Beta-adrenergic blockers were first approved for the therapy of angina in the mid-1960s, although controversy delayed their introduction in the United States. This class of therapy proved to be highly effective in the therapy of chronic angina [22, 23, 41–43]. Beta-blockers reduce myocardial oxygen demands by decreasing heart rate, blood pressure, and inotropic responses to exercise. By limiting the increase in heart rate in response to exercise, they can improve myocardial blood flow by increasing diastolic time intervals. A number of beta-blockers are available for the therapy of angina. The available agents have important differences in terms of pharmacokinetics, beta-1 receptor selectivity, routes of elimination, and lipophilicity. The choice of beta-blocker is driven primarily by pharmacokinetic properties and clinical characteristics of the patient. Once-daily preparations, in general, are preferred. Beyond that, the presence of chronic obstructive lung disease or diabetes favors the use of agents with beta-1 receptor selectivity. In those with significant renal insufficiency, beta-blockers that are eliminated primarily through the kidney should be avoided (Chaps.​ 5 and 8).

In the therapy of angina, it is important for the clinician to appreciate the wide variation in clinically effective doses. The pharmacokinetic properties of individual beta-blockers are quite variable, particularly in those that undergo primary hepatic elimination. Further, the effect of beta-blockers is dependent on the degree of underlying sympathetic activity and the sympathetic response to exercise. In the majority of patients, dosing is determined by resting heart rate and blood pressure responses. However, it should be remembered, particularly in the therapy of angina, that resting heart rate is a poor indication of the effect of a given dose on the heart rate response to exercise. Since the impact of beta-blockers on the chronotropic response to exercise is a crucial determinant of their effectiveness in the therapy of angina, patients who have a poor clinical response to initial dosing should undergo either a walk test or formal exercise testing to assess their heart rate response during stress. In the past, beta-blockers with intrinsic sympathomimetic activity (pindolol and acebutolol) were promoted for use in the setting of angina based on the assumption that they would be associated with less drug-induced fatigue; however, they appear to be less effective and are no longer in common clinical use.

A number of the calcium channel antagonists are effective in the treatment of stable angina [41–51]. All calcium channel antagonists have a common mechanism of action which is their ability to block L-type calcium channels in smooth muscle and myocardium, reducing cytosolic concentrations of calcium. There are three different types of calcium channel antagonists that have different hemodynamic, chronotropic, and inotropic effects. Dihydropyridines have pronounced effects on peripheral resistance vessels but little effect on heart rate or the cardiac conduction system. Nifedipine was the first dihydropyridine introduced into practice, initially in short-acting formulations but now widely available in slow-release formulations that allow once-daily dosing. In its long-acting formulation, nifedipine is effective in the therapy of both angina and hypertension. Immediate-release nifedipine capsules remain available for the therapy of angina but are not recommended because of their tendency to precipitate pronounced hypotension and/or worsening angina [52, 53]. Amlodipine is another dihydropyridine that has been widely approved for the therapy of angina and hypertension. It is a once per day drug with a long half-life and is generally well tolerated. A number of other dihydropyridine calcium channel antagonists are available including felodipine, nicardipine, and nisoldipine; however, these drugs are not approved for the therapy of angina in most countries and, if used in short-acting formulations, can increase the frequency of angina. Diltiazem, a benzothiazepine, and verapamil, a phenylalkylamine, are also effective in the treatment of angina. Although they reduce peripheral vascular resistance, these drugs also have prominent electrophysiologic effects, reducing heart rate and prolonging atrioventricular conduction (Chap.​ 48). Short-acting formulations of diltiazem and verapamil are still available but rarely used for chronic therapy. Long-acting, once-daily formulations of diltiazem are commonly used in the therapy of angina, reducing heart rate, blood pressure, and inotropic responses to exercise. Verapamil, although it is an effective antianginal, is not commonly used in the therapy of angina, presumably because of its recognized prominent negative inotropic effects.

The mechanism(s) of action of calcium channel antagonists in the therapy of angina is complex and varies by class. The dihydropyridines do not reduce heart rate at rest or in response to exercise but lower myocardial oxygen demand by reducing both blood pressure and inotropic responses during exercise. Diltiazem and verapamil also lower blood pressure and inotropic responses to exercise with additional negative chronotropic responses that can reduce myocardial oxygen consumption while increasing coronary blood flow. Some studies have suggested that calcium channel antagonists can directly increase coronary blood flow [54–56], although there is little evidence that this plays a significant role in patients with stable angina. This is not a great surprise since coronary blood flow responses to drug therapy during exercise are complex with variable interactions between coronary perfusion pressure, myocardial oxygen demand, and diastolic time intervals, all of which are superimposed on the autoregulation of coronary blood flow. It has also been suggested that calcium channel antagonists, particularly the dihydropyridines, can improve coronary endothelial function via favorable effects on nitric oxide bioavailability; however, the clinical relevance of this has never been established [57]. There has also been speculation that dihydropyridines might inhibit the progression of atherosclerosis, but it has never been clear whether this represents a primary effect of the drug on vascular atheroma or an indirect effect related to blood pressure and shear stress [58–60]. There are no discernible differences in the efficacy of the calcium channel antagonists in the therapy of angina. Therapeutic choices within this class are driven primarily by decisions as to whether or not a negative chronotropic effect is desired or situations in which the presence of left ventricular dysfunction makes the use of agents with negative inotropic effects contraindicated.

Nicorandil is a nicotinamide nitrate, effective in the therapy of exertional angina, which has been available for many years, although not in North America [61, 62]. Nicorandil is a nitric oxide donor, increasing the availability of cGMP, which causes relaxation of capacitance veins and dilation of conduit arteries. Nicorandil also opens mitochondrial K⁺-ATP channels, which causes relaxation of both peripheral and coronary resistance vessels [63–66]. Of note, its effect as an agonist of myocyte K⁺-sensitive ATP channels is responsible for its effects as a pharmacologic preconditioning agent [67]. However, as with all other preconditioning stimuli, it is not known if this effect persists during chronic therapy. In addition to its beneficial effects on the symptoms of angina, a large-scale clinical trial in patients with chronic CAD revealed modest improvements in long-term clinical outcome and confirmed its safety on this patient population [68].

Ivabradine belongs to a unique class of compounds that are selective sinus node inhibitors (Chaps.​ 1 and 48). The discovery of the existence and function of the cyclic nucleotide-gated I_f channel (the so-called inward funny channel), which mediates an inward, mixed Na⁺/K⁺ current, was followed by the recognition that this channel plays a critical role in the rate of sinus node repolarization [69–72]. Ivabradine is a selective inhibitor of this channel causing reductions in both resting and exercise-induced increases in heart rate [73]. Importantly, the drug has no effect on myocardial function or the peripheral vasculature. The I_f channel is also present in cells of the retina, and because of this, drugs like ivabradine can cause visual disturbances with increased sensitivity to bright light or the spontaneous sensation of light when no stimulus is present (these have been referred to as luminous phenomena or phosphenes) [71]. Visual disturbances were relatively common with earlier I_f channel inhibitors (e.g., zatebradine), but they are infrequent and usually transient with ivabradine [72–74]. Multiple studies have demonstrated the efficacy of ivabradine in the therapy of stable angina both as monotherapy and when given in addition to a beta-blocker, and the drug is approved for the therapy of angina in many countries [23, 74, 75]. Ivabradine has also been evaluated in patients with CAD and left ventricular dysfunction. In the BEAUTIFUL (morBidity-mortality EvAlUaTion of the I _f inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study, ivabradine had neutral effects on long-term outcome in patients with CAD and left ventricular dysfunction, although the subgroup with a baseline heart rate above 70 beats per minute did have a significant reduction in cardiovascular event rates [76]. In the SHIFT (Systolic Heart failure treatment with the I _f inhibitor ivabradine Trial) study, therapy with ivabradine improved outcome in patients with chronic heart failure due to left ventricular systolic dysfunction and a baseline heart rate greater than 70 beats per minute [77]. Although the results of these studies have been controversial, with questions raised concerning the adequacy of the dose of concurrent beta-blockade, they were consistent with the hypothesis that resting heart rate has an important impact on long-term cardiovascular outcome and that rate-reducing therapy could have beneficial effects in patients with coronary disease even in the absence of left ventricular dysfunction. This was the rationale for the SIGNIFY (Study assessInG the morbidity-mortality beNefits of the I _f inhibitor ivabradine in patients with coronarY artery disease) trial that randomized more than 19,000 patients with CAD and preserved left ventricular systolic function (ejection fraction >40 %) to ivabradine versus placebo on top of standard therapy. In this study, ivabradine had no effect on long-term clinical outcome [78]. However, in the subgroup of patients (n = 12049) with symptoms of angina classified as greater than or equal to Canadian Cardiovascular Society Class II, the primary endpoint (cardiovascular death or nonfatal myocardial infarction) was more common in the ivabradine group (relative risk of 1.18 as compared to placebo; Fig. 22.1) [78]. The implications of this finding are still being evaluated; however, they serve to emphasize that beneficial effects on long-term outcome cannot be assumed on the basis of beneficial effects observed in shorter studies using surrogate endpoints.

Trimetazidine is available in many countries, although not North America, for the treatment of stable angina in patients with coronary artery disease. Trimetazidine is believed to have a metabolic mechanism of action, inhibiting myocardial free fatty acid oxidation while increasing glucose metabolism, which increases the amount of ATP generated per molecule of oxygen (Chap.​ 17). It is an effective antianginal with no effect on heart rate, blood pressure, or inotropic state. It has been available for many years in Europe and is quite commonly prescribed in patients with angina [79]. There are reports that it is effective in the therapy of angina [80, 81]; however, evidence is limited, and the European Medicines Agency recently recommended that its use be limited to those patients who do not respond to standard antianginal therapy [82].

Ranolazine is an effective antianginal with a mechanism of action that does not rely on changes in myocardial oxygen demand or supply. Initially, it was felt to have a mechanism of action similar to trimetazidine in which free fatty oxidation is inhibited, leading to preferential metabolism of glucose and more efficient utilization of oxygen [83–85]. Although still somewhat controversial, more recent observations suggest that this metabolic mechanism is not operative in clinically relevant doses. It is now felt that ranolazine inhibits a late inward sodium channel, which favorably modifies intracellular sodium and calcium responses in the setting of ischemia (Chap.​ 52) [86–91]. Whatever the mechanism, ranolazine is effective in the therapy of angina both when used as monotherapy and when administered in addition to other antianginal agents (Fig. 22.2) [21, 86, 92]. The safety of ranolazine therapy was supported by the results of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes (MERLIN) study, in which 6,500 patients were followed for a median time of 348 days [93]. In this study, ranolazine had no beneficial effect on long-term outcome, however the study result confirmed the safety of this drug in a large population of patients with coronary artery disease. On the basis of this evidence of safety, ranolazine was approved in the United States as a first-line agent in the management of stable angina.

Any physician caring for patients with chronic angina knows that it is common to see patients who have been prescribed two and not infrequently three different drugs used for the therapy of angina. In some situations, where patients have refractory symptoms and revascularization is no longer possible, this approach is appropriate and can be beneficial. However, there are many patients who receive multiple-drug therapy in the absence of refractory symptoms [94–96]. The rationale for this may be to reduce side effects through the use of lower doses of each class and/or that the use of drugs with different mechanisms of action will be more efficacious. Studies examining combination therapy with organic nitrates, beta-blockers, and/or calcium channel antagonists have yielded inconsistent results and have been limited in their ability to define adverse effects because of small sample sizes and short-term follow-up [97–119]. This controversial area was reviewed in detail by Packer, who argued that in the absence of clear benefit, use of more than one antianginal agent puts patients at risk for side effects of combination therapy [120]. A common problem of studies using combination therapy is that they did not examine the effect of a second drug on top of maximum tolerated dose of monotherapy. Of note, consistent benefit has been demonstrated from the addition of a second agent when patients remain symptomatic on maximal monotherapy [97, 100, 109]. Recent studies of newer agents used in the therapy of angina (ivabradine and ranolazine) provide evidence that these medications are effective when these agents are added to background therapy with either a beta-blocker or calcium channel antagonists [21, 74]. However, in these cases, it is important to remember that the patients included in those studies had to remain symptomatic on background therapy in order to meet inclusion criteria.

There is no compelling evidence that any individual drug or class of drug is more effective at reducing symptoms of angina when compared to other agents. Despite this uncertainty, practice guidelines are uniform in their support of beta-blockers as first-line therapy, particularly in patients who have had a previous myocardial infarction (Chap.​ 20) [121, 122]. In patients where beta-blockers are contraindicated or not tolerated, either calcium channel antagonists or a long-acting nitrate can be used. Sometimes the choice of therapy is modified by the presence of concurrent clinical conditions such as a prior myocardial infarction (in which a beta-blocker is preferred) or the presence of severe concomitant hypertension (where a dihydropyridine calcium channel antagonist might be chosen). Many cardiologists choose beta-blockers as first-line therapy, even in the absence of a prior infarction. These drugs are very effective in the prevention of angina, can be titrated to heart rate responses, and have long been presumed to have beneficial or neutral effects on long-term outcome. Other physicians prescribe calcium channel antagonists as first-line therapy, since they are clinically effective and are felt to have a better side effect profile. Ranolazine is a reasonable choice in patients where a beta-blocker is not tolerated or is contraindicated. Both the American and European guidelines, for example, support its use as a second-line drug when symptoms are not controlled by monotherapy with another antianginal agent [121, 122]. Ivabradine, not yet available in North America, is recommended for patients who remain symptomatic while on a beta-blocker or if a beta-blocker is contraindicated. Ivabradine seems to be particularly helpful in patients who have resting heart rates ≥70 beats per minute either in the presence or absence of another negative chronotrope.

For many years, there was little or no information about the impact of most antianginals on the long-term outcome of patients with angina. In the absence of prior myocardial infarction, there has been no clear reason to make use of a particular class of antianginal in an effort to improve long-term clinical outcome. At times, concurrent conditions do drive treatment choices in patients with angina, often with reasonable assumptions that managing those conditions will be of long-term benefit. Typical examples include the presence of prior infarction, particularly with evidence of significant left ventricular dysfunction, a situation in which beta-blocker therapy would seem to be the best choice to improve long-term outcome. Another example is the presence of significant hypertension where a dihydropyridine represents a logical choice, particularly if angina and hypertension persist despite therapy with a beta-blocker.

In the case of long-acting nitrates, there have been no studies examining their effect on long-term clinical outcome in patients with stable angina. Clinical trials that led to the approval of these drugs for the therapy of angina had both small sample sizes and short-term follow-up [20, 32, 35]. In fact, there has never been a long-term study examining the impact of a long-acting nitrate on outcome in patients with chronic coronary artery disease. Although large post-myocardial infarction studies have included therapy with long-acting nitrates, the duration of therapy was short (4–6 weeks), preventing any assessment of the impact of nitrates on long-term outcome [123, 124]. There is increasing concern that long-held assumptions of safety concerning long-acting nitrate therapy may have been misplaced. Multiple studies have now documented that organic nitrate therapy leads to an increase in the bioavailability of free radicals and significant abnormalities in endothelial function [125–127]. These findings have led some to hypothesize that sustained nitrate therapy could have adverse effects in patients with CAD [40, 128], concerns that have been supported by retrospective analysis of patients with CAD treated with long-acting nitrates [129, 130].

It has generally been assumed that beta-blockers are protective in patients with chronic coronary artery disease. In patients with a myocardial infarction, therapy with beta-blockers has been shown to improve survival particularly in patients with congestive heart failure and left ventricular systolic dysfunction (Chap.​ 8) [131–137]. However, studies documenting the benefit of beta-blockers in patients with a prior myocardial infarction were carried out more than 30 years ago, before multiple other secondary prevention strategies had been introduced (antiplatelet, ACE inhibition, and statin therapy). It is possible that beta-blockers do not have protective effects, particularly in the setting of smaller infarctions, in the current era where patients receive multiple secondary prevention strategies. Furthermore, no large-scale outcome study has ever been conducted to examine the clinical impact of beta-blockers in patients with stable CAD without prior infarction. Studies examining the effects of beta-blockers on symptoms of angina were not powered to address their effect on long-term outcome [22, 23, 41–43, 138, 139]. Despite these shortcomings, it has generally been assumed that beta-blockers have either neutral or potentially beneficial effects on long-term clinical outcome. Of note, recent evidence from post hoc analysis of clinical trial data and from large registries has brought both of these assumptions into question, particularly in patients who have not suffered a myocardial infarction [140, 141].

In 1995, Furberg and Psaty reported results from meta-analyses suggesting that therapy with calcium channel antagonists was associated with a significant increase in the risk of myocardial infarction. This risk was observed in patients with hypertension and in those with angina [142, 143]. At that time, the use of calcium channel antagonists was rapidly increasing in both of these patient populations. These findings received international attention and highlighted the lack of studies examining the safety of calcium channel antagonists in patients with CAD. The resulting controversy concerning calcium channel antagonist safety led to the ACTION (effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment) study, in which 7,765 patients with coronary artery disease, a history of stable angina, and preserved left ventricular systolic function were randomized to therapy with sustained-release nifedipine or placebo. In this large study, nifedipine had no impact on mortality but was associated with lower cardiovascular event rates and reduced the rate of coronary revascularization procedures (Fig. 22.3) [144]. The safety and clinical effectiveness of diltiazem has not been tested in patients with stable angina; however, it is known that it should be avoided in patients with coronary disease and significant left ventricular systolic dysfunction [145]. Finally, although verapamil is less frequently used in the therapy of angina than other calcium channel antagonists and should be avoided in patients with left ventricular systolic dysfunction, data from the INVEST (INternational VErapamil SR-Trandolapril) study found no evidence of adverse effects in a large group of patients with CAD and hypertension [146].

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