(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Salient Clinical Features
Angina is a pain in the chest or adjacent areas caused by severe, but temporary, lack of blood (ischemia) to a segment of the heart muscle, hence the term myocardial ischemia. For stable angina, the most important feature is the causation of pain by a particular exertional activity and relief within minutes of cessation of the precipitating activity.
Angina may be classified as:
Stable angina
Unstable angina
Variant angina (Prinzmetal’s), coronary artery spasm (CAS), a rare disorder
The pain of angina must be differentiated from commonly occurring:
Gastroesophageal reflux and motility disorders
Musculoskeletal disorders, particularly costochondritis that causes tenderness without swelling of the second to fourth left costochondral junctions and may occur concomitantly with coronary artery disease
It is necessary to document the presence or absence of diabetes and cigarette smoking, which markedly increases risk and asthma, which contraindicates the use of beta-blocking drugs.
Physical examination should exclude secondary factors that may precipitate angina:
Anemia and hypertension
Aortic stenosis, severe valvular disease, and hypertrophic cardiomyopathy
Arrhythmias
Relevant baseline investigations include resting and stress electrocardiogram (ECG), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, as well as hemoglobin, glucose serum creatinine, and estimated glomerular filtration rate (eGFR).
Pathophysiologic Implications
Three determinants play major roles in the pathogenesis of myocardial ischemia to cause stable or unstable angina:
Atheromatous lesions are mainly concentric with stable angina and eccentric with unstable angina and cause >70 % coronary stenosis.
Myocardial oxygen demand is increased.
Catecholamines are released in response to exertional and emotional stress or other activity. Catecholamines cause an increase in heart rate, velocity, and force of myocardial contraction that increase oxygen demand and ischemia. Increased heart rate decreases the diastolic interval during which coronary artery perfusion occurs. Ischemia further stimulates catecholamine release, thereby perpetuating the vicious circle.
Catecholamine release initiates and perpetuates a dynamic process. Thus, beta-blocking agents play a key role in the management of patients with myocardial ischemia manifested by anginal pain or silent ischemia. The pathophysiology of unstable angina is more complex and is dealt with later in this chapter.
Treatment of Stable Angina
The ACC/AHA provided guidelines in 2014. It is crucial to control known risk factors for coronary artery disease strictly:
Cigarette smoking must be curtailed; weight and stress must be addressed.
Hypertension must be controlled with an appropriate drug; goal blood pressure (BP): systolic < 135 mmHg.
Hyperlipidemia must be brought to goal levels: LDL < 2.0 mmol/L (70 mg/dL) and for high-risk patients, example unstable angina < 60 mg/dL (1.6 mmol/L).
Diabetes must be treated aggressively.
The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE Boden et al. 2007) trial compared an initial strategy of PCI plus optimal medical therapy with optimal medical therapy alone for patients with stable angina. This RCT studied 2,287 patients who had objective evidence of myocardial ischemia, 1,149 patients to undergo PCI with optimal medical therapy (PCI group), and 1,138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal MI during a median follow-up of 4.6 years.
There were 211 primary events in the PCI group and 202 events in the medical-therapy group. The 4.6-year cumulative primary-event rates were 19 % in the PCI group and 18.5 % in the medical-therapy group.
In patients with stable angina, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to optimal medical therapy COURAGE Trial (Boden et al. 2007). During the trial period, 21 % crossed over and received PCI. There was rapidity of improvement in health status in both treatment groups; the majority of patients who received optimal medical therapy alone had improved symptoms within 3 months. This suggests that optimal antianginal medications are underused in practice.
The “take-home” message from the COURAGE trial is to pursue optimal medical therapy initially as it is effective in 75 % and if this is ineffective in 25 % resort to PCI (Peterson and Rumsfeld 2008).
Schomig et al. (2008) pooled together the results of 17 randomized trials comparing PCI and medical treatment as strategies in patients with stable angina and no acute coronary syndromes. Their meta-analysis concluded that a PCI-based invasive strategy may improve long-term survival in patients with stable coronary artery disease (CAD) and that this justifies a new clinical trial sufficiently powered to evaluate the impact of PCI on long-term mortality.
Based on the strength of available evidence, O’Rourke recommends “more aggressive medical therapy for patients with moderate to severe angina, and PCI or CABG for patients whose symptoms are bothersome. Optimal medical therapy is a proven option for chronic stable angina” (O’Rourke 2008). But there is little doubt that most post-PCI patients can engage in many more activities including golfing, swimming, and traveling, whereas medically treated patients do have to be cautious, and many cannot engage in activities that they like.
Usually PCI is done to relieve bothersome angina, but data are emerging to suggest that there may also be functional and a mortality benefit. Successful PCI for chronic total coronary occlusion was associated with improved long-term survival. The improvement was greatest in patients when complete revascularization was achieved (George et al. 2014).
Beta-Adrenoceptor Blocking Agents
All cardiologists now agree that beta-blockers are standard first-line therapy for stable and unstable angina. A table that compared beta-blockers, nitrates, and calcium antagonists and indicated the rationale for beta-blockers as first-line treatment has remained unaltered since the first edition in 1984 (Table 10-1).
Table 10-1
Beta-blocker: first-line oral drug treatment in angina pectoris
Effect on | Beta-blocker | Calcium antagonist | Oral nitrate |
|---|---|---|---|
Heart rate | ↓ | ↑↓ | — |
Drastolic filling of coronary arteries | ↑ | — | — |
Blood pressure | ↓↓ | ↓↓ | — |
Rate pressure product (RPP) | ↓ | —a | — |
Relief of angina | Yes | Yes | Variable |
Blood flow (subendocardial ischemic area)b | ↑ | ↓ | Variable |
First-line treatment for angina pectoris | Yes | No | No |
Prevention of recurrent ventricular fibrillation | Proven | No | No |
Prevention of cardiac death | Proven | No | No |
Prevention of pain from coronary artery spasm | No | Yes | Variable |
Prevention of death in patient with coronary artery spasm | No | No | No |
Many patients with left ventricular (LV) dysfunction and borderline and class II–III heart failure (HF) were deprived of beta-blocker therapy from 1970 to 1999. These drugs were believed to be contraindicated in HF. However, beta-blockers continue to surprise us (Cruickshank 2000). Randomized controlled trials (RCTs) have proved solidly that these drugs decrease mortality and morbidity in patients with all grades of HF (see Chap. 12), and at present they are strongly recommended in patients with angina and HF or LV dysfunction. Calcium antagonists and nitrates cannot reduce mortality or morbidity in these patients and are relegated to second-line therapy.
Virtually all patients with angina should receive a beta-blocker, preferably bisoprolol, carvedilol, metoprolol, propranolol, or timolol at a cardioprotective dosage (see the later discussion of cardioprotective dose); the widely used atenolol is not advisable; it is a poorly effective beta-blocker because it is non-lipophilic and attains poor brain concentration.
“Use should be limited to bisoprolol, carvedilol, metoprolol succinate (Toprol XL), or timolol which have been shown to reduce risk of death” ( Level of Evidence: A ).
These beta-blockers are chosen because they have been shown to decrease mortality in patients with coronary heart disease (see Chap. 1 ). Atenolol, a water-soluble drug, is frequently used worldwide for angina and hypertension. The water-soluble, non-lipid-soluble beta-blockers atenolol and nadolol, also pindolol and acebutolol, are not recommended (see Chaps. 1 and 2).
It is important to reemphasize that only the cardioselective, lipid-soluble beta-blockers metoprolol, timolol (Norwegian Multicenter Study Group 2001), propranolol (in nonsmokers), and carvedilol (CAPRICORN 2001) have been shown in RCTs to decrease mortality in post-MI patients. Beta-blockers have important subtle clinical differences (Khan 2005).
It remains probable that beta 1 and beta 2 effects are needed to render further cardioprotection (see Chap. 1). Timolol caused an outstanding unmatched 67 % reduction in sudden deaths in post-infarct patients (Norwegian Multicenter Study Group 1981), a result that has been lost to the cardiology world. The drug is rarely if ever used in the USA and Canada.
Beta-blockers significantly reduce the number of episodes of angina in more than 75 % of patients. Beta-blockers may prevent deaths in patients with angina, but reduction in mortality has not been documented in RCTs of patients with angina. Only a few small trials have been conducted and with poor methodology. Patients receiving a beta-blocking agent have the advantage of pretreatment before a subsequent severe ischemic episode (Norwegian Multicenter Study Group 1981; CAPRICORN 2001).
Observations have established that silent ischemia is common and is easily provoked by daily stressful activities (Deanfield et al. 1983, 1984). Patients with angina may have more silent than painful episodes. Beta-blockers and calcium antagonists have been shown to ameliorate silent ischemic episodes, but beta-blockers are superior. The salutary effects of beta-adrenoceptor blockade are illustrated in Fig. 1-1. These beneficial effects in myocardial ischemia result from:
A decrease in myocardial oxygen demand as a result of a decrease in heart rate.
A decrease in the velocity and force of myocardial contraction.
A fall in cardiac output and blood pressure; thus the rate pressure product (heart rate × systolic blood pressure) is reduced.
Improvement in blood supply caused by a decrease in heart rate, which lengthens the diastolic interval. Because the coronary arteries fill during diastole, coronary perfusion improves.
Blocking of exercise-induced catecholamine vasoconstriction at sites of coronary stenosis where atheroma could impair the relaxing effects of the endothelium.
Decreased conduction through the atrioventricular (AV) node resulting in the slowing of the ventricular response in atrial fibrillation or other supraventricular arrhythmias that may occur in patients with myocardial ischemia.
Decrease in phase four diastolic depolarization producing suppression of ventricular arrhythmias, especially those induced by catecholamines and/or ischemia.
Increase in ventricular fibrillation (VF) threshold reduces the incidence of VF and sudden deaths that could, at some stage, occur in patients with angina (see Chap. 1 for other mechanisms).
Cardioprotection and Dosage of Beta-Blocker
Table 1-4 gives dosages of beta-blockers. The dose of metoprolol is 100–200 mg, that of propranolol in nonsmokers is 160–240 mg, and that of timolol is 10–20 mg daily, because these doses have been shown to be effective in preventing sudden death and decreasing total cardiac deaths in well-designed clinical trials albeit in patients after MI. The salutary effect of smaller doses is unknown, and larger doses are likely to be nonprotective (see Chap. 1).
The dose of beta-blocker is kept within the cardioprotective range, to maintain a resting heart rate of 52–60 beats/min bearing in mind that no patient should be allowed to have significant adverse effects from medication. If side effects occur, the dose is reduced, and a nitrate or calcium antagonist is added. If the maximum cardioprotective dose is used and angina is not controlled, the dose of beta-blocker can be increased, but adverse effects may limit the increase. Some patients do better on an average dose of beta-blocker plus a nitrate or calcium antagonist. Trial and error is necessary in many patients.
Contraindications to Beta-Blockers
Contraindications to the use of a beta-blocking drug are the following:
Asthma.
Severe chronic obstructive pulmonary disease. Mild stable disease is not a contraindication.
Severe HF (decompensated class IV). These agents have been approved for cautious use in patients with compensated class IV HF.
Bradyarrhythmias (second- or third-degree AV block).
Brittle insulin-dependent diabetes and patients prone to hypoglycemia.
Raynaud’s phenomenon.
Calcium Antagonists
These agents are used as second-line therapy when beta-blockers are genuinely contraindicated. Several trials have shown that verapamil is as effective as beta-blockers in the control of angina, but this agent does not prolong life. Verapamil is a more effective antianginal agent than diltiazem or dihydropyridines (DHPs) and is considered a first choice, but the drug must be used with caution and must not be combined with a beta-blocker.
Contraindications to the use of verapamil and diltiazem include:
Heart failure, suspected LV dysfunction, and ejection fraction (EF) <40 %, because verapamil has a strongly negative inotropic action and diltiazem is moderately so.
Sinus or AV node disease.
Bradycardia.
Amlodipine (Norvasc) has a less negative inotropic effect than other DHPs, but in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE 1996) study, although amlodipine use was generally safe in patients with HF, it caused an increased incidence of pulmonary edema in patients with EF < 30 %. The drug is not recommended if the EF is <35 % and should not be combined with a beta-blocker if the EF is <40 %.
Combination of Beta-Blockers and Calcium Antagonists
Amlodipine has minimal negative inotropic effects and can be combined with a beta-blocker in patients with EF > 35 %. Although beta-blockers may be used in patients with EF < 30 %, the combination of a beta-blocker with diltiazem or dihydropyridine should be avoided in patients with EF < 40 %. Verapamil is contraindicated in patients with an EF < 40 %.
Verapamil and, to a lesser extent, diltiazem, when added to a beta-blocker, may cause conduction disturbances or HF, and the verapamil combination is considered unsafe. The hemodynamic, electrophysiologic, and pharmacokinetic effects, adverse effects, and relative effectiveness of calcium antagonists are given in Tables 5-2 and 5-3 and are discussed in Chap. 5.
Nitrates
Drug name: | Nitroglycerin: glyceryl trinitrate |
Supplied: | Sublingual nitroglycerin: 0.15, 0.3, 0.4 mg |
Sublingual glyceryl trinitrate: | 300, 500, 600 μg (UK) |
Spray (Nitrolingual): | 0.4 mg metered dose, 200 doses/vial |
The patient must be instructed that nitroglycerin tablets are to be kept in their dark, light-protected bottles; they may be rendered useless after 6 months, or even earlier, if they are not protected from light. Patients should be advised to have at least two bottles available. These two bottles must contain approximately 1-month supply and no cotton wool, to ensure rapid availability in emergencies. At the end of each month, the containers should be emptied and the supply replenished from a third-stock bottle. If pain occurs and is not relieved by two tablets, three 80–81 mg soft chewable aspirins should be taken; obtain ambulance assistance to a coronary intervention center or an emergency department.
Oral Nitroglycerin Tablets: For Nitrong SR 2.6 mg, the dosage is 1 tablet at 7 AM and 2 PM daily (Table 10-2). This will allow a 12-h nitrate-free interval to maintain the efficacy of the drug. The maximum dose 6.25-mg tab may cause bothersome headaches.
Table 10-2
Nitrates
Generic | Trade name or available asa | Supplied and dosageb |
|---|---|---|
Sublingual | ||
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