Abstract
Pharmacologic treatment of myocardial ischemia in patients with chronic stable angina (CSA) is mainly based on heart rate lowering drugs and vasodilator agents. Other drugs are available, however, that act by some peculiar mechanism (ranolazine, trimetazidine) and may add potential anti-ischemic and anti-anginal effects to standard therapeutic mechanisms. While anti-ischemic agents are crucial for controlling angina symptoms and improving quality of life, whether myocardial ischemia portends an ominous prognosis and its suppression improves clinical outcome in CSA patients remain debated issues.
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Introduction
Patients with chronic stable angina (CSA) usually develop myocardial ischemia and angina during physical efforts, or also under stressful situations or other conditions that increase myocardial oxygen consumption.
Pharmacological treatment developed to treat myocardial ischemia in CSA patients is based on the knowledge of the pathophysiological mechanisms involved in its occurrence. Thus, while general rules can be given for management of myocardial ischemia, some characteristics of myocardial ischemia/angina episodes may suggest that some class of drugs might be more helpful in controlling myocardial ischemia in individual patients.
Yet, although treatment of myocardial ischemia is an obvious objective of therapy, and is actually crucial for angina prevention, whether it portends an ominous prognosis and whether its suppression is associated with improvement of clinical outcome remain debated topics.
A brief discussion of the mechanisms involved in determining myocardial ischemia in CSA patients can be helpful to overview the management of myocardial ischemia in CSA.
Pathophysiologic Mechanisms of Myocardial Ischemia in CSA
In patients with CSA the pathophysiologic substrate for the occurrence of myocardial ischemia and angina is represented by the presence, in one or more major epicardial coronary vessels, of atherosclerotic plaques determining flow-limiting stenosis, and therefore a reduction of coronary flow reserve, i.e., of the maximal increase of coronary blood flow (CBF) achievable during increase of myocardial oxygen consumption (MVO2), which in normal people is 4 to 5 fold the basal CBF value.
By reducing the distal driving pressure, flow-limiting stenoses tend to reduce blood flow in the supplied myocardial territory. In basal conditions CBF is maintained in the normal range as the pressure drop is compensated by reduction of microvascular resistance, consequent to arteriolar dilatation, but this compensatory vasodilatation also results in a reduction of coronary flow reserve. The level of cardiac work at which it is not possible to further increase CBF to fully meet the increased metabolic requirements, thus resulting in myocardial ischemia (and angina), identifies the ischemic (and angina) threshold, which tends to be as much as lower as the severity of stenosis increases [1, 2].
It is worth reminding that myocardial ischemia in CSA patients almost always involves subendocardial layers only. The latter, indeed, have a lower flow reserve, and are therefore more vulnerable to ischemia compared to subepicardial layers, due to a slightly higher basal oxygen consumption related to their increased systolic stress and contractility, but also to some obstacle to subendocardial flow caused by the effects of intraventricular pressure [3]. Finally, shortening of diastole due to tachycardia and delayed or slow myocardial relaxation (favored by myocardial ischemia) contribute to make the resumption of subendocardial flow in diastole more difficult.
Factors Influencing Myocardial Ischemia in CSA
While the presence of a flow-limiting stenosis is the basis for the occurrence of myocardial ischemia following increase of MVO2, the induction and severity of ischemia can be influenced and modulated by several factors, which might cause a large variability in ischemic threshold and might constitute an objective of treatment in individual patients.
Dynamic Stenosis
Only a minor number of coronary stenoses are fixed, i.e., do not show any vasomotor change at their site able to influence blood flow; fixed stenoses tend to determine a stable and predictable pattern of myocardial ischemia and angina. Most stenoses, however, are dynamic, i.e., present vasomotor changes that can significantly modify ischemic threshold and severity, also resulting in a variable and less predictable pattern of myocardial ischemia and angina. The presence of a dynamic stenosis can be assessed by the intracoronary administration of vasodilator or vasoconstrictive substances [4].
Microvascular State
Variations of ischemic threshold may also depend on changes of resting coronary resistance. Basal microvascular tone is influenced by a large number of factors, including neurogenic and humoral factors. Variations in alpha-tone, for example, is likely a major mechanism for the circadian variation of ischemic angina threshold in CSA patients [5]. Of note, coronary microvascular constriction can be induced by exercise thus further influencing ischemic threshold [6].
Collateral Circulation
There is large variability among patients with flow-limiting epicardial stenosis in the development of collateral vessels, but, when present, they significantly contribute to myocardial perfusion in the territory supplied by the obstructed vessel. Variations in blood flow in collateral vessels, which are influenced by neural, humoral and autacoid stimuli, may also constitute a relevant mechanism for variations in ischemic threshold [7].
Coronary Steal
Coronary steal is a mechanism of myocardial ischemia that occurs when blood flow to a myocardial region supplied by a severely stenotic vessel becomes insufficient due to a diversion of a significant quota towards another myocardial region undergoing maximal arteriolar dilatation. It may typically occur in subendocardial layers as a result of arteriolar dilatation in subepicardial regions supplied by the same stenotic vessel [8], or in myocardial areas that depend on collateral circulation, when maximal dilatation occurs in the territory of the supplying normal coronary vessel [9].
Other Mechanisms
Several other factors may modify ischemic threshold in CSA patients, including, in particular, changes in afterload (e.g., level of blood pressure) or preload (e.g., blood volume), as well as the development of conditions that enhance myocardial oxygen requirement and/or impair oxygen supply (e.g., anemia, myocardial hypertrophy, increased thyroid function). Finally, ischemic preconditioning may increase ischemic threshold, as shown in exercise stress tests performed several minutes after a prior positive test [10].
Management of Myocardial Ischemia
As ischemic episodes in CSA patients are usually induced by physical efforts, a major objective of pharmacological therapy is to reduce the increase in myocardial work and oxygen requirements during physical efforts, in order to prevent or delay the achievement of ischemic threshold. In patients in whom exercise-induced or stress-induced myocardial ischemia is favored by vasoconstriction of a dynamic stenosis and/or coronary microcirculation, the use of dilator drugs may significantly contribute to their management. Drugs used to treat myocardial ischemia in CSA patients, however, often achieve their effects with the contribution of multiple mechanisms.
Heart Rate Lowering Drugs
Drugs that reduce heart rate (HR) at baseline and, even more, during exercise constitute the most important form of therapy for exercise-induced myocardial ischemia. HR is indeed the most important determinant of MVO2; accordingly, reducing HR for a given level of exercise results in lower myocardial O2 requests, and therefore in delay or full prevention of achievement of ischemic threshold.
HR lowering drugs are considered to achieve an optimal effect when HR at rest is maintained below 60 bpm and HR achieved at peak exercise is lower than 110 bpm.
Of note, an improvement of myocardial perfusion may contribute to the anti-ischemic effects of these agents, due to prolongation of diastolic time.
Beta-Blockers
Beta-blockers constitute the typical class of drugs that achieve their anti-ischemic effect by mainly reducing HR, and they are first-line agents for treating myocardial ischemia and anginal symptoms in CSA patients. Beta-blockers reduce HR by antagonizing adrenergic sinus node stimulation. Of note, other relevant anti-adrenergic effects, including reduction of myocardial contractility and blood pressure, contribute to the reduction of myocardial work and the overall anti-ischemic effect of these drugs.
Furthermore, beta-blockers may favor flow towards ischemic areas by increasing vascular resistance in non-ischemic areas (‘reverse coronary steal’ phenomenon).
Beta-1 selective agents (e.g., metoprolol, atenolol, bisoprolol) should be preferred for myocardial ischemia management, as they have less side-effects compared with non-selective drugs [11]. Beta-blockers exhibiting intrinsic sympathomimetic activity (e.g., acebutolol, pindolol) are instead usually avoided due to their lower effect on HR (in particular during exercise). Agents with long half-life (e.g., atenolol, bisoprolol) or extended-release formulations (e.g., metoprolol CR) can be used to allow single daily dose and increase adherence to therapy.
The significant effects of beta-blockers on exercise-induced myocardial ischemia and angina and on episodes of transient myocardial ischemia occurring during daily life in CSA patients have been shown in a large number of studies [12, 13]. Whether the anti-ischemic effects translate into improved clinical outcome, however, remains debatable. Beta-blockers were found to improve prognosis in old trials of patients discharged after an acute myocardial infarction [14, 15], and similar beneficial effects have been suggested to occur in patients with stable coronary artery disease (CAD). In a small study atenolol showed a lower rate of a combined endpoint, which included symptoms requiring treatment, in stable CAD patients compared to placebo [16]; however, prognosis did not differ significantly between the 2 groups.
The complex of the evidence suggests at present that beta-blockers are clearly indicated for prognostic purposes only in patients with stable or stabilized CAD with impaired left ventricular (LV) function and/or a recent acute myocardial infarction.
Non Dihydropirydine Calcium-Channel Blockers (CCBs)
Non dihydropirydine (NDHP) CCBs (verapamil, diltiazem) also exert most of their anti-ischemic effect through a reduction of HR, which results from the inhibition of the calcium current involved in the pacemaker activity of the sinus node. A reduction of myocardial contractility, due to their effects on calcium current of ventricular myocardial cells, may also significantly contribute to reduce myocardial work and improve ischemic threshold in CSA patients. As with all CCBs, NDHP drugs may also prevent myocardial ischemia through reduction of afterload (by inducing peripheral dilatation), and by coronary dilatation. The reduction of blood pressure, however, induces adrenergic activation that may limit the HR lowering effects of these drugs, but may avoid the negative effects on myocardial contractility that can sometimes trigger acute heart failure.
NDHP-CCBs can be added to beta-blockers to achieve optimal anti-anginal and anti-ischemic effects, but this association should be made with caution and under careful control of the patient, as there can be additional unwanted effects of bradyarrhythmias and LV depression.
Although in a few trials some benefits on prognosis have been found in patients with no ST-segment elevation acute coronary syndromes [17–19], the application of those results in the modern era of interventional and multi-drug therapy remains questionable. Moreover, beta-blockers, verapamil and diltiazem have not been studied in large outcome trials of CSA patients, and the complex of evidence does not support their use for prognostic purposes in these patients. On the other hand, they constitute a valid first-choice alternative to beta-blockers for treatment of myocardial ischemia in the absence of LV impairment or recent ST-segment elevation acute myocardial infarction.
In some trials, indeed, no significant differences in outcome and features of myocardial ischemia have been found between CSA patients treated with beta-blockers or NDHP-CCBs [20, 21], whereas in the APSIS trial verapamil was slightly better than metoprolol in increasing exercise tolerance [22]. A meta-analysis showed that beta blockers were more effective than CCBs in reducing anginal episodes, but there were no differences when considering NDHP-CCBs only; furthermore, the effects on exercise-induced myocardial ischemia were similar between the two classes of drugs [23].
Ivabradine
Ivabradine is an HR lowering agent that specifically acts by inhibiting the I f current of the sinus node [24]. Thus its main anti-ischemic effect is related to the reduction of MVO2 consequent to HR reduction. Its usual dose is 2.5–7.5 mg twice daily. In contrast with beta-blockers, ivabradine does not have unwanted systemic or cardiovascular effects other than excessive bradycardia, including lowering of blood pressure and negative inotropism. The main side effect is instead represented by mild visual disturbances, which subside with cessation of drug consumption.
The results of the main randomized trials of ivabradine in patients with stable ischemic heart disease are summarized in Table 1. These studies have shown that ivabradine is more effective than placebo in improving exercise-induced myocardial ischemia and angina in CSA patients [25], and the INITIATIVE study showed similar anti-angina effects compared to atenolol [26], thus suggesting that it might be used as a valid alternative to beta-blockers when patients have contraindications or show intolerance to these drugs. Furthermore, the ASSOCIATE trial [27] also showed that ivabradine has additional effects to beta-blockers in reducing exercise-induced myocardial ischemia without any apparent increase in side-effects, and in the BEAUTIFUL study ivabradine seemed to improve ischemic events (hospitalizations for fatal or non-fatal myocardial infarction and coronary revascularizations) in the subgroup of patients with basal HR >70 bpm [28].
In the recent SIGNIFY trial, however, no beneficial effects were observed in patients with stable CAD on the primary combined end-point of cardiovascular death or acute myocardial infarction, which was actually increased in the subgroup with angina [29]. While this surprising result was possibly related to a higher dose of ivabradine used in this study (10 mg twice a day), compared to previous studies, the results suggest that further data would be desirable to better delineate the role of the drug in CSA patients.
Vasodilator Drugs
Dihydropirydine CCBs
DHP-CCBs mainly act as anti-anginal agents by inhibiting entry of calcium into vascular smooth muscle cells, thus resulting in peripheral and coronary arterial dilatation, effects that are larger than those of NDHP-CCBs. The hypotensive effect, however, may cause significant reflex adrenergic activation with tachycardia, which may hamper the positive effects of vasodilatation. This unwanted effect, as well as other typical side effects related to vasodilation (headache, flushing, ankle oedema) can be reduced by using long-acting agents (e.g., amlodipine) or sustained release formulations of short-acting compounds (e.g., nifedipine, felodipine).
The adrenergic activation, however, contrasts the mild negative inotropic and chronotropic effects of these drugs. Accordingly, DHP-CCBs can be added more safely than NDHP-CCBs to beta-blockers. In fact, the anti-anginal and anti-ischaemic effects of DHP-CCBs can be additive to those of beta-blockers, which counteract their reflex sympathetic activation.
DHP-CCBs, instead, do not constitute first-line drugs for myocardial ischemia and angina treatment. Comparisons in clinical studies have shown that, on the whole, they are indeed less effective than beta-blockers on myocardial ischemia and angina symptoms in stable CAD. In the TIBET trial, in fact, atenolol and nifedipine showed similar beneficial effects, compared to placebo, on exercise-induced myocardial ischemia and on total ischemic burden during daily life [30]. In the IMAGE trial [31], however, metoprolol had greater effect on exercise tolerance than nifedipine, and bisoprolol also showed larger anti-ischaemic and anti-anginal effects than nifedipine in another study [32]. Finally, a meta-analysis showed that beta-blockers were more effective than DHP-CAs in reducing myocardial ischemia and anginal episodes [23].
As for NDHP-CCBs, and despite favorable effects on myocardial ischemia, there is no evidence that DHP-CCBs may have any prognostic effect in CSA patients, and high doses of short-acting agents (nifedipine) might, in fact, be associated with increased mortality [33, 34].
Long-Acting Nitrates
Nitrates exert their anti-ischemic effects by mainly reducing blood volume to the heart through peripheral vein dilatation, thus decreasing preload and myocardial work. Peripheral and coronary arterial dilator effects also variably contribute to the therapeutic effects of this class of drugs.
While short-acting nitrates remain the elective treatment for relief of angina, the role of long-acting nitrates for prevention of effort-related myocardial ischemia and angina remains debated, in spite of the long period of years during which they are being used in CSA patients. Indeed, only few studies showed some benefit on myocardial ischemia episodes, but tolerance to continuous oral or transdermal administration may develop rapidly and, therefore, make treatment unhelpful. Intermittent administration with nitrate-free intervals or modified delivery systems designed to provide a period of low blood nitrate concentrations in the day have been recommended to overcome the issue of tolerance [35, 36]. There is no evidence, on the other hand, that nitrates may have any favorable impact on prognosis in patients with CSA.
There are relatively few and small studies comparing the effects of nitrates with beta-blockers or calcium-antagonists. A meta-analysis, however, showed a trend towards fewer angina episodes with either beta-blockers or CCBs compared with long-acting nitrates [23].
Nicorandil
Nicorandil is a vasodilator drug that exerts its anti-myocardial ischemia effects by acting as an adenosine triphosphate-dependent potassium channel opener, but also as a nitrate-like compound. As a consequence of its effect on potassium channels, nicorandil seems also to exert ischemic preconditioning-like effects [37]. Compared to nitrates, nicorandil seems to develop tolerance less frequently, although that has been reported during long-term consumption [38].
Several studies have shown beneficial effects of the drug on myocardial ischemia and angina [39, 40]. In the randomized, placebo-controlled IONA trial, however, nicorandil failed to reduce angina attacks, thus questioning its major role for myocardial ischemia treatment [41]. Of note, the drug showed a significant reduction of hospital admission for acute cardiac chest pain, and also decreased major cardiac events, but the prognostic advantage was lost at follow-up. A limitation of nicorandil is that it is not available in several countries.
Other Anti-Anginal Drugs
While most medications introduced to treat myocardial ischemia mainly act through reduction of myocardial work and/or as vasodilators, some few other agents act through some different, peculiar pharmacological effects. The main relevance of these drugs is that they may add some further mechanism to those of classical anti-ischemic medications to achieve full control of myocardial ischemia and symptoms.
Ranolazine
Ranolazine is a recently introduced anti-ischemic drug that seems to act by selectively inhibiting the late sodium current of cardiomyocytes; this reduces intracellular sodium-dependent calcium overload and favors LV relaxation, with improvement of diastolic function and subendocardial perfusion [42]. Several randomized trials have shown significant effects of ranolazine (at the dose of 500–1500 mg twice daily) on exercise-induced myocardial ischemia and exercise tolerance as compared to placebo [43–45] (Table 1), with increased symptomatic relief when added to beta-blockers and/or calcium-antagonists. There is no evidence, however, that the drug may have any appreciable effect on clinical outcome.
Furthermore, in a recent large placebo-controlled trial, ranolazine did not reduce the primary end-point of ischemia-driven coronary revascularization or hospitalization in patients who had already undergone a percutaneous coronary intervention with incomplete revascularization [46] (Table 1), and a secondary analysis also showed no significant additional effects on angina episodes and quality of life [47]. While these results might be related to a lower ischemic burden related to partial revascularization, they suggest that larger trials of ranolazine in patients with stable angina despite on top of anti-angina treatment would be welcome.
Trimetazidine
Trimetazidine seems to exert anti-ischemic effects by preserving energy balance and prevent disturbance of ion homeostasis during ischemia thanks to modulatory effects on intracellular calcium; the drug, furthermore, also stimulates glucose oxidation and acts as a partial fatty acid oxidation inhibitor through a reduction of the mitochondrial activity of 3-ketoacyl coenzyme A thiolase [48].
Anti-ischemic and anti-anginal efficacy has been shown in several studies and reviewed in a meta-analysis [49], but large clinical trials convincingly supporting its use in combination with other drugs and, even more, as monotherapy, are lacking. A limitation of trimetazidine is that it is available in several European countries only.
Objectives in Management of Myocardial Ischemia
As observed above, a major obvious objective of anti-ischemic therapy is the control of angina attacks and, therefore, the improvement of physical performance and quality of life. On the other hand, whether suppression of myocardial ischemia may also result in improvement of clinical outcome and prognosis in patients with CSA is debated and still remains an unresolved issue [50, 51]. The question is not irrelevant as most (about 70 to 80 %) of myocardial ischemia episodes are silent (i.e., not associated with any symptom), and, in spite of full control of symptoms, several stable CAD patients continue to show evidence of stress-induced myocardial ischemia and also develop transient myocardial ischemia episodes during daily life.
Transient myocardial ischemia has consistently been shown to be predictive of adverse clinical outcome in patients with acute coronary syndromes [52, 53]; in contrast, discordant results have been reported in CSA patients. Early studies showed a significant association between exercise-induced myocardial ischemia and cardiac events in these patients, in particular when myocardial ischemia was induced at low workload or was extensive [54–56]; however, several recent studies failed to attribute to exercise-induced myocardial ischemia an independent association with clinical outcome after more consistently predictive variable, as exercise capacity and LV function, were taken into account [57, 58].
Other studies also reported a prognostic value for transient myocardial ischemia episodes occurring during daily life. Thus, in the Total Ischemic Burden Bisoprolol Study [32], cardiac events (death or acute coronary syndromes) at 12-month follow-up occurred in 4.7 % of patients with less than 2 ischemic episodes, but in 12.1 % of those with 2 or more transient ischemic episodes during Holter monitoring (p < 0.005). In the ACIP study a proportional association of the number of episodes of myocardial ischemia and rate of events was also observed [59]. Nevertheless, no significant association between transient myocardial ischemia and events could be found in other studies [60, 61].
The lack of association between myocardial ischemia and prognosis, however, is not unexpected from a pathophysiologic point of view, and various factors may contribute to this disappointing finding. First, the potential immediate risks that can potentially be triggered by myocardial ischemia per se (e.g., life-threatening arrhythmias and acute heart failure), seem very low during transient subendocardial ischemia as they would require severe and/or extensive ischemia [62]; accordingly, demonstration of possible detrimental effects would require studies including very large populations of patients.
Second, fatal and non fatal acute coronary events are mainly triggered by acute coronary plaque complications and thrombosis. This explains why life-style interventions and medications able to stabilize coronary plaques and prevent complications (mainly including antiplatelet agents and statins) have shown clear prognostic benefits and are now first-line recommended interventions in CSA management [63, 64].
Of note, while in older studies myocardial ischemia could be a relevant marker of risk because it likely reflected a significant extension of atherosclerotic CAD lesions, implying a higher probability of acute plaque complications, this significant predictive value may have considerably been blunted now by the marked reduction of acute plaque events determined by anti-athero-thrombotic drugs.
The recent doubts about the prognostic role of myocardial ischemia are in keeping with the scarce evidence that suppression of myocardial ischemia may improve clinical outcome in CSA patients. This issue, in fact, has only been specifically assessed in the ACIP trial, which included CSA patients with evidence of ischemic episodes during ECG Holter monitoring and showed that an ischemia-guided drug therapy was not definitely better than an angina-guided medical therapy in improving prognosis [65]. Moreover, while older trials showed benefits from surgical coronary revascularization, which results in better control of myocardial ischemia in patients with the most severe forms of coronary artery disease [66], recent clinical trials of stable CAD patients have questioned the real utility of treating myocardial ischemia with percutaneous, and perhaps also surgical, coronary revascularization [67–69]. It is hoped that the ongoing ISCHEMIA trial can give some more definitive responses to the issues concerning the relation of myocardial ischemia and its treatment with clinical outcome [70].
General Approach to Pharmacological Therapy of CSA
A scheme of long-term treatment of patients with CSA/stable CAD is illustrated in Fig. 1 [71]. Patients should first of all receive drugs demonstrated to improve prognosis, including aspirin (clopidogrel if aspirin is in some way contra-indicated) and a statin. In patients with LV dysfunction a beta-blocker and an ACE-inhibitor (or an angiotensin II receptor blocker) should be added for prognostic purposes, and a beta-blocker should also be added to patients with a recent myocardial infarction.
Schematic therapeutic approach to patients with chronic stable angina/coronary artery disease. AMI = acute myocardial infarction; LVD = left ventricular dysfunction. Derived and re-drawn from ref. 71
An HR-lowering agent, on the other hand, should constitute the first-line therapy of myocardial ischemia and angina in stable CAD patients. A beta-blocker is largely preferred to this scope. However, NDHP-CCBs constitute a valuable alternative in patients with normal LV function who present contraindications or intolerance to beta-blockers, or even in the few patients who show a relevant variability of ischemic/angina threshold, or also the occurrence of angina/myocardial ischemia with scarce increase of HR (as assessed by Holter monitoring) [72], suggesting a significant contribution of vasomotor changes to the mechanisms of myocardial ischemia. Ivabradine may constitute a valid choice when a pure bradycardic effect is desired.
In patients taking a beta-blocker but continue to report angina attacks, a DHP-CCB or, in selected cases, a NDHP-CCB, can be added to a beta-blocker as a second step, whereas, when necessary, a long-acting nitrate or some of the alternative anti-ischemic drugs can be added as a third step, according to the clinical characteristics of the patients and/or of angina and myocardial ischemic episodes. Thus, for example, in patients with a persistent relatively high HR (>70 bpm) ivabradine in standard doses might be the right choice, whereas ranolazine might be preferred in case of significant diastolic dysfunction.
In summary, pharmacological management of myocardial ischemia and angina in CSA patients requires careful evaluation of the clinical characteristics and, possibly, angina and myocardial ischemic episodes in individual patients. Coronary revascularization obviously constitutes the alternative to medical therapy and should be considered on the basis of symptoms and risk profile of individual patients.
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Lanza, G.A., Crea, F. Overview of Management of Myocardial Ischemia: a Mechanistic-Based Approach. Cardiovasc Drugs Ther 30, 341–349 (2016). https://doi.org/10.1007/s10557-016-6662-5
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DOI: https://doi.org/10.1007/s10557-016-6662-5