New therapies for angina pectoris

INTRODUCTION — Despite the increasing success of conventional medical therapies and the continued development and improvement of percutaneous coronary intervention (PCI), a significant number of patients with ischemic heart disease and angina pectoris cannot be successfully managed.

Many of these patients are not candidates for revascularization by PCI or coronary artery bypass graft surgery (CABG) because of one or more of the following [1]:

●Unsuitable anatomy, such as diffuse coronary disease.

●One or several prior PCIs or CABGs, which may limit further benefit or preclude further revascularization.

●Lack of vascular conduits for CABG.

●Severely impaired left ventricular function in patients with previous CABG or PCI.

●Concurrent diseases that increase perioperative or postoperative morbidity or mortality (eg, cerebrovascular disease, advanced complications of diabetes, chronic kidney disease).

●Age, often in combination with other factors.

In addition, a substantial proportion of patients undergoing PCI or CABG do not achieve complete revascularization. Many of these patients continue to experience residual anginal symptoms or myocardial ischemia despite maximal medical therapy. (See "Chronic coronary syndrome: Overview of care" and "Chronic coronary syndrome: Indications for revascularization".)

The newer medical and mechanical therapies that are currently being evaluated for treating patients with refractory angina will be reviewed here [2,3].

MEDICAL THERAPIES — A number of medical therapies are being evaluated for the treatment of refractory angina. Only ranolazine has been approved for use in the United States.

Ranolazine — Ranolazine was approved by the United States Food and Drug Administration (FDA) in 2006 for management of chronic stable angina. Although initially thought to act by partial inhibition of fatty acid oxidation, it was later realized that ranolazine had that effect only at serum levels not achieved with the usual dosing.

A more important mechanism for ranolazine may be the prevention of both calcium overload and the subsequent increase in diastolic tension due to inhibition of late inward sodium channel [4,5]. Since this sodium channel frequently fails to inactivate in a number of important myocardial disease states such as ischemia and hypertrophy, excess entry of sodium ions leads to activation of the sodium/calcium exchanger, thereby raising calcium concentration [6]. Given the normal rapid inaction of the late inward sodium channel in normal myocytes, the drug does not exert a significant effect on the normal myocardium at usual dosages. This potentially increases its therapeutic window.

The initial dose of ranolazine is 500 mg twice daily. For patients who remain symptomatic, 1000 mg twice daily may be used.

Acute coronary syndrome — A separate issue from the efficacy of ranolazine for symptom control is whether it might improve cardiovascular outcomes. The lack of such benefit was demonstrated in the MERLIN-TIMI 36 trial in which over 6000 patients with an acute coronary syndrome were randomly assigned to placebo or to ranolazine (initiated intravenously and followed by oral therapy of extended release 1000 mg twice daily) [7]. At one year, there was no significant difference between the two groups in the primary composite, efficacy end point of cardiovascular death, myocardial infarction (MI), or recurrent ischemia or any of the safety end points including total mortality or symptomatic documented arrhythmias.

Stable angina — The efficacy of ranolazine in patients with chronic stable angina has been demonstrated in several randomized trials [8-10]. The following observations illustrate the range of findings:

●In the MARISA trial, ranolazine monotherapy resulted in a dose-dependent increase in pain-free exercise duration and time to angina in 191 patients, with a 1000 mg twice daily dose being more effective than a lower dose [10].

●In the CARISA trial, 823 patients receiving background antianginal therapy (calcium channel blocker or atenolol) were randomly assigned to placebo or one of two doses of ranolazine (750 or 1000 mg twice daily) [8]. After 12 weeks of therapy, both doses of ranolazine significantly increased symptom-limited exercise duration, time to onset of angina, and (at peak ranolazine blood level) time to ST segment depression, and reduced angina frequency by 0.8 and 1.2 episodes per week, compared to placebo.

●In the ERICA trial, 565 stable patients with more than three anginal attacks per week were randomly assigned to either ranolazine (1000 mg/day) or placebo [9]. All patients were taking 10 mg of amlodipine per day and were allowed to be on long-acting nitrates but not beta blockers; the patients had 5.63 episodes of angina per week at baseline. Ranolazine significantly improved the primary end point of anginal episodes per week compared to placebo (2.88 versus 3.31).

●In the TERISA trial, 949 patients with diabetes and stable angina treated with one to two antianginal drugs were randomly assigned to ranolazine or placebo for eight weeks [11]. Weekly angina frequency was lower with ranolazine (3.8 versus 4.3 episodes; p = 0.008) as was weekly sublingual nitroglycerin use (1.7 versus 2.1 doses; p = 0.003). Although statistically significant and in agreement with findings in other ranolazine studies, the absolute effects of ranolazine in this study are modest.

Incomplete revascularization after PCI — Many patients with chronic stable angina do not receive complete revascularization at the time of percutaneous coronary intervention (PCI). The issue of whether ranolazine might improve outcomes in such patients was evaluated in the RIVER-PCI trial, which randomly assigned 2651 patients to ranolazine or placebo after incomplete revascularization with PCI [12]. There was no difference in the rate of the primary efficacy end point (time to first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization) between the two groups (26 versus 28 percent; hazard ratio 0.95, 95% CI 0.82-1.10) after a median follow-up of 643 days.

Unstable angina — A different population was studied in the MERLIN-TIMI 36 trial cited above of patients with an acute coronary syndrome [7,13]. In the subset of 3565 patients who had prior chronic angina, ranolazine significantly reduced the primary end point of cardiovascular death, MI, and recurrent ischemia due entirely to a significant reduction in recurrent ischemia (hazard ratio [HR] 0.78, 95% CI 0.67-0.91) [13]. There was also an almost significant trend toward a lower rate of worsening angina (HR 0.77, 95% CI 0.55-1.00) and a significant improvement in exercise duration on a treadmill (514 versus 482 seconds).

Glycometabolic effect — Treatment with ranolazine in the MERLIN-TIMI-36 trial population resulted in a statistically significant 0.3 percent absolute reduction in HbA1c levels that was even more pronounced in patients with diabetes mellitus. There may also have been a reduction in progression to overt clinical diabetes as defined by increase in fasting blood sugar above 110 mg/dL (6.1 mmol/liter) [14]. The mechanism of this effect is unclear.

Adverse effects — Since ranolazine produces a dose-dependent increase in the QT interval, the United States Food and Drug Administration recommended that it should be reserved for patients who have not had an adequate response with other antianginal drugs [15]. We would be more restrictive, limiting the use of ranolazine to patients who have failed all other antianginal therapies. Ranolazine is contraindicated in patients with preexisting QT interval prolongation or hepatic disease, and in patients taking other drugs that prolong the QT interval or that are potent or moderately potent inhibitors of CYP3A4, such as diltiazem and verapamil. Ranolazine also inhibits pathways involved in the metabolism of digoxin and simvastatin, and dose reduction may be required.

Like other drugs that prolong the QT interval, ranolazine inhibits the KCNH2 channel (formerly called HERG channel) [16,17]. However, the effect is generally less than with other drugs (mean QTc prolongation 2.4 ms in a review of 746 patients treated for almost three years) [18] and torsade de pointes has not yet been described [15-19]. Most drugs that cause torsade de pointes show reverse use dependence, which is defined as the inverse correlation between the heart rate and QT interval. The apparent lack of reverse use dependence with ranolazine may protect against the development of torsade de pointes [17]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Pathophysiology'.)

In the largest reported long-term (greater than one year) experience with ranolazine (746 patients treated for almost three years), 10 percent discontinued therapy due to adverse events attributed to ranolazine [18]. Only advanced age (>64 years) was predictive of the need to withdraw the drug. The annual mortality rate was 3.0 percent and did not exceed predicted rates.

In the MERLIN-TIMI 36 trial, treatment with ranolazine was associated with a 3 percent lower frequency of ventricular tachycardia (VT), a 10.3 percent lower incidence of supraventricular tachycardia, and a 0.7 percent reduction in the onset of new atrial fibrillation [20].

Antiarrhythmic effect — Ranolazine has not been evaluated as a primary anti-arrhythmic agent, although it has exhibited a favorable anti-arrhythmic profile in the MERLIN-TIMI 36 Trial (see above).

Summary — In patients with a history of chronic stable angina, including those who are stable after an acute coronary syndrome, ranolazine is effective at reducing anginal symptoms and improving exercise capacity, when added to standard antianginal therapy. It may also be an effective anti-arrhythmic agent, although that aspect of its activity needs more extensive clinical testing.

We agree with the following weak recommendation which was made in 2012 guideline on the diagnosis and management of stable ischemic heart disease from the American College of Cardiology Foundation/American Heart Association/American College of Physicians/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society for Cardiovascular Angiography and Interventions/Society of Thoracic Surgeons (ACCF/AHA/ACP/AATS/PCNA/SCAI/STS) [21-23]:

●Ranolazine can be a substitute for beta blockers for relief of anginal symptoms if initial treatment with beta blockers leads to unacceptable side effects or is ineffective or is contraindicated.

Ranolazine can be combined with beta blockers for relief of symptoms if initial monotherapy with beta blockers is unsuccessful.

Inhibition of fatty acid oxidation — Drugs in this category are rarely used for angina, and they have significant side effects. Inhibition of fatty acid oxidation represents a different approach to the management of angina. Switching from fatty acid oxidation to glucose oxidation increases cardiac metabolic efficiency. Three such agents are ranolazine, trimetazidine, and perhexiline [24,25]. However, ranolazine is discussed separately above because inhibition of fatty acid oxidation may not be its primary mode of action.

Although the heart uses both glucose and fatty acids as fuel, during periods of stress the heart uses more fatty acids, which is less oxygen efficient. Inhibition of fatty acid oxidation shifts the equilibrium toward increased use of glucose, improving the efficient use of oxygen.

A potential advantage of these drugs is that, in contrast to nitrates, they may be safe in patients taking sildenafil or other phosphodiesterase type 5 inhibitor for erectile dysfunction [26]. (See "Sexual activity in patients with cardiovascular disease".)

Trimetazidine — Trimetazidine, which achieves its antiischemic action by improving the metabolic efficiency of ischemic myocardium, has not been conclusively shown to improve anginal symptomatology, and we do not use this drug.

A 2005 meta-analysis that included 23 studies of 1378 patients [27] showed that compared with placebo, trimetazidine was associated with a reduction in weekly angina episodes (mean 1.44) and improved exercise time to 1 mm ST-segment depression. Despite the reported findings, we are reluctant to make recommendations based on this 2005 study of patients who were treated using older therapies, particularly less aggressive preventive strategies.

The 2020 placebo-controlled, randomized ATPCI trial assessed the antianginal effects and safety of trimetazidine in 6007 patients who had undergone successful PCI for stable angina or non-ST-elevation myocardial infarction less than 30 days before admission to the study [28]. Trimetazidine 35 mg or placebo were administered twice daily. All patients were receiving standard preventive and antianginal therapy. After a median follow-up of 47.5 months, there was no significant difference between the two groups with respect to cardiac death, hospital admission for a cardiac event, recurrence or persistence of angina requiring an addition, switch, increase of the dose of at least one antianginal drug, or the need for repeat coronary angiography. No statistically significant increase in major side effects was reported comparing trimetazidine with placebo.

Perhexiline — The antianginal efficacy of perhexiline was demonstrated in older trials, even in patients not controlled with other antianginal drugs [24,25,29,30]. However, its use markedly declined in the early 1980s after reports of hepatotoxicity and peripheral neuropathy [25]. These complications most often occur in patients who are slow hydroxylators and their incidence can be dramatically reduced by maintaining plasma drug concentrations between 150 and 600 ng/mL [25,30]. These findings led to increased use in some areas, such as Australia and Europe, in patients with refractory angina who are not candidates for or refuse revascularization [25].

Nicorandil — Nicorandil, a potassium channel activator, is used for the treatment of angina in a number of countries, but not the United States. It has multiple actions that are beneficial in coronary artery disease. It is an arterial and venous dilator and improves coronary blood flow due to potassium channel opening and nitrate effect. Since ATP-dependent potassium channels play a role in ischemic preconditioning, nicorandil may also mimic a natural process of ischemic preconditioning, protecting the heart from subsequent ischemic attacks. (See "Myocardial ischemic conditioning: Pathogenesis".)

The effect of nicorandil (20 mg twice per day) on coronary events was evaluated in the IONA trial of 5126 patients with chronic stable angina who were receiving other standard therapies (antiplatelet drugs, beta blockers, calcium channel blockers, statins, and angiotensin converting enzyme [ACE] inhibitors) [31]. After a mean follow-up of 1.6 years, nicorandil reduced the primary end point (coronary death, nonfatal MI, or unplanned hospitalization for angina) by 17 percent (13 versus 15.5 for placebo, hazard ratio 0.83, 95% CI 0.72-0.97). There was an almost significant reduction in the secondary end point of death and nonfatal MI (4.2 versus 5.2 percent) and significant reductions in the incidence of an acute coronary syndrome (6 versus 7.6 percent) and all cardiovascular events (14.7 versus 17 percent).

IONA was an outcome study and provided little information regarding the effects of nicorandil on symptoms of angina. Worsening of anginal status was not significantly different in patients taking nicorandil compared to those on placebo (22 versus 24 percent, respectively).

Nicorandil is available in Europe and elsewhere for the treatment of angina.

Allopurinol — Allopurinol, a xanthine oxidase inhibitor used in the prevention of recurrent gout, should rarely be used to treat angina.

The potential use of allopurinol as an antianginal agent, when added to standard therapy, was evaluated in a crossover study that randomly assigned 65 patients with documented coronary artery disease to either allopurinol 600 mg per day or placebo for six weeks before crossover [32]. Allopurinol, compared to placebo, significantly increased the median time to ST depression (298 versus 249 seconds, respectively, from a baseline of 232 seconds) and median total exercise time (393 versus 307 seconds, respectively, from a baseline of 301 seconds). Further evaluation of allopurinol is necessary before it can be recommended as an antianginal agent.

The mechanism of the anti-ischemic effect of allopurinol was evaluated in a study of 80 patients with stable coronary artery disease (CAD) on optimal medical therapy who were randomly assigned to either allopurinol (600 mg/day) or placebo [33]. The drug significantly improved measures of endothelium-dependent vasodilation and completely abolished oxidative stress.

Endothelin receptor blockers — Endothelin (ET)-1, which is produced by the vascular endothelium, modulates vascular tone via two receptors (ET-A and ET-B). It has been suggested that they might be valuable in patients with angina, but we do not recommend their use for this purpose, in part because have significant side effects. (See "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Endothelin'.)

Endogenous endothelin causes vasoconstriction in epicardial coronary arteries in patients with coronary artery disease [34,35]. These findings suggest a possible role for endothelin antagonists, such as bosentan, in the treatment of angina.

However, no clinical trials to date have examined the role of endothelin receptor blockers for reducing anginal symptoms. Furthermore, selective ET-A receptor blockade may have an adverse effect. This possibility was illustrated in a report of 30 patients undergoing PCI that found that, compared with intracoronary saline, an intracoronary injection of a selective ET-A receptor blocker prevented the normal reduction in myocardial ischemia on repeat balloon inflations [36]. This may be due to a "steal effect" on collateral blood flow.

Ivabradine — Based on the results of the SIGNIFY trial [37], we do not recommend the use of ivabradine in patients with stable angina who do not have clinical heart failure.

A rationale for the use of ivabradine emerged from data indicating that an elevated heart rate is associated with increased risk of cardiovascular events in patients with stable ischemic heart disease [38,39]. Ivabradine inhibits a specific sinus node pacemaker current, thereby lowering the heart rate. The drug has been shown to increase exercise capacity and reduce anginal frequency and severity [40-42]. Post-hoc analyses of a randomized trial have suggested that ivabradine might improve cardiovascular outcomes such as death, myocardial infarction, or hospitalization for heart failure in patients with stable disease [43,44]. However, data from SIGNIFY trial [37] fail to confirm these findings.

The SIGNIFY trial randomly assigned 19,102 patients with stable coronary artery disease without clinical heart failure and a heart rate of 70 beats per minute or more to ivabradine or placebo [37]. All patients were treated with optimal medical therapy including aspirin, statin, angiotensin converting enzyme inhibitor, and a beta blocker. The majority of patients (63 percent) had Canadian Cardiovascular Society class (CCS) II or higher angina (table 1). The following findings were noted:

●Patients in the ivabradine group had a heart rate that was about 10 beats per minute lower than those in the placebo group.

●In the subgroup of patients with CCS class II angina or higher, patients in the ivabradine group more frequently improved their CCS angina class (24.0 versus 18.8 percent; p = 0.01).

●There was no difference in the rate of the composite end point of cardiovascular death or nonfatal myocardial infarction after a median follow-up of about 28 months (6.8 versus 6.4 percent, respectively; HR 1.08, 95% CI 0.96-1.20).

●Among patients with angina CCS II angina or higher, there was an increase in the incidence of the primary end point (7.6 versus 6.5 percent; HR 1.18, 95% CI 1.03-1.35).

While ivabradine improves angina in patients with CCS class II angina or higher taking optimal medical therapy, we are concerned about an increase in the risk of cardiovascular death and nonfatal myocardial infarction.

Fasudil — Initial observational studies suggested that fasudil, an inhibitor of Rho kinase that is involved in the vascular smooth muscle contractile response, is of benefit in patients with stable and microvascular angina (ie, angina with normal coronary arteries) [45]. We do not recommend its use to treat angina.

In a multicenter, placebo-controlled trial, 84 patients with stable angina and reproducible exercise times were randomly assigned to fasudil (titrated to a dose of 80 mg twice daily) or placebo [46]. Fasudil therapy produced a significantly greater time to ≥1 mm ST segment depression at both peak (172 versus 44 s with placebo) and trough (93 versus 24 s) but no difference in time to angina, frequency of angina or nitroglycerin use, or Canadian Cardiovascular Society (CCS) functional class (table 2).

Testosterone — There is some evidence that testosterone improves endothelial dysfunction and may be an effective antianginal agent [47]. (See "Coronary endothelial dysfunction: Clinical aspects".) This was addressed in a trial of 46 men with stable angina pectoris who were randomly assigned to placebo or a daily low dose (5 mg) transdermal testosterone patch for 12 weeks, in addition to other antianginal medications [48]. Testosterone significantly increased the time to 1 mm ST segment depression on treadmill exercise testing compared to placebo (309 versus 361 s at 12 weeks).

Given the potential for side effects, further trials are warranted before testosterone can be considered as a therapy for angina.

Stem cell therapy — Transplantation of hematopoietic or bone marrow mesenchymal stem cells has been evaluated as a therapeutic option in patients after myocardial infarction or with ischemic cardiomyopathy. Its use to treat angina is investigational. (See "Investigational therapies for management of heart failure", section on 'Stem cell therapy'.)

Therapeutic angiogenesis — The data evaluating the possible role of therapeutic angiogenesis for refractory angina are discussed elsewhere. (See "Therapeutic angiogenesis for management of refractory angina".)

In patients with cardiovascular disease, statin therapy can reduce mortality and the incidence of acute coronary syndromes. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Our approach'.)

In addition, there is increasing evidence that high-dose therapy reduces the incidence of anginal episodes in patients with stable ischemic heart disease. Two trials, AVERT and DUAAL, compared high-dose statin therapy to nonstatin-containing antianginal regimens. The applicability of these trials to current practice is unclear since statin therapy is recommended in virtually all patients with ischemic heart disease. Nevertheless, they are compatible with an antianginal effect of statin therapy.

In the AVERT trial, 80 mg of atorvastatin daily led to a reduction in the rate of hospitalization for worsening angina compared to patients treated with angioplasty but not statins [49]. In the DUAAL trial, 311 patients with stable ischemic heart disease, who were on aspirin and other antianginal therapy, were randomly assigned to one of three treatment arms: amlodipine 10 mg/day; atorvastatin 80 mg/day; or amlodipine 10 mg/day plus atorvastatin 80 mg/day [50]. The primary efficacy end point, the number of ischemic episodes during 48-hour ambulatory electrocardiographic monitoring, decreased significantly from baseline (>66 percent) in all three groups. There was no significant difference in outcome among the three groups, with more than 50 percent of patients becoming free of episodes of transient myocardial ischemia at 26 weeks.

NON-MEDICAL THERAPIES — Five non-medical therapies (enhanced external counterpulsation, spinal cord stimulation, transmyocardial laser revascularization, a coronary sinus reducing device, and apheresis) have been evaluated for the treatment of refractory angina.

External counterpulsation — External counterpulsation (ECP), also referred to as enhanced external counterpulsation (EECP), is a technique that increases arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation). Cuffs are wrapped around the patient’s calves, thighs, and pelvis and, using compressed air, sequential pressure (up to 300 mmHg) is applied in early diastole to propel blood back to the heart.

The efficacy of ECP was evaluated in the MUST-EECP trial, which randomly assigned 139 outpatients with angina, documented coronary artery disease, and a positive exercise tolerance test to 35 hours of active EECP using a cuff pressure of 300 mmHg or inactive counterpulsation using a cuff pressure of 75 mmHg over a four- to seven-week period of time [51]. The following results were seen:

●Active EECP was well tolerated without limiting side effects.

●Exercise duration increased to a similar degree in both the active and inactive EECP groups; there was also no significant difference in nitroglycerin use.

●Patients undergoing active EECP had a significant increase in time to ≥1 mm ST segment depression compared to baseline (379 versus 337 seconds), while there was no change in the inactive group.

●More patients undergoing active EECP had a decrease in anginal episodes and fewer had an increase in angina compared to the inactive group.

Similar findings have been noted in multicenter registries [52,53]. In a series of 363 patients, 72 percent improved from severe to no or mild angina and 52 percent discontinued the use of nitroglycerin [53]. At two years, the decrease in angina persisted in 55 percent of patients, survival was 83 percent, and major adverse cardiac event-free survival was 70 percent. Repeat ECP was required in 20 percent.

The mechanism of these benefits is not clear, but is probably related, at least in part, to improvements in stress-induced myocardial perfusion, left ventricular diastolic filling, peripheral arterial flow-mediated dilation [54], and endothelial function [54-59].

The 2014 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society for Cardiovascular Angiography and Interventions/Society of Thoracic Surgeons focused update on prior stable ischemic heart states that ECP may be considered for relief of refractory angina [21-23]. ECP has met with only limited acceptance in practice.

The Centers of Medicare and Medicaid Services (CMS) in the United States have approved payment for ECP in patients with Canadian Cardiovascular Society class III or IV angina (table 2) who, in the opinion of a cardiologist or cardiovascular surgeon, are not readily amenable to percutaneous coronary intervention or coronary artery bypass graft surgery because the patient is inoperable or at high risk for complications, or the coronary anatomy is not suitable for revascularization [60].

Spinal cord stimulation — Despite advances in medical and surgical therapies for angina patients, there remains a small number of patients with refractory angina. Spinal cord stimulation at the T1 to T2 level is another approach to the management of refractory angina. Spinal cord stimulation was originally developed to treat neurogenic pain and then applied to the refractory angina population. While the approach is clearly effective in some, objective evidence of its efficacy is not compelling. Studies of this therapy tend to be small and open label randomized trials or observational studies [61-64].

Its mechanism of action is poorly understood. This technique may have beneficial effects on angina by suppressing the capacity of intrinsic cardiac neurons to generate activity during myocardial ischemia [65]; alternatively, it may provide benefit by reducing sympathetic activity or by redistributing myocardial blood flow from nonischemic to ischemic areas [66].

In the largest trial (ESBY), 104 patients at high risk for surgery were randomly assigned to coronary artery bypass graft surgery (CABG) or spinal cord stimulation [61]. The following findings were noted:

●Both techniques reduced angina and the use of nitrates to a similar extent.

●The CABG group had a greater increase in exercise capacity, less ST-segment depression at maximum and comparable workloads, and an increase in the rate-pressure product both at maximum and comparable workloads compared to the group receiving spinal cord stimulation.

●On the other hand, spinal cord stimulation was associated with a lower six-month mortality (1.9 versus 13.7 percent with CABG) and fewer cerebrovascular events (3.8 versus 15.7 percent).

●At later follow-up, cessation of spinal cord stimulation was associated with a lack of effect on ischemic ST changes but a reduction in anginal symptoms, suggesting a primary analgesic effect [62].

The SPiRiT trial compared spinal cord stimulation to percutaneous myocardial laser revascularization in 60 patients with refractory angina [63]. There was no significant difference between the groups in terms of the primary end point of total exercise time or in other parameters such as CCS functional class (table 2). Although CCS functional class improved by ≥2 CCS classes at one year in about 25 percent of patients in both groups, there was no placebo control. This is an important limitation, since the only blinded, placebo-controlled trial of percutaneous transmyocardial laser revascularization (DIRECT), using low-dose or high-dose laser channels or no laser channels blinded as a sham procedure, showed no benefit [67]. (See "Transmyocardial laser revascularization for management of refractory angina".)

Some patients with cardiac syndrome X (angina with normal coronary arteries) have frequent episodes of severe chest pain that are refractory to maximal antianginal therapy. In a small randomized crossover trial of 10 such patients, spinal cord stimulation reduced the number, duration, and severity of spontaneous anginal episodes and prolonged the time to angina and to ST segment depression during dobutamine stress [68]. (See "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'Management of refractory angina'.)

Overall, spinal cord stimulation is an unproven procedure given the current state of knowledge. It should be reserved for a few carefully selected patients, if any.

Transmyocardial laser revascularization — The data evaluating the efficacy of transmyocardial laser revascularization in the treatment of refractory angina are discussed elsewhere. (See "Transmyocardial laser revascularization for management of refractory angina".)

Coronary sinus reducing device — A coronary sinus reducing device has been shown to improve outcomes in patients with refractory angina [69]. This device is mounted on a balloon catheter and inserted into the coronary sinus percutaneously. Balloon expansion leads to the permanent implantation of an hourglass-shaped metal mesh that leads, over time, to partial obstruction of the coronary sinus. It is postulated that the development of an upstream pressure gradient favors perfusion of ischemic territories.

In the small, phase 2 COSIRA trial, 104 patients with Canadian Cardiovascular Society (CCS) class III or IV refractory angina (table 1) and documented myocardial ischemia were randomly assigned to the device or a sham procedure [70]. The primary end point of the proportion of patients with an improvement of at least two CCS angina classes at six months occurred more frequently in the device group (35 versus 15 percent; p=0.02). In addition, quality of life, as assessed with the Seattle Angina Questionnaire was improved in the treatment group, as compared with the control group. Adverse outcomes such as myocardial infarction or death did not appear to differ significantly between the groups.

Apheresis — The potential role of apheresis in the treatment of patients with refractory angina and a significantly elevated level of lipoprotein(a) is discussed elsewhere. (See "Lipoprotein(a)", section on 'Lipoprotein apheresis' and "Lipoprotein(a)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic coronary syndrome".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Medicines for angina (chest pain) (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Background – Most patients with stable angina pectoris can have an acceptable frequency (and severity) of angina with conventional medical therapies, such as beta blockers, calcium channel blockers, nitrates, and/or myocardial revascularization with either percutaneous coronary intervention (PCI) or coronary bypass graft surgery (CABG). For these patients for whom angina remains problematic, a number of medical and mechanical therapies have been evaluated for the treatment of refractory angina. Only ranolazine has demonstrated significant efficacy in large trials. (See 'Medical therapies' above.)

●Ranolazine – Ranolazine is effective at reducing anginal symptoms and improving exercise capacity when added to conventional medical therapy. The initial dose is 500 mg twice daily. For patients who remain symptomatic, 1000 mg twice daily may be used. (See 'Ranolazine' above.)

●Emerging therapies – Other medical therapies such as fatty acid oxidation inhibitors or nicorandil have demonstrated some efficacy in studies. Until further supporting evidence is available, our authors do not recommend their use for the prevention of anginal episodes. (See 'Medical therapies' above.)

●External counterpulsation – This is the best studied of possible mechanical therapies to improve angina. While approved for use in some countries, it is not widely used. (See 'Non-medical therapies' above.)