Angina treatments and prevention of cardiac events: an appraisal of the evidence

Abstract

Angina pectoris is the symptomatic manifestation of transient myocardial ischaemia. At the most fundamental level, angina arises when myocardial oxygen demand exceeds the ability of the coronary circulation to provide adequate oxygen delivery to maintain normal myocardial metabolic function. In vivo, the balance of oxygen demand and delivery is a complex physiological process that can be altered by a variety of interventions. Lifestyle modification is a cornerstone of cardiovascular disease management, with or without angina. Additional pharmaceutical and physical interventions are usually applied to patients with angina. Mechanisms of action for these interventions include heart rate modulation, vascular smooth muscle relaxation, metabolic manipulation, revascularization, and others. A number of these interventions have overlapping mechanisms that target angina. Additionally, some interventions may directly or indirectly prevent or delay adverse outcomes such as myocardial infarction or death. This review summarizes current evidence for many applied ischaemia treatments documented to modify angina and comments on available evidence relating to improvement in cardiovascular outcomes.

Introduction

Angina pectoris (AP) is the clinical manifestation of inadequate myocardial oxygen delivery and is common among patients with stable ischaemic heart disease (SIHD). Heberden's classic description of the symptoms was a ‘painful and most disagreeable sensation in the breast, which seems as if it would extinguish life…but the moment they stand still, all this uneasiness vanishes’.¹ These symptoms, and the underlying myocardial oxygen supply–demand mismatch, may result from a limited oxygen supply, increased oxygen demand, or both. This notion, however, oversimplifies the complex process of appropriately delivering and distributing adequate oxygen to functioning cardiomyocytes. In fact, the mechanisms that may result in AP are very complex. Nevertheless, a number of potential strategies to successfully ameliorate ischaemia and related symptoms and adverse outcomes have emerged.

Reducing symptoms is an important task for all clinicians; however, reducing mortality, myocardial infarctions (MI), hospitalizations, and other cardiovascular events is crucial as well. Some treatments are effective for AP, while others reduce both symptoms and major adverse cardiovascular events (MACE). In this review, we summarize the evidence for a wide array of pharmaceutical agents and physical interventions aimed at treatment of AP, and we discuss the effect of these treatments on symptoms as well as MACE.

Management of the patient with angina centres on treatments that modify symptoms (AP) and those that prevent adverse events. An appraisal of the available evidence strongly supports both lifestyle modification and pharmacological management in all of these patients.

Risk management

Lifestyle modification

The general management of patients with angina must include an attempt to improve prognosis. This begins with evidence-based lifestyle modification focusing on control of coronary artery disease (CAD) risk factors and patient education. Lifestyle recommendations are detailed in recent guidelines.^2,3 Briefly, tobacco smoking, including environmental exposure, must be avoided as the benefits of smoking cessation are extensively documented. There is evidence that encouragement and pharmacological aids (e.g. nicotine replacement, bupropion, and varenicline) improve success rates.

Also there is evidence that a healthy diet reduces risk. Maintaining or obtaining a healthy weight (defined as body mass index < 25 kg/m²) is very important. Consumption of N-3 polyunsaturated fatty acids, mainly from oily fish rather than from supplements, is associated with benefit. A ‘Mediterranean diet’, supplemented with extra-virgin olive oil or nuts, reduces MACE in patients at high risk.

Strong evidence supports regular physical activity incorporated into the angina patient's usual daily activities. Aerobic exercise may be suggested as part of a structured cardiac rehabilitation programme, with need for an evaluation of both exercise capacity and exercise-associated risk. Patients with stable angina may undergo moderate intensity aerobic exercise training ≥3 times a week for 30 min per session. Sedentary patients are strongly encouraged to begin light-intensity exercise risk stratification. Exercise training offers an additional means of symptom alleviation and improves prognosis as well as quality of life.

Blood pressure (BP) control is fundamental in risk management as well as in management of angina. Hypertension is the most prevalent, modifiable risk condition for CAD (including angina and MI), heart failure, stroke, atrial fibrillation, peripheral artery disease (PAD), diabetes, and chronic kidney disease (CKD). Strong evidence supports lowering systolic BP (SBP) to <140 mmHg and diastolic BP to <90 mmHg, and recent results support benefits of achieving a SBP < 120 mmHg.⁴ Lower targets may be more beneficial among those with CKD and/or diabetes. Management of hypercholesterolaemia, particularly reduction of LDL-cholesterol levels with a statin, decreases risk for adverse outcomes (MI, cardiovascular disease hospitalizations, and cardiovascular mortality). Among angina patients, statin-related benefits are supported by very strong evidence regardless of LDL-cholesterol levels. They also reduce coronary atherosclerosis progression and improve endothelial and vascular smooth muscle function. Diabetes promotes CAD progression and other complications (neuropathy, retinopathy, and nephropathy), and glucose control forestalls these complications: glycated haemoglobin (HbA1c) levels <7.0% are supported by strong evidence. Some psychosocial factors (e.g. depression, anxiety, and post-traumatic distress) are prevalent among CAD patients and may promote angina. Patients with angina who have symptoms of depression, anxiety, and/or hostility should be appropriately evaluated and referred for therapy. There is evidence that such an approach to management reduces symptoms and enhances quality of life.

Pharmaceutical agents

Angina is a symptomatic manifestation of complex physiological processes and can be manipulated pharmacologically through multiple pathways: within each pathway, several options are available (Table 1). Some agents have been available for decades, while recent advancements have brought newer, better tolerated, or even more effective alternatives. Although these pharmacological options may influence ischaemia via several processes, they are reviewed according to the major mechanism though which they operate in the angina patient.

Table 1.

Summary of angina therapies and prevention of major cardiac events and/or symptoms

	Reduces MACE	Reduces symptoms	Further study
Vascular smooth muscle relaxing agents
Nitrates	No	Moderate effect	No
PDE inhibitors	Unknown	No	Yes
cGMP stimulators	Unknown	Unknown	Yes
Rho kinase inhibitors	Unknown	Mild effect	Yes
Calcium antagonists	Maybea	Moderate effect	No
Metabolic modulation
Trimetazidine	Unknown	Moderate effect	Yes
Perhexiline	Unknown	Moderate effect	Yes
Heart rate reduction
β-Blocking agents	Maybeb,c	Moderate effect	Yes
Sinus node inhibitors	Maybed	Moderate effect	Yes
Other agents
Ranolazine	Noc	Moderate effect	Yes
Amiodarone	Noc	Mild effect	No
Dronedarone	Noc	Mild effect	Yes
Arginine	No	No	Yes
Allopurinol	Unknown	Mild effect	Yes
Testosterone	May increase	Unknown	Yes
Omapatrilat	Unknown	Mild effect	Yes
Physical interventions
Revascularization	Noe	Significant effect	Yes
Spinal cord stimulators	No	Mild effect	No
EECP	No	Mild effect	No
Transmyocardial revascularization	No	Mild effect	Yes
Coronary sinus restrictor	No	Moderate effect	Yes
Acupuncture	No	No	No
Angiogenesis and myocardial regeneration	Unknown	Unknown	Yes

cGMP, cyclic guanyl monophosphate; EECP, enhanced external counter-pulsation; PDE, phosphodiesterase.

^aThrough indirect means such as reducing blood pressure.

^bThe data suggest that certain subpopulations may derive benefit: those with left ventricular dysfunction and/or those with a recent MI.

^cHas antiarrhythmic properties.

^dThe data suggest that certain subpopulations may derive benefit: those with left ventricular dysfunction and hazard ratio ≥ 70 b.p.m. with or without angina.

^eMACE is reduced in certain patient subgroups, for most with chronic stable angina MACE is not reduced.

Heart rate reduction

Considerable evidence documents that heart rate is the most important determinant of myocardial ischaemia: therefore, reduction of and/or limiting heart rate increases are fundamental in the management of AP.⁵ Elevated heart rate is a marker of increased cardiovascular risk in the general population and also among patients with ischaemic heart disease (IHD).⁶ β-Adrenergic blocking agents (BBs) were synthesized for this purpose. In addition, the non-dihydropyridine calcium antagonists (CAs) exert some anti-anginal effect through suppression of heart rate. The most recent addition to drugs that reduce heart rate are those that specifically block the sinus node I(f) channel directly without altering BP or contractility.

β-Adrenergic receptor blockade

β-Adrenergic blocking agents directly oppose the β-adrenergic receptors of the adrenergic nervous system. Within the heart, this reduces heart rate and contractility thereby decreasing myocardial oxygen demand. While these effects at rest are minimal, BBs modify the heart rate increase occurring with physical and emotional stress. Additionally, they may reduce ischaemia by redistribution of microvascular flow to increase perfusion of ischaemic areas (by prolonging diastole) and increasing resistance in non-ischaemic areas (related to reduction in oxygen demand).

Because of strong evidence, BBs are recommended by SIHD management guidelines as first-line therapy for patients with AP.^2,3 Ample evidence has also documented that certain subpopulations may derive a mortality benefit from chronic BB therapy, specifically those with left ventricular dysfunction and/or those with a recent MI.⁷ Absent these indications, for patients with AP, BB therapy will reduce symptoms but is not likely to reduce mortality.⁸ These agents also cause a variety of side effects including fatigue, depression, bradycardia, sexual dysfunction, and metabolic changes. β-Adrenergic blocking agents, particularly the non-selective agents, may aggravate intermittent claudication in patients with PAD. Unfortunately, such side effects may be more bothersome for certain patients than their underlying AP that the BB aims to treat.⁹

The BBs can be combined with dihydropyridines CAs to better control angina but should not be combined with either verapamil or diltiazem due to the risk of severe bradycardia or high-degree atrioventricular block. The BBs with intrinsic sympathomimetic activity (ISA) (e.g. pindolol and penbutolol) mimic effects of epinephrine and norepinephrine and can increase BP and/or heart rate. In our opinion, BBs with ISAs should not be used in patients with angina or known IHD.

Sinus node inhibitors

A number of drugs that reduce heart rate through inhibition of the I(f) pacemaking current of the sinus node have been evaluated in IHD and/or AP, but only ivabradine reached approval. In addition to an excellent side effect profile, an advantage of ivabradine is lack of direct negative inotropic activity or decreased BP like other heart rate lowering drugs (e.g. BBs). Ivabradine is recommended as ‘second line’ for AP by the European guidelines³; US guidelines have not been updated since ivabradine was approved by the US Food and Drug Administration.¹⁰ Multiple trials document that ivabradine improves exercise tolerance and reduces angina severity and frequency.^11–13 Ivabradine improved outcomes among patients in sinus rhythm, receiving a BB (if tolerated), with recent heart failure hospitalization mostly due to IHD in the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT).¹⁴ Benefit included reduced heart failure hospitalizations with no effect on cardiovascular deaths. Overall, less serious adverse events occurred with ivabradine vs. placebo, but 5% of ivabradine patients had symptomatic bradycardia (vs. 1% with placebo). Visual side effects (phosphenes) occurred in 3% of patients on ivabradine vs. 1% on placebo. Then a trial (BEAUTIFUL) restricted to CAD patients with systolic dysfunction and resting heart rate ≥60 b.p.m. receiving appropriate conventional cardiovascular medications found that ivabradine did not reduce cardiovascular death or hospitalization; however, a prespecified analysis suggested that ivabradine improved outcomes (mainly reduced hospitalizations for MI) among patients with resting heart rate ≥70 b.p.m., particularly those with angina.¹⁵ Most recently, the Study Assessing the Morbidity–Mortality Benefits of the I(f)Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) without heart failure found that adding ivabradine to standard background therapy did not improve outcomes.¹⁶ This trial provided further evidence of known side effects including bradycardia, phosphenes, and atrial fibrillation.

Amiodarone and dronedarone

Amiodarone and its derivative dronedarone are complex compounds with many cardiovascular effects via multi-channel blockade that include heart rate reduction. Amiodarone was initially developed as an anti-anginal agent; however, enthusiasm was tempered by its potentially dangerous side effects.¹⁷ But a randomized, double-blind, placebo-controlled trial in patients with New York Class Association Class 3 stable AP and abnormal exercise treadmill tests receiving triple anti-anginal therapy documented remarkable effectiveness.¹⁸ With 600 mg/day for 10 days followed by 200 mg/day, significant increases in exercise duration (0.4 min at 1 month and 1.3 min at 2 months) occurred as rate-pressure product and peak ST-segment depression decreased. The well-known side effect profile of amiodarone (liver, lung, peripheral nerve, and thyroid dysfunction) limits application for the treatment of AP. However, in selected elderly AP patients with no other treatment options, low-dose amiodarone (50–200 mg/d) may offer angina control and improved quality of life.

Dronedarone, its iodine-free methane-sulfonyl group derivative with lower side effect profile, has not been specifically studied as an anti-anginal agent. However, in the randomized, double-blind, placebo-controlled ATHENA trial of elderly patients with atrial fibrillation, dronedarone significantly decreased acute coronary syndromes and costs associated with hospitalizations. An analysis from ATHENA on safety and cardiovascular outcomes in CAD patients confirmed reduced adverse outcomes (cardiovascular hospitalization or death similar to that found in the overall ATHENA population) and reduced first occurrence of acute coronary syndrome.¹⁹ Importantly, the safety profile in this subpopulation was good. The conclusion was that in patients with stable CAD and non-permanent atrial fibrillation, dronedarone reduces the incidence of acute coronary events. Dronedarone reduces the pressure rate product, thereby potentially limiting demand ischaemia. This effect is most marked in patients with breakthrough atrial fibrillation and in patients with left ventricular dysfunction. In patients with moderate to severe heart failure and atrial fibrillation, dronedarone was associated with increased mortality. Dronedarone warrants formal evaluation as an anti-anginal agent in a long-term clinical outcome trial of patients with acute and chronic AP without atrial fibrillation in combination with moderate to severe heart failure.

Vascular smooth muscle relaxation

Relaxation of vascular smooth muscle is regulated by a cascade of signals involving nitric oxide (NO), S-nitrosothiol, and cyclic guanylate cyclase. A variety of agents manipulate this pathway through inhibition or promotion of different steps in the cascade. An additional pathway for manipulating regulation of smooth muscle is through the L-type calcium channel that controls influx of calcium ions into cardiomyocytes.

Nitrate preparations

A variety of commercially available products are based on delivery of nitrate moieties which, in vivo, generate NO resulting in systemic venous and arteriolar smooth muscle relaxation. This venous dilatation markedly reduces venous return to decrease left ventricular preload, thereby reducing myocardial oxygen demand. The peripheral arteriolar dilation reduces systemic BP to further decrease myocardial oxygen demand, while the coronary dilation improves myocardial flow and/or its distribution to improve oxygen delivery to ischaemic regions.

In addition to relieving or preventing the usual angina episode provoked by increases in myocardial oxygen demand, nitrate preparations are remarkably effective alone and in combination with CAs for relief/prevention of angina due to coronary spasm. Short-acting preparations can be taken in response to acute symptoms, while longer-acting preparations are intended for AP prophylaxis, but all require a ‘nitrate-free’ interval to avoid development of nitrate tolerance that markedly diminishes their effectiveness. A recent meta-analysis found nitrates effective for reducing AP symptoms; however, evidence for an improved quality of life was lacking.²⁰ This analysis found sporadic evidence relating to MI and death. While not well studied in contemporary populations, nitrates are commonly accepted to not significantly reduce MACE. Headache is the most common side effect, occurring in up to half of patients, but can usually be circumvented by starting with very low doses and slowly up-titrating over days to weeks. Precaution must be taken with patients taking phosphodiesterase inhibitors (PDEi) and those with hypotension and/or orthostatic hypotension. All nitrate preparations also provoke migraine.

Nitrate donors

As a nitrate derivative of nicotinamide, nicorandil stimulates potassium-sensitive adenosine triphosphate receptors dilating epicardial coronary arteries and was studied for decades.²¹ The Impact Of Nicorandil in Angina (IONA) trial examined patients with stable AP randomly assigned to active drug or placebo. The MACE endpoint was significantly reduced with nicorandil without reducing cardiovascular death/MI.²² Available in Europe but not in the USA, the drug has a ‘second-line’ recommendation in the European guidelines.³ Nicorandil causes headaches, dizziness, and gastrointestinal ulceration. Blood pressure can be lowered, and precaution should be taken if used with phosphodiesterase-5 (PDE5) inhibitors.

Phosphodiesterase inhibitors

Reminiscent of amiodarone, PDEi were also initially developed as anti-anginal drugs. The mechanism of effect is reduction of metabolism of cyclic guanyl monophosphate (cGMP), thereby potentiating effects of endogenous NO. The first clinically tested PDEi, sildenafil, did not significantly reduce AP symptoms in clinical trials; however, the drug was effective at restoring erectile potency. The drug was later approved in Europe and the USA for that indication. Later studies confirmed a beneficial effect on the pulmonary vasculature, adding to treatment options for pulmonary hypertension.²³

Cyclic guanyl monophosphate stimulators

Failure to respond completely to PDE5 inhibitors like sildenafil indicates that cGMP production is severely impaired in the target microvessels and is linked to low NO levels. So PDE5 inhibitors prevent cGMP degradation and thus rely on sufficient NO input at the beginning of the NO–sGC–cGMP pathway. Cinaciguat, ataciguat, riociguat, etc. are among many others used in pulmonary hypertension and undergoing trials for heart failure, CKD, IHD, etc.

Calcium channel blockers (calcium antagonists)

The CAs exert their effects primarily through vasodilatory effects that reduce systemic and peripheral vascular resistance to decrease SBP and myocardial oxygen demand. While inhomogeneous in chemical composition, they share their effect through blockade of the L-type calcium channel in myocardial and smooth muscle tissues. Two general types are the dihydropyridines (amlodipine and nifedipine) and the non-dihydropyridines (verapamil and diltiazem). The non-dihydropyridines also reduce heart rate and depress myocardial contractility to further reduce myocardial oxygen demand. Calcium antagonists share a first-line recommendation in European guidelines, while American recommendations combine them with a BB when the BB is ineffective alone.^2,3 Outcomes in SIHD patients treated with a CA-based strategy compared with a BB-based strategy are similar.^24,25 In a trial comparing CAs with an angiotensin-converting enzyme inhibitor and placebo, CAs demonstrated a modest advantage regarding AP on revascularization, but not other MACE.²⁶ In a meta-analysis of CAs vs. a variety of agents, stroke appears to be reduced.²⁷ Calcium antagonists are remarkably effective alone and in combination with nitrates for relief/prevention of angina due to coronary artery spasm. Calcium antagonists, specifically the non-dihydropyridines, are to be avoided in patients with a depressed ejection fraction, high-degree atrioventricular block, or sick sinus syndrome. Side effects can include fatigue, constipation, bradycardia, headache, and peripheral oedema.

Rho kinase inhibitors

The Rho kinase signalling pathway is another way to manipulate intracellular signalling of the nitrate cascade. Fasudil is the agent at the most advanced level of investigation which alters rho kinase activity. In a study of 84 patients with AP, time to peak ST depression was increased compared with placebo (172 vs. 44 s, P = 0.001).²⁸ Angina pectoris class, AP frequency, and nitroglycerine use were not different.

Late sodium current inhibition

Ranolazine

Selective inhibition of the late sodium current with ranolazine results in anti-ischaemic properties, probably via a redistribution of myocardial blood flow towards ischaemic regions. A notable advantage of this drug over others is the minimal effect on BP and heart rate. Both contemporary sets of guidelines recommend the drug as second line for AP.^2,3 In a series of randomized controlled trials, ranolazine has documented reduced AP symptoms both alone and in combination with other agents.^29–32 These trials have demonstrated the safety of ranolazine; however, no evidence exists demonstrating reduction in MACE. Results from the RIVER-PCI study examining ranolazine's impact on outcomes in patients with percutaneous coronary intervention (PCI; stenting) are expected shortly and will address MACE, with mortality as a secondary outcome.³³ In those studied after an acute event, ranolazine reduced the incidence of newly increased HbA1c by about a third. In the recent TERISA study (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina), ranolazine reduced angina episodes in diabetes patients receiving other anti-anginal drugs and also resulted in less nitroglycerine use.³⁴ Benefits appeared more prominent in patients with higher vs. lower HbA1c levels. Ranolazine is well tolerated; side effects, such as nausea and constipation, are infrequent. Monitoring of the QT duration and concurrent use of QT prolonging drugs, however, are important safety considerations.

Several daughter drugs of ranolazine (e.g. GS-6615) that are more potent and longer acting (e.g. eleclazine) are in development. In addition, a ranolazine–dronedarone combination is under evaluation for atrial fibrillation and may also be useful for angina.

Metabolic modulation

Trimetazidine exerts its cardiovascular effects by inhibiting fatty acid oxidation, thereby enhancing myocardial glucose utilization; it has been described as a ‘metabolic modulator’ of the ischaemic cascade.³ In patients with chronic stable angina, trimetazidine delays the onset of ischaemia associated with exercise and reduces the number of weekly angina episodes and weekly nitroglycerine consumption both in monotherapy and in combination with haemodynamic agents.³⁵ The anti-ischaemic effects are not associated with changes in heart rate or SBP. In diabetic persons, trimetazidine improved HbA1c and glycaemia, while increasing forearm glucose uptake. Several studies have demonstrated effectiveness to reduce AP; few data exist on the effect of trimetazidine on cardiovascular endpoints, mortality, or quality of life; however, no large-scale studies have been conducted on MACE.^35,36 Caution should be taken in patients with motion disorders, such as Parkinson's disease and restless leg syndrome.³⁶

Perhexiline inhibits carnitine palmitoyltransferase-1, preventing long-chain fatty acids from β-oxidation in mitochondria, and is thought to reduce AP by shifting myocardial metabolism preferentially to carbohydrates. The drug first came under study decades ago and was among the most effective anti-angina agents that we (C.J.P.) evaluated,^37,38 but enthusiasm was dampened by neurologic and hepatic side effects.³⁹ These adverse effects were related to plasma perhexiline concentration, and adverse effects were prevented if plasma concentrations were kept below defined values.^2,3 Little has been published recently on perhexiline as an anti-anginal; however, its benefit demonstrates the utility of further study on this pathway as a treatment for AP. Perhexiline has been shown to correct energy deficiency and improve exercise capacity in symptomatic patients with hypertrophic cardiomyopathy.⁴⁰ Since these patients often have angina and correction of myocardial anaerobic energetics is essential in ischaemia, these results support the prevention of ischaemia hypothesis by perhexiline in conditions other than CAD (e.g. diastolic heart failure).

Arginine

In the United States, arginine is classed as a dietary supplement and not a drug; therefore, it is not subject to the same regulatory restrictions. l-Arginine is widely available ‘over the counter’, although manufacturers are not required to demonstrate potency, purity, or standardize dosing. Large-scale study data are absent; however, some data suggest plausibility for l-arginine as an anti-anginal drug. It has been shown to promote angiogenesis and serve as a precursor for generation of NO.^41,42 The compound is not mentioned in guidelines for management of stable IHD.^2,3

Allopurinol

Allopurinol inhibits xanthine oxidase and is a common treatment for gout. A recent randomized, placebo-controlled trial of high-dose allopurinol spurred interest in the agent as a possible treatment for AP. In CAD patients with AP, median exercise time was increased significantly. The proposed mechanism for reducing AP is reduction in oxidative stress within vascular tissue.⁴³ The evidence base is small and inadequate for this to be recommended by guidelines; however, enthusiasm is growing.⁴⁴ Allopurinol is often well tolerated, but has serious side effects that include cytopenia and toxic epidermal necrolysis particularly among patients with CKD.

Testosterone

Men with CAD have lower androgen levels vs. men with normal coronary angiograms.⁴⁵ Others have associated lower testosterone (T) levels with more severe CAD among men age 43–72 years old with AP.⁴⁶ These data raise the question of T replacement. Low-dose transdermal T was evaluated in a randomized, double-blind, placebo-controlled trial of older men⁴⁷ and found effective in prolonging the time to ischaemic-type ST-segment depression compared with placebo. However, more recently, others have associated T therapy with mortality, MI, and stroke in men with low T levels.⁴⁸ Also it has been suggested that increased risk of non-fatal MI may occur following T therapy.⁴⁹ However, this work has been criticized because neither of these studies measured oestrogen, and this is critical because T is converted to oestrogen by aromatase. Additionally, T can increase red blood cells to raise blood viscosity, which increases thrombosis risk, and neither study measured red blood cell numbers. Finally, neither study measured T levels in all patients at follow-up. The usefulness of T replacement for AP remains an important knowledge gap.

Physical interventions

Revascularization

A detailed review of revascularization options is beyond the scope of this article; both European and American societies have guidelines dedicated to acute and chronic revascularization for coronary disease. Briefly, physically restoring coronary flow, whether by coronary artery bypass surgery (CABG) or PCI, is a commonly applied strategy for reducing AP. Incredible advances in revascularization have improved effectiveness, reduced recovery times, and minimized complications. The current generation of drug-eluting and bare-metal stent platforms may soon be supplanted by dissolvable, bio-organic devices that could further improve safety. Considerable evidence documents that certain patient groups derive a survival benefit from revascularization. These include CABG for left main stenosis or multi-vessel obstructive CAD and CABG or PCI for survivors of sudden cardiac arrest and obstructive CAD.^2,3 Additionally, the patient with diabetes and angina due to multi-vessel CAD may benefit from CABG with reduced all-cause mortality as well as MI. For the majority of SIHD patients with AP, however, revascularization is effective for reducing symptoms persisting with pharmacotherapy but not for reducing mortality.⁵⁰

Spinal cord stimulators

Application of direct current to the central and peripheral nervous system has proven effective for treatment of a movement disorders and chronic pain. A review of observational studies on spinal cord stimulators for treatment of refractory AP found that the number of angina attacks, use of nitrates, and AP class could be reduced. These studies are limited by lack of blinding and, as with other implanted devices, risks include infections and device migration/misplacement.⁵¹ Stimulators are infrequently used and typically reserved for AP refractory to medication and unsuitable for revascularization.

Enhanced external counter-pulsation

Based on the favourable haemodynamic profile generated by an intra-aortic balloon pump, enhanced external counter-pulsation is a mechanical device externally applied to patients, which compresses the peripheral circulation in time with the cardiac cycle. Treatment is performed in a series of daily, hour-long therapy sessions for several (usually 4) weeks. The purported mechanisms are similar to the balloon pump, increasing coronary perfusion pressure and decreasing afterload. Because the benefits appear to persist beyond the active treatment periods, it seems likely that other mechanisms are at play including placebo effect and improvements in vascular function and passive conditioning. While blinded trials are difficult, reductions in AP symptoms have been present with uncontrolled and high-quality studies; no evidence exists to suggest reduction in MACE.⁵² Enhanced external counter-pulsation has a IIa recommendation in European and IIb recommendation in American guidelines.^2,3 Treatment can cause bruising and abrasions; precautions must be taken for patients with arrhythmia, heart failure, PAD, and uncontrolled hypertension.

Transmyocardial revascularization

Lasers can be used to create channels within the myocardium. Intended as a strategy to improve blood flow to damaged tissue directly from the left ventricular cavity, the channels appear to close shortly after the procedure. Evidence suggests that other mechanisms including denervation, enhanced angiogenesis, and, of course, placebo, are at play. A 2005 meta-analysis demonstrated significant improvement in AP symptoms with no effect on survival.⁵³ The resulting recommendations are to avoid this therapy (European) or that it may be considered (American).^2,3

Coronary sinus restrictors

A novel device for reducing AP currently under evaluation is the percutaneous coronary sinus restrictor based on the original surgical procedure by Beck. The purported mechanism is that by restricting coronary venous emptying, the induced pressure elevation in the coronary venous microvessels will improve redistribution of blood flow to ischaemic areas of myocardium perfused by obstructed coronary arteries. In a recent randomized, controlled trial, the coronary sinus restrictor significantly reduced the angina class vs. the control group at 6 months.⁵⁴ Clearly, this intervention requires more evaluation.

Acupuncture

Acupuncture is based on a theory that a life force, called qi, can be manipulated with subcutaneous insertion of needles along meridians (tracks in the body through which qi travels). People actively researching acupuncture as a medical treatment largely do not subscribe to this theory, but rather recognize that puncturing the skin could alter blood flow or autonomic nervous system responses. No convincing evidence of benefit has been demonstrated for SIHD or AP.²

Angiogenesis and myocardial regeneration

Regeneration of myocardial tissue and/or regeneration of coronary vasculature are strategies for treating SIHD and AP that are currently under intense research. Two promising areas of treatment options are genetic therapy and stem cell therapy. The challenges in these fields are numerous: isolation of key genes and cells, identifying the relevant intracellular signalling processes, development of compounds that alter genetic expression, autologous extraction and isolation of effective progenitor cells, and ultimately identifying the optimal route and timing for delivery of active compounds/cells. Measuring and isolating the desired activity to the regions of myocardial ischaemia or damage have proven difficult. Attempts have been made to deliver compounds by intravenous, intracoronary, and intramyocardial routes. Potential targets for angiogenesis include vascular endothelial growth factor and fibroblast growth factor. Progenitor cells derived from bone marrow, adipose tissue, and the myocardium have been studied. The results of available studies to date are divergent, mostly showing subjective improvement, but limited, if any, proof of change in myocardial perfusion.

Conclusion

Many pharmaceutical and physical interventions are available for managing the patient with AP. A large number of interventions have controlled trial evidence that they reduce angina to improve quality of life. Only BB and revascularization reduce both AP and MACE. Many AP therapies either do not reduce MACE or have not been adequately studied to reach conclusions about their effects on adverse outcomes, while some others (T) may increase the risk of MI and death. Other AP treatments may reduce MACE indirectly, such as CA when used to lower BP. Clearly, there are many knowledge gaps, and innovative therapies are needed for the treatment of AP.

Funding

This work was supported, in part, by the National Institutes of Health/National Center for Advancing Translational Sciences (grant number UL1 TR001427).

Conflict of interest: none declared.