes, and the small amount of data available did not allow
firm conclusions to be drawn. There was, however, a non-significant
trend towards a greater number of episodes of angina in patients
taking nitrates compared with calcium antagonists (
P=0.10) and
a similar trend towards increased glyceryl trinitrate use for
nitrates compared with beta-blockers (
P=0.08).
It is possible that long-term nitrate treatment is deleterious. Nitrate therapy leads to increased production of oxygen-free radicals and endothelial dysfunction.7 Tolerance occurs after 24 h of continuous treatment with any formulation of organic nitrate, and intermittent treatment is recommended. However, rebound phenomena, including impaired endothelial function, vascular hyperactivity associated with more frequent ischaemic episodes, up-regulation of platelet activity, and loss of ischaemic pre-conditioning activity, can occur during the nitrate-free periods of intermittent therapy.8,9
Further concern about the safety of nitrates was raised by a Cox analysis of results from 1042 patients enrolled in the observational Multicenter Study of Myocardial Ischemia (MSMI) and 1779 patients enrolled in the randomized Multicenter Diltiazem Post Infarction Trial (MDPIT).10 In this analysis, long-acting nitrate treatment was associated with a significantly increased mortality risk in patients who had recovered from an acute coronary event. The hazard ratio associated with nitrate use was 3.78 (95% CI 1.36–10.47; P=0.011) in MSMI and 1.61 (95% CI 1.08–238; P=0.019) in MDPIT.1
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Other potential anti-anginal therapies
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ACE-inhibitors are used to reduce the risk of MI and death in
patients with CAD; the Quinapril Anti-Ischemia and Symptoms
of Angina Reduction (QUASAR) trial investigated whether they
also have anti-ischaemic/anti-anginal effects.
11 QUASAR randomized
336 CAD patients with stable angina and exertional ischaemia
(no hypertension, left ventricular dysfunction, or previous
MI) to quinapril 40 mg/day or placebo. After 8 weeks, no
differences were found between placebo and quinapril in time
to 1 mm ST-segment depression (4.7 vs. 4.8 min), time
to angina (6.1 vs. 6.6 min) or exercise duration (6.4 vs.
6.7 min). There were also no differences in the number
of ischaemic episodes per 24 h or scores on the Seattle
Angina Questionnaire. In a further 8-week period, patients in
the placebo group were given quinapril 80 mg/day, whereas
those in the quinapril group continued on 40 mg/day; no
significant differences in any parameters between the two groups
were seen at the end of this period. Thus, ACE-inhibitors, although
effective in reducing MI and death, cannot be considered as
potentially useful anti-anginal agents.
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Conclusion
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Many patients with chronic stable angina are managed solely
with pharmacological treatment. However, the options currently
available for treating the symptoms of angina and reducing the
occurrence of ischaemia have drawbacks and are of limited efficacy.
Combining agents from different drug classes is also of limited
value. A clear need thus exists for new anti-anginal drugs.
Conflict of interest: none declared.
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References
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- Daly C, Clemens F, Tavazzi L et al. The impact of guideline compliant medical therapy and revascularisation on clinical outcome in patients with stable angina: findings from the Euro Heart Survey on Stable Angina. Eur Heart J, in press.
- Lenzen MJ, Boersma E, Bertrand ME et al. Management and outcome of patients with established coronary artery disease: the Euro Heart Survey on coronary revascularization. Eur Heart J 2005; 26:1169–1179.[Abstract/Free Full Text]
- Committee on the Management of Patients With Chronic Stable Angina. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. www.acc.org and www.americanheart.org.
- Klein WW, Jackson G, Tavazzi L. Efficacy of monotherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: a meta-analysis. Coron Artery Dis 2002;13:427–436.[CrossRef][Web of Science][Medline]
- Bitar F, Akhter MW, Khan S et al. Survey of organic nitrates for the treatment of chronic congestive heart failure in the United States. Am J Cardiol 2004;94:1465–1468.[Medline]
- Heidenreich PA, McDonald KM, Hastie T et al. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA 1999;281:1927–1936.[Abstract/Free Full Text]
- Gori T, Parker JD. Nitrate tolerance: a unifying hypothesis. Circulation 2002;106:2510–2513.[Free Full Text]
- Parker JD. Potential problems with intermittent nitrate therapy. Can J Cardiol 1996;12(Suppl. C):22C–24C.
- Gori T, Fineschi M, Parker JD et al. Therapy with organic nitrates: newer ideas, more controversies. Ital Heart J 2005;6:541–548.[Medline]
- Nakamura Y, Moss AJ, Brown MW et al. Long-term nitrate use may be deleterious in ischemic heart disease: a study using the databases from two large-scale postinfarction studies. Am Heart J 1999;138:577–585.[CrossRef][Web of Science][Medline]
- Pepine CJ, Rouleau JL, Annis K et al. Effects of angiotensin-converting enzyme inhibition on transient ischemia: the Quinapril Anti-Ischemia and Symptoms of Angina Reduction (QUASAR) trial. J Am Coll Cardiol 2003;42:2049–2059.[Abstract/Free Full Text]
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Does stable angina need...