2013 ESC Guidelines on Management of Stable CAD
2013 ESC Guidelines on Management of Stable CAD
7.1.1 General Management of Stable Coronary Artery Disease Patients. The aim of the management of SCAD is to reduce symptoms and improve prognosis. The management of CAD patients encompasses lifestyle modification, control of CAD risk factors, evidence-based pharmacological therapy and patient education. Lifestyle recommendations are described in recent ESC guidelines.
7.1.2 Lifestyle Modifications and Control of Risk Factors. 7.1.2.1 Smoking: Smoking is a strong and independent risk factor for CVD and all smoking, including environmental smoking exposure, must be avoided in all patients with CVD. The benefits of smoking cessation have been extensively reported, and quitting smoking is potentially the most effective of all preventive measures, being associated with a reduction in mortality of 36% after MI. Clinicians treating patients with CAD can take advantage of the unique situation and emphasize that the risk of future CAD events can be dramatically reduced by smoking cessation. Thus, smoking status should be assessed systematically (including passive smoking) and all smokers should be advised to quit and offered cessation assistance. Quitting smoking is complex because smoking is both pharmacologically and psychologically highly addictive. Advice, encouragement and pharmacological aid consistently improve success rates. Nicotine replacement therapy is safe in patients with CAD and should routinely be offered. Bupropion and varenicline have been found safe to use in patients with stable CAD in some studies, although the safety of varenicline has recently been questioned in a meta-analysis, being associated with a small but statistically significant increase in CVD.
7.1.2.2 Diet (Table 25): A healthy diet reduces CVD risk. Cornerstones of a healthy diet are summarized below. Energy intake should be limited to the amount of energy needed to maintain (or obtain) a healthy weight—that is, a BMI <25 kg/m. In general, when following the rules for a healthy diet, no dietary supplements are needed. N-3 polyunsaturated fatty acid (PUFA) consumption, mainly from oily fish, is potentially associated with beneficial effects on cardiac risk factors, notably reduction in triglycerides, but not all randomized, controlled trials have shown reductions in CV events. Thus current recommendations are to increase PUFA intake through fish consumption, rather than from supplements. Recently, the largest study ever conducted with a so-called 'Mediterranean' diet, supplemented with extra-virgin olive oil or nuts, reduced the incidence of major cardiovascular events in patients at high risk of CV events but without prior CV disease.
7.1.2.3 Physical Activity: Regular physical activity is associated with a decrease in CV morbidity and mortality in patients with established CAD and physical activity should be incorporated into daily activities. Aerobic exercise should be offered to patients with known CAD, usually as part of a structured cardiac rehabilitation program, with the need for an evaluation of both exercise capacity and exercise-associated risk. Patients with previous acute MI, CABG, percutaneous coronary intervention (PCI), stable angina pectoris or stable chronic heart failure should undergo moderate-to-vigorous intensity aerobic exercise training ≥3 times a week and for 30 min per session. Sedentary patients should be strongly encouraged to start light-intensity exercise programmes after adequate exercise-related risk stratification. In patients with significant CAD who are not candidates for revascularization, exercise training may offer an alternative means of symptom alleviation and improved prognosis.
7.1.2.4 Sexual Activity: Sexual activity is associated with an exercise workload of up to 6 METS (1 MET = approximately 3.5 mL oxygen consumption/kg/min) depending on the type of activity. Sympathetic activation is intrinsic to sexual arousal and heart rate and blood pressure (BP) response may be higher than expected from the level of exercise. Sexual activity may thus trigger ischaemia, and nitroglycerin prior to sexual intercourse may be helpful as in other physical activity.
Patients with mild angina, successful coronary revascularization and New York Heart Association (NYHA) functional Class I heart failure generally do not need specific evaluation before resuming sexual activity. Patients with more symptomatic heart disease, including moderate angina, may be guided by an exercise stress test as a means of assessing risk and reassuring the patient. Exercise training should be advocated to improve exercise capacity and reduce myocardial oxygen consumption during sexual activity.
Erectile dysfunction (ED) is associated with cardiac risk factors and is more prevalent in patients with CAD. The common denominator between erectile dysfunction and CAD is endothelial dysfunction and antihypertensive medication—in particular β-blockers and thiazides—increases the risk of erectile dysfunction.
Lifestyle and pharmacological intervention—including weight loss, exercise training, smoking cessation and statin treatment—ameliorate ED. Pharmacological therapy with phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil and vardenafil) are effective, safe and well tolerated in men with stable CAD. Low-risk patients, as defined above, can usually receive PDE5 inhibitors without cardiac work-up. However, use of nitric oxide donors, i.e. all of the preparations of nitroglycerin as well as isosorbide mononitrate and isosorbide dinitrate, are absolute contra-indications to the use of PDE5 inhibitors because of the risk of synergistic effects on vasodilation, causing hypotension and haemodynamic collapse. PDE5 inhibitors are not recommended in patients with low blood pressure, with severe heart failure (NYHA III–IV), refractory angina or recent CV events. Patients must be informed about the potentially harmful interactions between PDE5 inhibitors and nitrates. If a patient on a PDE5 inhibitor develops chest pain, nitrates should not be administered in the first 24 hours (sildenafil, vardenafil) to 48 hours (tadalafil).
7.1.2.5 Weight Management: Both overweight and obesity are associated with an increased risk of death in CAD. Weight reduction in overweight and obese people is recommended in order to achieve favourable effects on BP, dyslipidaemia and glucose metabolism. The presence of sleep apnoea symptoms should be carefully assessed, especially in obese patients. Sleep apnoea has been associated with an increase in CV mortality and morbidity.
7.1.2.6 Lipid Management: Dyslipidemia should be managed according to lipid guidelines with pharmacological and lifestyle intervention. Patients with established CAD are regarded as being at very high risk for cardiovascular events and statin treatment should be considered, irrespective of low density lipoprotein (LDL) cholesterol (LDL-C) levels. The goals of treatment are LDL-C below 1.8 mmol/L (<70 mg/dL) or >50% LDL-C reduction when target level cannot be reached. In the majority of patients this is achievable through statin monotherapy. Other interventions (e.g. fibrates, resins, nicotinic acid, ezetimibe) may lower LDL cholesterol but no benefit on clinical outcomes has been reported for these alternatives. Although elevated levels of triglycerides and low HDL cholesterol (HDL-C) are associated with increased CVD risk, clinical trial evidence is insufficient to specify treatment targets, which should be regarded as not indicated.
For patients undergoing PCI for SCAD, high dose atorvastatin has been shown to reduce the frequency of peri-procedural MI in both statin-naïve patients and patients receiving chronic statin therapy. Thus reloading with high intensity statin before PCI may be considered.
7.1.2.7 Arterial Hypertension: Particular attention should be given to control of elevated BP but thresholds for the definition of hypertension by 24-h ambulatory and home BP monitoring differ from those measured at office or clinic (see Table 26 ). Elevated BP is a major risk factor for CAD as well as heart failure, cerebrovascular disease and renal failure. There is sufficient evidence to recommend that systolic BP (SBP) be lowered to <140 mmHg and diastolic BP (DBP) to <90 mmHg in SCAD patients with hypertension. Based on current data, it may be prudent to recommend lowering SBP/DBP to values within the range 130–139/80–85 mmHg. BP targets in diabetes are recommended to be <140/85 mmHg (see below).
7.1.2.8 Diabetes and Other Disorders (See Also Chapter 9 and Web Addenda): Diabetes mellitus is a strong risk factor for CV complications, increases the risk of progression of coronary disease and should be managed carefully, with good control of glycated haemoglobin (HbA1c) to <7.0% (53 mmol/mol) generally and <6.5%–6.9% (48–52 mmol/mol) on an individual basis. Glucose control should be based on individual considerations, depending on the patient's characteristics including age, presence of complications and diabetes duration.
As for other disorders, attention to management of risk factors is recommended, including weight management, exercise recommendations and statin treatment with an LDL-C target of 1.8 mmol/L (<70 mg/dL) in diabetic patients with angiographically proven CAD. The traditional treatment goal for BP in diabetes, i.e. below 130 mmHg, is not supported by outcome evidence in trials and has been difficult to achieve in the majority of patients. Thus, the BP target in patients with CAD and diabetes is to be <140/85 mmHg. An angiotensin converting enzyme (ACE) inhibitor or renin-angiotensin receptor blocker should always be included because of the renal protective effects.
Patients with chronic kidney disease (CKD) are at high risk and particular care should be taken to address risk factors and achieve BP and lipid targets. Statins are generally well tolerated in CKD stages 1–2 (GFR >60–89 mL/min/1.73 m) whereas, in CKD stages 3–5, statins with minimal renal excretion should be chosen (atorvastatin, fluvastatin, pitavastatin, rosuvastatin).
7.1.2.9 Psychosocial Factors: Depression, anxiety and distress are common in patients with CAD. Patients should be assessed for psychosocial distress and appropriate care offered. Refer for psychotherapy, medication or collaborative care in the case of clinically significant symptoms of depression, anxiety and hostility. This approach can reduce symptoms and enhance quality of life, although evidence for a definite beneficial effect on cardiac endpoints is inconclusive.
7.1.2.10 Cardiac Rehabilitation: A comprehensive risk-reduction regimen, integrated into comprehensive cardiac rehabilitation, is recommended to patients with CAD. Cardiac rehabilitation is commonly offered after MI or recent coronary intervention, but should be considered in all patients with CAD, including those with chronic angina. Exercise-based cardiac rehabilitation is effective in reducing total- and CV mortality and hospital admissions, whereas effects on total MI or revascularization (CABG or PCI) are less clear, especially in the long term.
Evidence also points towards beneficial effects on health-related quality of life (QoL). In selected sub-groups, centre-based cardiac rehabilitation may be substituted for home-based rehabilitation, which is non-inferior. Patient participation in cardiac rehabilitation remains far too low, particularly in women, the elderly and the socio-economically deprived, and could benefit from systematic referral.
7.1.2.11 Influenza Vaccination: An annual influenza vaccination is recommended for patients with CAD, especially the elderly.
7.1.2.12 Hormone Replacement Therapy: For decades, evidence from epidemiological and laboratory studies led us to believe that circulating oestrogens had a beneficial effect on the risk of CVD and that this could be transferred to the benefits of hormone replacement therapy (HRT). However, results from large randomized trials have not supported this; on the contrary, HRT increases the risk of CVD in women above the age of 60.
The mechanisms are unclear and, if instituted at an earlier age (i.e. at the time of menopause) in women with intact vascular endothelium and few CV risk factors, the effect of HRT is still debated. However, HRT is at present not recommended for primary or secondary prevention of CVD.
7.1.3 Pharmacological Management of Stable Coronary Artery Disease Patients. 7.1.3.1 Aims of Treatment: The two aims of the pharmacological management of stable CAD patients are to obtain relief of symptoms and to prevent CV events.
Relief of Anginal Symptoms: rapidly acting formulations of nitroglycerin are able to provide immediate relief of the angina symptoms once the episode has started or when the symptom is likely to occur (immediate treatment or prevention of angina). Anti-ischaemic drugs—but also lifestyle changes, regular exercise training, patient education and revascularization—all have a role to play in minimizing or eradicating symptoms over the long term (long-term prevention).
To Prevent the Occurrence of CV Events: efforts to prevent MI and death in coronary disease focus primarily on reducing the incidence of acute thrombotic events and the development of ventricular dysfunction. These aims are achieved by pharmacological or lifestyle interventions which: (i) reduce plaque progression; (ii) stabilize plaque, by reducing inflammation and (iii) prevent thrombosis, should plaque rupture or erosion occur. In patients with severe lesions in coronary arteries supplying a large area of jeopardized myocardium, a combined pharmacological and revascularization strategy offers additional opportunities for improving prognosis by improving heart perfusion or providing alternative perfusion routes.
7.1.3.2 Drugs: Evidence supporting the optimal medical therapy (OMT) for SCAD has been reviewed and detailed elsewhere, and is summarized below. Table 27 indicates the main side-effects, contra-indications and major drug–drug interactions for each drug class. Table 28 presents the recommendations for drug therapy.
7.1.3.3 Anti-ischaemic Drugs: 7.1.3.3.1 Nitrates: Nitrates offer coronary arteriolar and venous vasodilatation, which are the basis of symptomatic relief of effort angina, acting by their active component nitric oxide (NO) and by the reduction of preload.
Short-acting Nitrates for Acute Effort Angina. Sublingual nitroglycerin is the standard initial therapy for effort angina. When angina starts, the patient should rest sitting (standing promotes syncope, lying down enhances venous return and heart work) and take sublingual nitroglycerin (0.3–0.6 mg) every 5 min until the pain goes or a maximum of 1.2 mg has been taken within 15 min. Nitroglycerin spray acts more rapidly. Nitroglycerin can be used prophylactically when angina can be expected, such as activity after a meal, emotional stress, sexual activity and in colder weather.
Isosorbide dinitrate (5 mg sublingually) helps to abort anginal attacks for about 1 h. Because the dinitrate requires hepatic conversion to the mononitrate, the onset of anti-anginal action (within 3–4 min) is slower than with nitroglycerin. After oral ingestion, haemodynamic and anti-anginal effects persist for several hours, conferring longer protection against angina than sublingual nitroglycerin.
Long-acting Nitrates for Angina Prophylaxis. Long-acting nitrates are not continuously effective if regularly taken over a prolonged period without a nitrate-free or nitrate-low interval of about 8–10 hours (tolerance). Worsening of endothelial dysfunction is a potential complication of long-acting nitrates, hence the common practice of the routine use of long-acting nitrates as first line therapy for patients with effort angina needs re-evaluation.
Isosorbide dinitrate (oral preparation) is frequently given for the prophylaxis of angina. In a crucial placebo-controlled study, exercise duration improved significantly for 6–8 h after single oral doses of 15–120mg isosorbide dinitrate, but for only 2 h when the same doses were given repetitively four times daily, despite much higher plasma isosorbide dinitrate concentrations during sustained than during acute therapy. With the extended-release formulation of isosorbide dinitrate, eccentric twice-daily dosing, with 40 mg in the morning, repeated 7 hours later, was not superior to placebo in a large multicentre study. Thus prolonged therapy with isosorbide dinitrate is not evidence-based.
Mononitrates have similar dosage and effects to those of isosorbide dinitrate. Nitrate tolerance—likewise a potential problem—can be prevented by changes in dosing and timing of administration, as well as by using slow-release preparations. Thus only twice-daily rapid-release preparations or very high doses of slow-release mononitrate—also twice daily—give sustained anti-anginal benefit.
Transdermal nitroglycerin patches fail to cover 24 h during prolonged use. A discontinuous administration at 12 h intervals allows on and off effects to start within minutes and last 3–5 h. There are no efficacy data for second or third doses during chronic administration.
Nitrate side-effects. Hypotension is the most serious, and headache the most common side-effect of nitrates. Headaches (aspirin may relieve these) may facilitate loss of compliance, yet often pass over.
Failure of therapy. Apart from non-compliance, treatment failure includes nitric oxide resistance and nitrate tolerance.
Nitrate drug interactions. Many are pharmacodynamic, including potentiation of vasodilator effects with calcium channel blockers (CCBs). Note that serious hypotension can occur with the selective PDE5 inhibitors (sildenafil and others) for erectile dysfunction or for the treatment of pulmonary hypertension. Sildenafil decreases the BP by about 8.4/5.5 mmHg and by much more with nitrates. In the case of inadvertent PDE5–nitrate combinations, emergency α-adrenergic agonists or even norepinephrine may be needed. Nitrates should not be given with α-adrenergic blockers. In men with prostatic problems, taking tamsulosin (α1A and α1D blocker), nitrates can be given.
7.1.3.3.2 β-blockers: β-blockers act directly on the heart to reduce heart rate, contractility, atrioventricular (AV) conduction and ectopic activity. Additionally, they may increase perfusion of ischaemic areas by prolonging the diastole and increasing vascular resistance in non-ischaemic areas. In post-MI patients, β-blockers achieved a 30% risk reduction for CV death and MI. Thus β-blockers may also be protective in patients with SCAD, but without supportive evidence from placebo-controlled clinical trials. However, a recent retrospective analysis of the REACH registry suggested that, in patients with either CAD risk factors only, known prior MI, or known CAD without MI, the use of β-blockers was not associated with a lower risk of cardiovascular events. Although propensity score matching was used for the analysis, the demonstration lacks the strength of a randomized evaluation. Among other limitations, most of the β-blocker trials in post-MI patients were performed before the implementation of other secondary prevention therapies, such as statins and ACE inhibitors, leaving uncertainty regarding their efficacy when added to modern therapeutic strategies. β-Blockers are clearly effective in controlling exercise-induced angina, improving exercise capacity and limiting both symptomatic as well as asymptomatic ischaemic episodes. Regarding angina control, β-blockers and CCBs are similar. β-Blockers can be combined with dihydropyridines (DHPs) to control angina. Combination therapy of β-blockers with verapamil and diltiazem should be avoided because of the risk of bradycardia or AV block ( Table 27 ).
The most widely used β-blockers in Europe are those with predominant β1-blockade, such as metoprolol, bisoprolol, atenolol or nevibolol. Carvedilol, a non-selective β-α1blocker, is also often used. All of these reduce cardiac events in patients with heart failure. In summary, there is evidence for prognostic benefits from the use of β-blockers in post-MI patients, or in heart failure. Extrapolation from these data suggests that β-blockers may be the first-line anti-anginal therapy in stable CAD patients without contra-indications. Nevibolol and bisoprolol are partly secreted by the kidney, whereas carvedilol and metoprolol are metabolized by the liver, hence being safer in patients with renal compromise.
7.1.3.3.3 Calcium Channel Blockers: Calcium antagonists (i.e. CCBs) act chiefly by vasodilation and reduction of the peripheral vascular resistance. CCBs are a heterogeneous group of drugs that can chemically be classified into the DHPs and the non-DHPs, their common pharmacological property being selective inhibition of L-channel opening in vascular smooth muscle and in the myocardium. Distinctions between the DHPs and non-DHPs are reflected in different binding sites on the calcium channel pores and in the greater vascular selectivity of the DHP agents (amlodipine, nifedipine, felodipine).
The non-DHPs, by virtue of nodal inhibition, tend to reduce the heart rate (heart rate-lowering agents, verapamil and diltiazem) and explain the anti-anginal properties.
• Non-dihydropyridine (Heart Rate-lowering Calcium Channel Blocker s)
Verapamil. Among CCBs, verapamil has a large range of approved indications, including all varieties of angina (effort, vasospastic, unstable), supraventricular tachycardias and hypertension.
Indirect evidence suggests good safety but with risks of heart block, bradycardia and heart failure. Compared with metoprolol, the anti-anti-anginal activity was similar. Compared with atenonol in hypertension with CAD, verapamil gave less new diabetes, fewer anginal attacks, and less psychological depression. β-Blockade combined with verapamil is not advised (due to risk of heart block): instead, use DHP-β-blockade.
Diltiazem. Diltiazem, with its low side-effect profile, has advantages, compared with verapamil, in the treatment of effort angina. Like verapamil, it acts by peripheral vasodilation, relief of exercise-induced coronary constriction, a modest negative inotropic effect and sinus node inhibition. There are no outcome studies comparing diltiazem and verapamil. As with verapamil, combination with β-blockade, as well as the use in patients with CAD and left ventricular dysfunction, is not advised.
• Dihydropyridines
Long-acting nifedipine. This agent is a powerful arterial vasodilator with few serious side-effects. Long-acting nifedipine is especially well-tested in hypertensive anginal patients when added to β-blockade. In ACTION, a large placebo-controlled trial long-acting nifedipine in SCAD proved to be safe and reduced the need for coronary angiography and cardiovascular interventions. Contra-indications to nifedipine are few (severe aortic stenosis, obstructive cardiomyopathy, or heart failure) and careful combination with β-blockade is usually feasible and desirable. Vasodilatory side-effects include headache and ankle oedema.
Amlodipine. The very long half-life of amlodipine and its good tolerability make it an effective once-a-day anti-anginal and antihypertensive agent, setting it apart from agents that are taken either twice or three times daily. Side-effects are few; mainly ankle oedema. In patients with CAD and normal blood pressure, amlodipine reduced CV events in a 24-month trial. Exercise-induced ischaemia is more effectively reduced by amlodipine than by the β-blocker atenolol and the combination is even better.
However, the CCB–β-blocker combination is often underused, even in some studies reporting 'optimally treated' stable effort angina.
Others. Felodipine, lacidipine and lercanidipine share the standard properties of other long-acting DHPs.
7.1.3.3.4 Ivabradine: Ivabradine is a heart rate-lowering agent selectively inhibiting the sinus node I(f) pacemaking current, thereby decreasing the myocardial oxygen demand without effect on inotropism or BP. It was approved by the European Medicines Agency (EMA) for therapy of chronic stable angina in patients intolerant to—or inadequately controlled by—β-blockers and whose heart rate exceeded 60 b.p.m. (in sinus rhythm). Ivabradine was as effective as atenolol or amlodipine in patients with SCAD; adding ivabradine 7.5 mg twice daily to atenolol therapy gave better control of heart rate and anginal symptoms. In 1507 patients with prior angina enrolled in the Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction (BEAUTIFUL) trial, ivabradine reduced the composite primary endpoint of CV death, hospitalization with MI and HF, and reduced hospitalization for MI. The effect was predominant in patients with a heart rate ≥70 bpm. Ivabradine is thus an effective anti-anginal agent, alone or in combination with β-blockers.
7.1.3.3.5 Nicorandil: Nicorandil is a nitrate derivative of nicotinamide that can be used for the prevention and long-term treatment of angina, and may be added after β-blockers and CCBs. It is EMA- but not FDA approved. Nicorandil dilates epicardial coronary arteries and stimulates ATP-sensitive potassium channels (KATP) in vascular smooth muscle. In the prospective Impact Of Nicorandil in Angina (IONA) study, over a mean of 1.6 years in 5126 patients with SCAD, CV events were reduced by 14% (relative risk 0.86; P = 0.027). However, symptom relief was not reported. Long-term use of oral nicorandil may stabilize coronary plaque in patients with stable angina. Occasional side-effects include oral, intestinal and peri-anal ulceration.
7.1.3.3.6 Trimetazidine: Trimetazidine is an anti-ischaemic metabolic modulator, with similar anti-anginal efficacy to propranolol in doses of 20 mg thrice daily. The heart rate and rate × pressure product at rest and at peak exercise remained unchanged in the trimetazidine group, thus showing a non-mechanical anti-ischaemic action.
Trimetazidine (35 mg twice daily) added to beta-blockade (atenolol) improved effort-induced myocardial ischaemia, as reviewed by the EMA in June 2012, and remains contra-indicated in Parkinson's disease and motion disorders [such as tremor (shaking), muscle rigidity and walking disorders and restless leg syndrome]. In diabetic persons, trimetazidine improved HbA1c and glycaemia, while increasing forearm glucose uptake. Trimetazidine has not been evaluated in large outcome studies in SCAD patients.
7.1.3.3.7 Ranolazine: Ranolazine is a selective inhibitor of late sodium current with anti-ischaemic and metabolic properties. Doses of 500–2000 mg daily reduced angina and increased exercise capacity without changes in heart rate or BP. The EMA approved ranolazine in 2009 for add-on treatment in stable angina in patients inadequately controlled by—or intolerant to—first-line agents (beta-blockers and/or calcium antagonists). In the 6560 patients of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes: Thrombolysis In Myocardial Infarction (MERLIN-TIMI 36) trial presenting with recent non-ST-elevation ACS (NSTE-ACS), ranolazine therapy showed no overall benefit. In patients with prior chronic angina enrolled in the MERLIN trial, ranolazine reduced recurrent ischaemia [hazard ratio (HR) 0.78; P = 0.002]. In those studied after the coronary event, ranolazine reduced the incidence of newly increased HbA1c by 32%. In the recent TERISA study (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina), ranolazine reduced episodes of stable angina in 949 diabetes patients already receiving one or two anti-anginal drugs and led to less use of sublingual nitroglycerin, and the benefits appeared more prominent in patients with higher rather than lower HbA1c levels. These results suggest that this drug can be added to other well-established anti-anginal drugs, in particular in patients with higher HbA1c levels, who may also more often rely on medical management.
Ranolazine plasma levels increase with cytochrome P3A (CYP3A) inhibitors (diltiazem, verapamil, macrolide antibiotics, grapefruit juice). Ranolazine clearance is reduced by renal and hepatic impairment. Ranolazine increases QTc, and should therefore be used carefully in patients with QT prolongation or on QT-prolonging drugs.
7.1.3.3.8 Allopurinol: Allopurinol, an inhibitor of xanthine oxidase that reduces uric acid in persons with gout, is also anti-anginal. There is limited clinical evidence but, in a randomized crossover study of 65 patients with SCAD, allopurinol 600 mg/day increased times to ST-segment depression and to chest pain. In renal impairment, such high doses may have toxic side-effects. In optimally treated SCAD patients, allopurinol reduced vascular oxidative stress, while in heart failure patients it conserved ATP.
7.1.3.3.9 Molsidomine: This direct NO donor has anti-ischaemic effects similar to those of isosorbide dinitrate. The long-acting once-daily 16 mg formulation is as effective as 8 mg twice daily.
7.1.3.4 Patients With Low Blood Pressure: Anti-anginal drugs should be started at very low doses, with preferential use of drugs with no- or limited impact on BP, such as ivabradine (in patients with sinus rhythm), ranolazine or trimetazidine.
7.1.3.5 Patients With Low Heart Rate:Several studies have shown that increased resting heart rate is a strong independent risk factor for adverse outcome in patients with SCAD. There is a linear relationship between resting heart rate and major cardiovascular events, with a persistent decrease in CV risk with lower heart rate. A clinical benefit has been demonstrated of heart rate reduction using various drugs. Although lowering the heart rate <60 b.p.m. is an important goal in the treatment of SCAD, patients presenting with low heart rate should be treated differently. Heart rate lowering drugs (β-blockers, ivabradine, heart rate lowering CCBs) should be avoided or used with caution and, if needed, started at very low doses. Anti-anginal drugs without heart lowering effects should preferably be given.
7.2.1 Antiplatelet Agents. Antiplatelet agents decrease platelet aggregation and may prevent formation of coronary thrombus. Due to a favourable ratio between benefit and risk in patients with stable CAD and its low cost, low-dose aspirin is the drug of choice in most cases and clopidogrel may be considered for some patients. The use of antiplatelet agents is associated with a higher bleeding risk.
7.2.1.1 Low-dose Aspirin: Aspirin remains the cornerstone of pharmacological prevention of arterial thrombosis. It acts via irreversible inhibition of platelet cyclooxygenase-1 (COX-1) and thus thromboxane production, which is normally complete with chronic dosing ≥75 mg/day. Contrary to the antiplatelet effects, the gastrointestinal side-effects of aspirin increase at higher doses. The optimal risk–benefit ratio appears to be achieved with an aspirin dosage of 75–150 mg/day.
7.2.1.2 P2Y12 Inhibitors: P2Y12 inhibitors, including thienopyridines, act as antagonists of the platelet adenosine diphosphate (ADP) receptor P2Y12, thereby inhibiting platelet aggregation. The major study supporting the use of thienopyridine in stable coronary patients is the Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, which showed an overall benefit of clopidogrel as compared with aspirin (with also a favourable safety profile) in preventing CV events in three categories of patients with previous MI, previous stroke or peripheral vascular disease (PVD). The clopidogrel benefit was driven by the peripheral vascular disease (PVD) sub-group and the dose of aspirin with which it was compared (325 mg/day) may not be the safest dose. Clopidogrel should thus be proposed as a second-line treatment, especially for aspirin-intolerant CVD patients. Prasugrel and ticagrelor are new P2Y12 antagonists that achieve greater platelet inhibition, compared with clopidogrel. Prasugrel and ticagrelor are both associated with a significant reduction of CV outcomes as compared with clopidogrel in ACS patients, but no clinical studies have evaluated the benefit of these drugs in SCAD patients. After unstable angina or myocardial infarction without ST-segment elevation when patients are stabilized and medically managed, there are no data supporting a beneficial effect of intensified platelet inhibition.
7.2.1.3 Combination of Antiplatelet Agents: Dual antiplatelet therapy combining aspirin and a thienopyridine is the standard of care for patients with ACS, including after the acute phase, when the patients are stabilized, or in SCAD patients who have undergone elective PCI. However, in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study, Dual antiplatelet therapy did not confer benefit in patients with stable vascular disease or at risk of atherothrombotic events, although a significant benefit was observed in a post-hoc analysis of patients with documented atherothrombotic disease, and in particular in coronary patients with a prior history of MI. Combined antiplatelet therapy was also recently tested with an antagonist of protease activated receptor type 1 (PAR-1). The primary efficacy endpoint—a composite of CV death, MI or stroke—was significantly reduced with vorapaxar in addition to standard antiplatelet therapy in patients with stable atherosclerosis, and this benefit was particularly evident in the post-MI group of patients. However, it increased the risk of moderate or severe bleeding, including intracranial haemorrhage. Altogether, on the basis of these post-hoc analyses, combined antiplatelet therapy may be beneficial only in selected patients at high risk of ischaemic events, but cannot be recommended systematically in SCAD patients.
7.2.1.4 Poor Response to Antiplatelet Agents: There is a wide variation in response to antiplatelet therapy and a great interest has recently emerged in the use of functional and/or genetic assays to guide such treatment. High platelet reactivity on aspirin and/or clopidogrel treatment results from multiple factors, including non-compliance, accelerated platelet turnover, drug interactions, patient characteristics (such as age, gender, diabetes) and single nucleotide polymorphisms [cytochrome P450 2C19 (CYP2C19*2), ATP-binding cassette sub-family B member 1(ABCB1) for clopidogrel). The influence of genetic variants on the response to antiplatelet agents, especially clopidogrel, has been well established in patients with ACS and planned PCI, but not in patients with stable CAD. However, there is currently no recommendation to perform genetic testing in patients with stable CAD. Platelet function testing in SCAD patients undergoing PCI is not recommended as a routine (see chapter 8).
7.2.2 Lipid-lowering Agents (See Lipid Management, Above). Patients with documented CAD are regarded as being at very high risk and should be treated with statins, in line with recommendations in the ESC/European Atherosclerosis Society Guidelines for the management of dyslipidaemia. The treatment target is LDL-C <1.8 mmol/L and/or >50% reduction if the target level cannot be reached.
7.2.3 Renin-angiotensin-aldosterone System Blockers. Angiotensin converting enzyme inhibitors reduce total mortality, MI, stroke and heart failure among specific subgroups of patients, including those with heart failure, previous vascular disease alone, or high-risk diabetes. Hence, it is appropriate to consider ACE inhibitors for the treatment of patients with SCAD, especially with co-existing hypertension, LVEF ≤40%, diabetes or CKD, unless contra-indicated.
However, not all clinical trials have demonstrated that the ACE inhibitors reduce all-cause mortality, CV mortality, non-fatal MI, stroke and heart failure in patients with atherosclerosis and preserved LV function. In SCAD patients with hypertension, a combination therapy consisting of an ACE inhibitor and a DHP CCB, such as perindopril/amlodipine in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trial and benazepril/amlodipine in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, is preferred. In contrast, adding an angiotensin II receptor antagonist (ARB) to an ACE inhibitor was associated with more adverse events, without an increase in benefit.
Hence, ARB treatment may be an alternative therapy for patients with SCAD when ACE inhibition is indicated but not tolerated. There are, however, no clinical outcome studies showing a beneficial effect of ARB in SCAD.
Aldosterone blockade with spironolactone or eplerenone is recommended for use in post-MI patients without significant renal dysfunction or hyperkalaemia, who are already receiving therapeutic doses of an ACE inhibitor and a β-blocker, have an LVEF ≤40% and have either diabetes or heart failure.
7.3.1 Analgesics. The use of selective cyclooxygenase-2 (COX-2) inhibitors and traditional non-selective non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased risk for CV events in recent clinical trials in arthritis and cancer prevention and are not recommended. In patients at increased CV risk in need of pain relief, it is therefore recommended to commence with acetaminophen or aspirin at the lowest efficacious dose, especially for short-term needs.
If adequate pain relief requires the use of NSAIDs, these agents should be used in the lowest effective doses and for the shortest possible duration. In patients with atherosclerotic vascular disease—and in SCAD in particular—NSAID treatment should, when this is indicated for other reasons, be combined with low-dose aspirin to ensure effective platelet inhibition.
Figure 4 summarizes the medical management of SCAD patients. This common strategy might be adjusted according to patient comorbidities, contra-indications, personal preference and drug costs. The medical management consists of a combination of at least a drug for angina relief plus drugs to improve prognosis, as well as use of sublingual nitroglycerin for chest pain management. It is recommended that either a β-blocker or a CCB to a short-acting nitrate be added as first-line treatment to control heart rate and symptoms. If the symptoms are not controlled, it is advised to switch to the other option (CCB or β-blocker) or to combine a β-blocker and a DHP CCB. The combination of a heart-lowering CCB with a β-blocker is not advised. Other anti-anginal drugs might be used as a second-line treatment when symptoms are not satisfactorily controlled. In selected patients with intolerance or contra-indications to both β-blockers and CCBs, second-line drugs can be used as a first-line treatment. The event prevention is optimally achieved by the prescription of antiplatelet agents and statins. In selected patients, the use of ACE inhibitors or ARBs can be considered.
(Enlarge Image)
Figure 4.
Medical management of patients with stable coronary artery disease. ACEI = angiotensin converting enzyme inhibitor; CABG = coronary artery bypass graft; CCB = calcium channel blockers; CCS = Canadian Cardiovascular Society; DHP = dihydropyridine; PCI = percutaneous coronary intervention.
Data for diabetics.
if intolerance, consider clopidogrel
7.5.1 Microvascular Angina. All patients with microvascular angina should achieve optimal coronary risk factor control. Symptomatic treatment is empirical because of the limited knowledge of its causes. Furthermore, the results of available therapeutic trials cannot be accepted as conclusive because of variable patient selection, small sample size, inadequate design and lack of demonstration of clinical improvement of microvascular disease.
Traditional anti-ischaemic drugs are the first step in medical treatment. Short-acting nitrates can be used to treat anginal attacks, but often they are only partially effective. β-Blockers seem a rational approach because the dominant symptom is effort-related angina; they were indeed found to improve symptoms in several studies and should constitute the first choice of therapy, particularly in patients with evidence of increased adrenergic activity (e.g. high heart rate at rest or during low-workload exercise).
Calcium antagonists and long-acting nitrates have shown variable results in clinical trials and are more helpful when used in addition to β-blockers in the case of insufficient control of symptoms. Calcium antagonist, however, can be first-line therapy in patients with a significant variable threshold of effort angina. In patients with persisting symptoms despite optimal anti-ischaemic drug therapy, several other treatments have been proposed. ACE inhibitors (and possibly ARBs) may improve microvascular function by counteracting the vasoconstrictor effects of angiotensin II; they have improved symptoms and exercise results in small trials and can be helpful, particularly in patients with hypertension or diabetes mellitus. α-Adrenergic antagonists may decrease sympathetic-mediated vasoconstriction and may be considered in individual patients, although clinical benefits have usually been disappointing. Improvement of exercise capacity has been observed in a small trial with nicorandil. Improvement of anginal symptoms, probably mediated primarily by improvement of endothelial function, has been reported with statins and with oestrogen replacement treatment. In patients with angina refractory to various combinations of the previous medications, other forms of treatment can be proposed. Xanthine derivatives (aminophylline, bamiphylline) can be added to anti-ischaemic treatment to reduce angina by adenosine receptor blockade; adenosine is indeed a major mediator of cardiac ischaemic pain (see Table 29). New anti-ischaemic drugs such as ranolazine or ivabradine have shown good effects in some patients with microvascular angina. Finally, in case of refractory angina, additional interventions may be discussed (see section 9 on refractory angina).
In patients with microvascular angina, the susceptibility of symptoms to medical treatment is extremely variable and experimentation of different drug combinations, is needed before establishing satisfactory symptom control.
7.5.2 Treatment of Vasospastic Angina. All patients with vasospastic angina should achieve optimal coronary risk factor control, in particular through smoking cessation and aspirin. A drug-related cause (e.g. cocaine or amphetamines) should be systemically researched and managed if detected. Chronic preventive treatment of vasospastic angina is mainly based on the use of CCBs. Average doses of these drugs (240–360 mg/day of verapamil or diltiazem, 40–60 mg/day of nifedipine) usually prevent spasm in about 90% of patients. Long-acting nitrates can be added in some patients to improve the efficacy of treatment and should be scheduled to cover the period of the day in which ischaemic episodes most frequently occur, in order to prevent nitrate tolerance. β-Blockers should be avoided, as they might favour spasm by leaving α-mediated vasoconstriction unopposed by β-mediated vasodilation.
In about 10% of cases, coronary artery spasm is refractory to standard vasodilator therapy, although refractoriness is usually limited to brief periods in most patients. Very high doses of calcium antagonists and nitrates usually prevent transient ischaemic episodes in these critical periods. In the very rare patients in whom even this treatment is insufficient, the addition of anti-adrenergic drugs like guanethidine or clonidine might be helpful. PCI with stent implantation at the site of spasm (even in the absence of significant stenosis), as well as chemical or surgical sympathectomy, have also been reported but are not recommended. Because of the high prevalence of silent ischaemic episodes and possible arrhythmias, 24-hour ambulatory ECG monitoring can be used to verify the treatment efficiency.
Implantation of an automatic cardioverter defibrillator or of a pacemaker is indicated in patients with ischaemia-related life-threatening tachyarrhythmias or bradyarrhythmias, respectively, when coronary spasm presents a poor or uncertain response to medical therapy.
7. Lifestyle and Pharmacological Management
7.1 Risk Factors and Ischaemia Management
7.1.1 General Management of Stable Coronary Artery Disease Patients. The aim of the management of SCAD is to reduce symptoms and improve prognosis. The management of CAD patients encompasses lifestyle modification, control of CAD risk factors, evidence-based pharmacological therapy and patient education. Lifestyle recommendations are described in recent ESC guidelines.
7.1.2 Lifestyle Modifications and Control of Risk Factors. 7.1.2.1 Smoking: Smoking is a strong and independent risk factor for CVD and all smoking, including environmental smoking exposure, must be avoided in all patients with CVD. The benefits of smoking cessation have been extensively reported, and quitting smoking is potentially the most effective of all preventive measures, being associated with a reduction in mortality of 36% after MI. Clinicians treating patients with CAD can take advantage of the unique situation and emphasize that the risk of future CAD events can be dramatically reduced by smoking cessation. Thus, smoking status should be assessed systematically (including passive smoking) and all smokers should be advised to quit and offered cessation assistance. Quitting smoking is complex because smoking is both pharmacologically and psychologically highly addictive. Advice, encouragement and pharmacological aid consistently improve success rates. Nicotine replacement therapy is safe in patients with CAD and should routinely be offered. Bupropion and varenicline have been found safe to use in patients with stable CAD in some studies, although the safety of varenicline has recently been questioned in a meta-analysis, being associated with a small but statistically significant increase in CVD.
7.1.2.2 Diet (Table 25): A healthy diet reduces CVD risk. Cornerstones of a healthy diet are summarized below. Energy intake should be limited to the amount of energy needed to maintain (or obtain) a healthy weight—that is, a BMI <25 kg/m. In general, when following the rules for a healthy diet, no dietary supplements are needed. N-3 polyunsaturated fatty acid (PUFA) consumption, mainly from oily fish, is potentially associated with beneficial effects on cardiac risk factors, notably reduction in triglycerides, but not all randomized, controlled trials have shown reductions in CV events. Thus current recommendations are to increase PUFA intake through fish consumption, rather than from supplements. Recently, the largest study ever conducted with a so-called 'Mediterranean' diet, supplemented with extra-virgin olive oil or nuts, reduced the incidence of major cardiovascular events in patients at high risk of CV events but without prior CV disease.
7.1.2.3 Physical Activity: Regular physical activity is associated with a decrease in CV morbidity and mortality in patients with established CAD and physical activity should be incorporated into daily activities. Aerobic exercise should be offered to patients with known CAD, usually as part of a structured cardiac rehabilitation program, with the need for an evaluation of both exercise capacity and exercise-associated risk. Patients with previous acute MI, CABG, percutaneous coronary intervention (PCI), stable angina pectoris or stable chronic heart failure should undergo moderate-to-vigorous intensity aerobic exercise training ≥3 times a week and for 30 min per session. Sedentary patients should be strongly encouraged to start light-intensity exercise programmes after adequate exercise-related risk stratification. In patients with significant CAD who are not candidates for revascularization, exercise training may offer an alternative means of symptom alleviation and improved prognosis.
7.1.2.4 Sexual Activity: Sexual activity is associated with an exercise workload of up to 6 METS (1 MET = approximately 3.5 mL oxygen consumption/kg/min) depending on the type of activity. Sympathetic activation is intrinsic to sexual arousal and heart rate and blood pressure (BP) response may be higher than expected from the level of exercise. Sexual activity may thus trigger ischaemia, and nitroglycerin prior to sexual intercourse may be helpful as in other physical activity.
Patients with mild angina, successful coronary revascularization and New York Heart Association (NYHA) functional Class I heart failure generally do not need specific evaluation before resuming sexual activity. Patients with more symptomatic heart disease, including moderate angina, may be guided by an exercise stress test as a means of assessing risk and reassuring the patient. Exercise training should be advocated to improve exercise capacity and reduce myocardial oxygen consumption during sexual activity.
Erectile dysfunction (ED) is associated with cardiac risk factors and is more prevalent in patients with CAD. The common denominator between erectile dysfunction and CAD is endothelial dysfunction and antihypertensive medication—in particular β-blockers and thiazides—increases the risk of erectile dysfunction.
Lifestyle and pharmacological intervention—including weight loss, exercise training, smoking cessation and statin treatment—ameliorate ED. Pharmacological therapy with phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil and vardenafil) are effective, safe and well tolerated in men with stable CAD. Low-risk patients, as defined above, can usually receive PDE5 inhibitors without cardiac work-up. However, use of nitric oxide donors, i.e. all of the preparations of nitroglycerin as well as isosorbide mononitrate and isosorbide dinitrate, are absolute contra-indications to the use of PDE5 inhibitors because of the risk of synergistic effects on vasodilation, causing hypotension and haemodynamic collapse. PDE5 inhibitors are not recommended in patients with low blood pressure, with severe heart failure (NYHA III–IV), refractory angina or recent CV events. Patients must be informed about the potentially harmful interactions between PDE5 inhibitors and nitrates. If a patient on a PDE5 inhibitor develops chest pain, nitrates should not be administered in the first 24 hours (sildenafil, vardenafil) to 48 hours (tadalafil).
7.1.2.5 Weight Management: Both overweight and obesity are associated with an increased risk of death in CAD. Weight reduction in overweight and obese people is recommended in order to achieve favourable effects on BP, dyslipidaemia and glucose metabolism. The presence of sleep apnoea symptoms should be carefully assessed, especially in obese patients. Sleep apnoea has been associated with an increase in CV mortality and morbidity.
7.1.2.6 Lipid Management: Dyslipidemia should be managed according to lipid guidelines with pharmacological and lifestyle intervention. Patients with established CAD are regarded as being at very high risk for cardiovascular events and statin treatment should be considered, irrespective of low density lipoprotein (LDL) cholesterol (LDL-C) levels. The goals of treatment are LDL-C below 1.8 mmol/L (<70 mg/dL) or >50% LDL-C reduction when target level cannot be reached. In the majority of patients this is achievable through statin monotherapy. Other interventions (e.g. fibrates, resins, nicotinic acid, ezetimibe) may lower LDL cholesterol but no benefit on clinical outcomes has been reported for these alternatives. Although elevated levels of triglycerides and low HDL cholesterol (HDL-C) are associated with increased CVD risk, clinical trial evidence is insufficient to specify treatment targets, which should be regarded as not indicated.
For patients undergoing PCI for SCAD, high dose atorvastatin has been shown to reduce the frequency of peri-procedural MI in both statin-naïve patients and patients receiving chronic statin therapy. Thus reloading with high intensity statin before PCI may be considered.
7.1.2.7 Arterial Hypertension: Particular attention should be given to control of elevated BP but thresholds for the definition of hypertension by 24-h ambulatory and home BP monitoring differ from those measured at office or clinic (see Table 26 ). Elevated BP is a major risk factor for CAD as well as heart failure, cerebrovascular disease and renal failure. There is sufficient evidence to recommend that systolic BP (SBP) be lowered to <140 mmHg and diastolic BP (DBP) to <90 mmHg in SCAD patients with hypertension. Based on current data, it may be prudent to recommend lowering SBP/DBP to values within the range 130–139/80–85 mmHg. BP targets in diabetes are recommended to be <140/85 mmHg (see below).
7.1.2.8 Diabetes and Other Disorders (See Also Chapter 9 and Web Addenda): Diabetes mellitus is a strong risk factor for CV complications, increases the risk of progression of coronary disease and should be managed carefully, with good control of glycated haemoglobin (HbA1c) to <7.0% (53 mmol/mol) generally and <6.5%–6.9% (48–52 mmol/mol) on an individual basis. Glucose control should be based on individual considerations, depending on the patient's characteristics including age, presence of complications and diabetes duration.
As for other disorders, attention to management of risk factors is recommended, including weight management, exercise recommendations and statin treatment with an LDL-C target of 1.8 mmol/L (<70 mg/dL) in diabetic patients with angiographically proven CAD. The traditional treatment goal for BP in diabetes, i.e. below 130 mmHg, is not supported by outcome evidence in trials and has been difficult to achieve in the majority of patients. Thus, the BP target in patients with CAD and diabetes is to be <140/85 mmHg. An angiotensin converting enzyme (ACE) inhibitor or renin-angiotensin receptor blocker should always be included because of the renal protective effects.
Patients with chronic kidney disease (CKD) are at high risk and particular care should be taken to address risk factors and achieve BP and lipid targets. Statins are generally well tolerated in CKD stages 1–2 (GFR >60–89 mL/min/1.73 m) whereas, in CKD stages 3–5, statins with minimal renal excretion should be chosen (atorvastatin, fluvastatin, pitavastatin, rosuvastatin).
7.1.2.9 Psychosocial Factors: Depression, anxiety and distress are common in patients with CAD. Patients should be assessed for psychosocial distress and appropriate care offered. Refer for psychotherapy, medication or collaborative care in the case of clinically significant symptoms of depression, anxiety and hostility. This approach can reduce symptoms and enhance quality of life, although evidence for a definite beneficial effect on cardiac endpoints is inconclusive.
7.1.2.10 Cardiac Rehabilitation: A comprehensive risk-reduction regimen, integrated into comprehensive cardiac rehabilitation, is recommended to patients with CAD. Cardiac rehabilitation is commonly offered after MI or recent coronary intervention, but should be considered in all patients with CAD, including those with chronic angina. Exercise-based cardiac rehabilitation is effective in reducing total- and CV mortality and hospital admissions, whereas effects on total MI or revascularization (CABG or PCI) are less clear, especially in the long term.
Evidence also points towards beneficial effects on health-related quality of life (QoL). In selected sub-groups, centre-based cardiac rehabilitation may be substituted for home-based rehabilitation, which is non-inferior. Patient participation in cardiac rehabilitation remains far too low, particularly in women, the elderly and the socio-economically deprived, and could benefit from systematic referral.
7.1.2.11 Influenza Vaccination: An annual influenza vaccination is recommended for patients with CAD, especially the elderly.
7.1.2.12 Hormone Replacement Therapy: For decades, evidence from epidemiological and laboratory studies led us to believe that circulating oestrogens had a beneficial effect on the risk of CVD and that this could be transferred to the benefits of hormone replacement therapy (HRT). However, results from large randomized trials have not supported this; on the contrary, HRT increases the risk of CVD in women above the age of 60.
The mechanisms are unclear and, if instituted at an earlier age (i.e. at the time of menopause) in women with intact vascular endothelium and few CV risk factors, the effect of HRT is still debated. However, HRT is at present not recommended for primary or secondary prevention of CVD.
7.1.3 Pharmacological Management of Stable Coronary Artery Disease Patients. 7.1.3.1 Aims of Treatment: The two aims of the pharmacological management of stable CAD patients are to obtain relief of symptoms and to prevent CV events.
Relief of Anginal Symptoms: rapidly acting formulations of nitroglycerin are able to provide immediate relief of the angina symptoms once the episode has started or when the symptom is likely to occur (immediate treatment or prevention of angina). Anti-ischaemic drugs—but also lifestyle changes, regular exercise training, patient education and revascularization—all have a role to play in minimizing or eradicating symptoms over the long term (long-term prevention).
To Prevent the Occurrence of CV Events: efforts to prevent MI and death in coronary disease focus primarily on reducing the incidence of acute thrombotic events and the development of ventricular dysfunction. These aims are achieved by pharmacological or lifestyle interventions which: (i) reduce plaque progression; (ii) stabilize plaque, by reducing inflammation and (iii) prevent thrombosis, should plaque rupture or erosion occur. In patients with severe lesions in coronary arteries supplying a large area of jeopardized myocardium, a combined pharmacological and revascularization strategy offers additional opportunities for improving prognosis by improving heart perfusion or providing alternative perfusion routes.
7.1.3.2 Drugs: Evidence supporting the optimal medical therapy (OMT) for SCAD has been reviewed and detailed elsewhere, and is summarized below. Table 27 indicates the main side-effects, contra-indications and major drug–drug interactions for each drug class. Table 28 presents the recommendations for drug therapy.
7.1.3.3 Anti-ischaemic Drugs: 7.1.3.3.1 Nitrates: Nitrates offer coronary arteriolar and venous vasodilatation, which are the basis of symptomatic relief of effort angina, acting by their active component nitric oxide (NO) and by the reduction of preload.
Short-acting Nitrates for Acute Effort Angina. Sublingual nitroglycerin is the standard initial therapy for effort angina. When angina starts, the patient should rest sitting (standing promotes syncope, lying down enhances venous return and heart work) and take sublingual nitroglycerin (0.3–0.6 mg) every 5 min until the pain goes or a maximum of 1.2 mg has been taken within 15 min. Nitroglycerin spray acts more rapidly. Nitroglycerin can be used prophylactically when angina can be expected, such as activity after a meal, emotional stress, sexual activity and in colder weather.
Isosorbide dinitrate (5 mg sublingually) helps to abort anginal attacks for about 1 h. Because the dinitrate requires hepatic conversion to the mononitrate, the onset of anti-anginal action (within 3–4 min) is slower than with nitroglycerin. After oral ingestion, haemodynamic and anti-anginal effects persist for several hours, conferring longer protection against angina than sublingual nitroglycerin.
Long-acting Nitrates for Angina Prophylaxis. Long-acting nitrates are not continuously effective if regularly taken over a prolonged period without a nitrate-free or nitrate-low interval of about 8–10 hours (tolerance). Worsening of endothelial dysfunction is a potential complication of long-acting nitrates, hence the common practice of the routine use of long-acting nitrates as first line therapy for patients with effort angina needs re-evaluation.
Isosorbide dinitrate (oral preparation) is frequently given for the prophylaxis of angina. In a crucial placebo-controlled study, exercise duration improved significantly for 6–8 h after single oral doses of 15–120mg isosorbide dinitrate, but for only 2 h when the same doses were given repetitively four times daily, despite much higher plasma isosorbide dinitrate concentrations during sustained than during acute therapy. With the extended-release formulation of isosorbide dinitrate, eccentric twice-daily dosing, with 40 mg in the morning, repeated 7 hours later, was not superior to placebo in a large multicentre study. Thus prolonged therapy with isosorbide dinitrate is not evidence-based.
Mononitrates have similar dosage and effects to those of isosorbide dinitrate. Nitrate tolerance—likewise a potential problem—can be prevented by changes in dosing and timing of administration, as well as by using slow-release preparations. Thus only twice-daily rapid-release preparations or very high doses of slow-release mononitrate—also twice daily—give sustained anti-anginal benefit.
Transdermal nitroglycerin patches fail to cover 24 h during prolonged use. A discontinuous administration at 12 h intervals allows on and off effects to start within minutes and last 3–5 h. There are no efficacy data for second or third doses during chronic administration.
Nitrate side-effects. Hypotension is the most serious, and headache the most common side-effect of nitrates. Headaches (aspirin may relieve these) may facilitate loss of compliance, yet often pass over.
Failure of therapy. Apart from non-compliance, treatment failure includes nitric oxide resistance and nitrate tolerance.
Nitrate drug interactions. Many are pharmacodynamic, including potentiation of vasodilator effects with calcium channel blockers (CCBs). Note that serious hypotension can occur with the selective PDE5 inhibitors (sildenafil and others) for erectile dysfunction or for the treatment of pulmonary hypertension. Sildenafil decreases the BP by about 8.4/5.5 mmHg and by much more with nitrates. In the case of inadvertent PDE5–nitrate combinations, emergency α-adrenergic agonists or even norepinephrine may be needed. Nitrates should not be given with α-adrenergic blockers. In men with prostatic problems, taking tamsulosin (α1A and α1D blocker), nitrates can be given.
7.1.3.3.2 β-blockers: β-blockers act directly on the heart to reduce heart rate, contractility, atrioventricular (AV) conduction and ectopic activity. Additionally, they may increase perfusion of ischaemic areas by prolonging the diastole and increasing vascular resistance in non-ischaemic areas. In post-MI patients, β-blockers achieved a 30% risk reduction for CV death and MI. Thus β-blockers may also be protective in patients with SCAD, but without supportive evidence from placebo-controlled clinical trials. However, a recent retrospective analysis of the REACH registry suggested that, in patients with either CAD risk factors only, known prior MI, or known CAD without MI, the use of β-blockers was not associated with a lower risk of cardiovascular events. Although propensity score matching was used for the analysis, the demonstration lacks the strength of a randomized evaluation. Among other limitations, most of the β-blocker trials in post-MI patients were performed before the implementation of other secondary prevention therapies, such as statins and ACE inhibitors, leaving uncertainty regarding their efficacy when added to modern therapeutic strategies. β-Blockers are clearly effective in controlling exercise-induced angina, improving exercise capacity and limiting both symptomatic as well as asymptomatic ischaemic episodes. Regarding angina control, β-blockers and CCBs are similar. β-Blockers can be combined with dihydropyridines (DHPs) to control angina. Combination therapy of β-blockers with verapamil and diltiazem should be avoided because of the risk of bradycardia or AV block ( Table 27 ).
The most widely used β-blockers in Europe are those with predominant β1-blockade, such as metoprolol, bisoprolol, atenolol or nevibolol. Carvedilol, a non-selective β-α1blocker, is also often used. All of these reduce cardiac events in patients with heart failure. In summary, there is evidence for prognostic benefits from the use of β-blockers in post-MI patients, or in heart failure. Extrapolation from these data suggests that β-blockers may be the first-line anti-anginal therapy in stable CAD patients without contra-indications. Nevibolol and bisoprolol are partly secreted by the kidney, whereas carvedilol and metoprolol are metabolized by the liver, hence being safer in patients with renal compromise.
7.1.3.3.3 Calcium Channel Blockers: Calcium antagonists (i.e. CCBs) act chiefly by vasodilation and reduction of the peripheral vascular resistance. CCBs are a heterogeneous group of drugs that can chemically be classified into the DHPs and the non-DHPs, their common pharmacological property being selective inhibition of L-channel opening in vascular smooth muscle and in the myocardium. Distinctions between the DHPs and non-DHPs are reflected in different binding sites on the calcium channel pores and in the greater vascular selectivity of the DHP agents (amlodipine, nifedipine, felodipine).
The non-DHPs, by virtue of nodal inhibition, tend to reduce the heart rate (heart rate-lowering agents, verapamil and diltiazem) and explain the anti-anginal properties.
• Non-dihydropyridine (Heart Rate-lowering Calcium Channel Blocker s)
Verapamil. Among CCBs, verapamil has a large range of approved indications, including all varieties of angina (effort, vasospastic, unstable), supraventricular tachycardias and hypertension.
Indirect evidence suggests good safety but with risks of heart block, bradycardia and heart failure. Compared with metoprolol, the anti-anti-anginal activity was similar. Compared with atenonol in hypertension with CAD, verapamil gave less new diabetes, fewer anginal attacks, and less psychological depression. β-Blockade combined with verapamil is not advised (due to risk of heart block): instead, use DHP-β-blockade.
Diltiazem. Diltiazem, with its low side-effect profile, has advantages, compared with verapamil, in the treatment of effort angina. Like verapamil, it acts by peripheral vasodilation, relief of exercise-induced coronary constriction, a modest negative inotropic effect and sinus node inhibition. There are no outcome studies comparing diltiazem and verapamil. As with verapamil, combination with β-blockade, as well as the use in patients with CAD and left ventricular dysfunction, is not advised.
• Dihydropyridines
Long-acting nifedipine. This agent is a powerful arterial vasodilator with few serious side-effects. Long-acting nifedipine is especially well-tested in hypertensive anginal patients when added to β-blockade. In ACTION, a large placebo-controlled trial long-acting nifedipine in SCAD proved to be safe and reduced the need for coronary angiography and cardiovascular interventions. Contra-indications to nifedipine are few (severe aortic stenosis, obstructive cardiomyopathy, or heart failure) and careful combination with β-blockade is usually feasible and desirable. Vasodilatory side-effects include headache and ankle oedema.
Amlodipine. The very long half-life of amlodipine and its good tolerability make it an effective once-a-day anti-anginal and antihypertensive agent, setting it apart from agents that are taken either twice or three times daily. Side-effects are few; mainly ankle oedema. In patients with CAD and normal blood pressure, amlodipine reduced CV events in a 24-month trial. Exercise-induced ischaemia is more effectively reduced by amlodipine than by the β-blocker atenolol and the combination is even better.
However, the CCB–β-blocker combination is often underused, even in some studies reporting 'optimally treated' stable effort angina.
Others. Felodipine, lacidipine and lercanidipine share the standard properties of other long-acting DHPs.
7.1.3.3.4 Ivabradine: Ivabradine is a heart rate-lowering agent selectively inhibiting the sinus node I(f) pacemaking current, thereby decreasing the myocardial oxygen demand without effect on inotropism or BP. It was approved by the European Medicines Agency (EMA) for therapy of chronic stable angina in patients intolerant to—or inadequately controlled by—β-blockers and whose heart rate exceeded 60 b.p.m. (in sinus rhythm). Ivabradine was as effective as atenolol or amlodipine in patients with SCAD; adding ivabradine 7.5 mg twice daily to atenolol therapy gave better control of heart rate and anginal symptoms. In 1507 patients with prior angina enrolled in the Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction (BEAUTIFUL) trial, ivabradine reduced the composite primary endpoint of CV death, hospitalization with MI and HF, and reduced hospitalization for MI. The effect was predominant in patients with a heart rate ≥70 bpm. Ivabradine is thus an effective anti-anginal agent, alone or in combination with β-blockers.
7.1.3.3.5 Nicorandil: Nicorandil is a nitrate derivative of nicotinamide that can be used for the prevention and long-term treatment of angina, and may be added after β-blockers and CCBs. It is EMA- but not FDA approved. Nicorandil dilates epicardial coronary arteries and stimulates ATP-sensitive potassium channels (KATP) in vascular smooth muscle. In the prospective Impact Of Nicorandil in Angina (IONA) study, over a mean of 1.6 years in 5126 patients with SCAD, CV events were reduced by 14% (relative risk 0.86; P = 0.027). However, symptom relief was not reported. Long-term use of oral nicorandil may stabilize coronary plaque in patients with stable angina. Occasional side-effects include oral, intestinal and peri-anal ulceration.
7.1.3.3.6 Trimetazidine: Trimetazidine is an anti-ischaemic metabolic modulator, with similar anti-anginal efficacy to propranolol in doses of 20 mg thrice daily. The heart rate and rate × pressure product at rest and at peak exercise remained unchanged in the trimetazidine group, thus showing a non-mechanical anti-ischaemic action.
Trimetazidine (35 mg twice daily) added to beta-blockade (atenolol) improved effort-induced myocardial ischaemia, as reviewed by the EMA in June 2012, and remains contra-indicated in Parkinson's disease and motion disorders [such as tremor (shaking), muscle rigidity and walking disorders and restless leg syndrome]. In diabetic persons, trimetazidine improved HbA1c and glycaemia, while increasing forearm glucose uptake. Trimetazidine has not been evaluated in large outcome studies in SCAD patients.
7.1.3.3.7 Ranolazine: Ranolazine is a selective inhibitor of late sodium current with anti-ischaemic and metabolic properties. Doses of 500–2000 mg daily reduced angina and increased exercise capacity without changes in heart rate or BP. The EMA approved ranolazine in 2009 for add-on treatment in stable angina in patients inadequately controlled by—or intolerant to—first-line agents (beta-blockers and/or calcium antagonists). In the 6560 patients of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes: Thrombolysis In Myocardial Infarction (MERLIN-TIMI 36) trial presenting with recent non-ST-elevation ACS (NSTE-ACS), ranolazine therapy showed no overall benefit. In patients with prior chronic angina enrolled in the MERLIN trial, ranolazine reduced recurrent ischaemia [hazard ratio (HR) 0.78; P = 0.002]. In those studied after the coronary event, ranolazine reduced the incidence of newly increased HbA1c by 32%. In the recent TERISA study (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina), ranolazine reduced episodes of stable angina in 949 diabetes patients already receiving one or two anti-anginal drugs and led to less use of sublingual nitroglycerin, and the benefits appeared more prominent in patients with higher rather than lower HbA1c levels. These results suggest that this drug can be added to other well-established anti-anginal drugs, in particular in patients with higher HbA1c levels, who may also more often rely on medical management.
Ranolazine plasma levels increase with cytochrome P3A (CYP3A) inhibitors (diltiazem, verapamil, macrolide antibiotics, grapefruit juice). Ranolazine clearance is reduced by renal and hepatic impairment. Ranolazine increases QTc, and should therefore be used carefully in patients with QT prolongation or on QT-prolonging drugs.
7.1.3.3.8 Allopurinol: Allopurinol, an inhibitor of xanthine oxidase that reduces uric acid in persons with gout, is also anti-anginal. There is limited clinical evidence but, in a randomized crossover study of 65 patients with SCAD, allopurinol 600 mg/day increased times to ST-segment depression and to chest pain. In renal impairment, such high doses may have toxic side-effects. In optimally treated SCAD patients, allopurinol reduced vascular oxidative stress, while in heart failure patients it conserved ATP.
7.1.3.3.9 Molsidomine: This direct NO donor has anti-ischaemic effects similar to those of isosorbide dinitrate. The long-acting once-daily 16 mg formulation is as effective as 8 mg twice daily.
7.1.3.4 Patients With Low Blood Pressure: Anti-anginal drugs should be started at very low doses, with preferential use of drugs with no- or limited impact on BP, such as ivabradine (in patients with sinus rhythm), ranolazine or trimetazidine.
7.1.3.5 Patients With Low Heart Rate:Several studies have shown that increased resting heart rate is a strong independent risk factor for adverse outcome in patients with SCAD. There is a linear relationship between resting heart rate and major cardiovascular events, with a persistent decrease in CV risk with lower heart rate. A clinical benefit has been demonstrated of heart rate reduction using various drugs. Although lowering the heart rate <60 b.p.m. is an important goal in the treatment of SCAD, patients presenting with low heart rate should be treated differently. Heart rate lowering drugs (β-blockers, ivabradine, heart rate lowering CCBs) should be avoided or used with caution and, if needed, started at very low doses. Anti-anginal drugs without heart lowering effects should preferably be given.
7.2 Event Prevention
7.2.1 Antiplatelet Agents. Antiplatelet agents decrease platelet aggregation and may prevent formation of coronary thrombus. Due to a favourable ratio between benefit and risk in patients with stable CAD and its low cost, low-dose aspirin is the drug of choice in most cases and clopidogrel may be considered for some patients. The use of antiplatelet agents is associated with a higher bleeding risk.
7.2.1.1 Low-dose Aspirin: Aspirin remains the cornerstone of pharmacological prevention of arterial thrombosis. It acts via irreversible inhibition of platelet cyclooxygenase-1 (COX-1) and thus thromboxane production, which is normally complete with chronic dosing ≥75 mg/day. Contrary to the antiplatelet effects, the gastrointestinal side-effects of aspirin increase at higher doses. The optimal risk–benefit ratio appears to be achieved with an aspirin dosage of 75–150 mg/day.
7.2.1.2 P2Y12 Inhibitors: P2Y12 inhibitors, including thienopyridines, act as antagonists of the platelet adenosine diphosphate (ADP) receptor P2Y12, thereby inhibiting platelet aggregation. The major study supporting the use of thienopyridine in stable coronary patients is the Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, which showed an overall benefit of clopidogrel as compared with aspirin (with also a favourable safety profile) in preventing CV events in three categories of patients with previous MI, previous stroke or peripheral vascular disease (PVD). The clopidogrel benefit was driven by the peripheral vascular disease (PVD) sub-group and the dose of aspirin with which it was compared (325 mg/day) may not be the safest dose. Clopidogrel should thus be proposed as a second-line treatment, especially for aspirin-intolerant CVD patients. Prasugrel and ticagrelor are new P2Y12 antagonists that achieve greater platelet inhibition, compared with clopidogrel. Prasugrel and ticagrelor are both associated with a significant reduction of CV outcomes as compared with clopidogrel in ACS patients, but no clinical studies have evaluated the benefit of these drugs in SCAD patients. After unstable angina or myocardial infarction without ST-segment elevation when patients are stabilized and medically managed, there are no data supporting a beneficial effect of intensified platelet inhibition.
7.2.1.3 Combination of Antiplatelet Agents: Dual antiplatelet therapy combining aspirin and a thienopyridine is the standard of care for patients with ACS, including after the acute phase, when the patients are stabilized, or in SCAD patients who have undergone elective PCI. However, in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study, Dual antiplatelet therapy did not confer benefit in patients with stable vascular disease or at risk of atherothrombotic events, although a significant benefit was observed in a post-hoc analysis of patients with documented atherothrombotic disease, and in particular in coronary patients with a prior history of MI. Combined antiplatelet therapy was also recently tested with an antagonist of protease activated receptor type 1 (PAR-1). The primary efficacy endpoint—a composite of CV death, MI or stroke—was significantly reduced with vorapaxar in addition to standard antiplatelet therapy in patients with stable atherosclerosis, and this benefit was particularly evident in the post-MI group of patients. However, it increased the risk of moderate or severe bleeding, including intracranial haemorrhage. Altogether, on the basis of these post-hoc analyses, combined antiplatelet therapy may be beneficial only in selected patients at high risk of ischaemic events, but cannot be recommended systematically in SCAD patients.
7.2.1.4 Poor Response to Antiplatelet Agents: There is a wide variation in response to antiplatelet therapy and a great interest has recently emerged in the use of functional and/or genetic assays to guide such treatment. High platelet reactivity on aspirin and/or clopidogrel treatment results from multiple factors, including non-compliance, accelerated platelet turnover, drug interactions, patient characteristics (such as age, gender, diabetes) and single nucleotide polymorphisms [cytochrome P450 2C19 (CYP2C19*2), ATP-binding cassette sub-family B member 1(ABCB1) for clopidogrel). The influence of genetic variants on the response to antiplatelet agents, especially clopidogrel, has been well established in patients with ACS and planned PCI, but not in patients with stable CAD. However, there is currently no recommendation to perform genetic testing in patients with stable CAD. Platelet function testing in SCAD patients undergoing PCI is not recommended as a routine (see chapter 8).
7.2.2 Lipid-lowering Agents (See Lipid Management, Above). Patients with documented CAD are regarded as being at very high risk and should be treated with statins, in line with recommendations in the ESC/European Atherosclerosis Society Guidelines for the management of dyslipidaemia. The treatment target is LDL-C <1.8 mmol/L and/or >50% reduction if the target level cannot be reached.
7.2.3 Renin-angiotensin-aldosterone System Blockers. Angiotensin converting enzyme inhibitors reduce total mortality, MI, stroke and heart failure among specific subgroups of patients, including those with heart failure, previous vascular disease alone, or high-risk diabetes. Hence, it is appropriate to consider ACE inhibitors for the treatment of patients with SCAD, especially with co-existing hypertension, LVEF ≤40%, diabetes or CKD, unless contra-indicated.
However, not all clinical trials have demonstrated that the ACE inhibitors reduce all-cause mortality, CV mortality, non-fatal MI, stroke and heart failure in patients with atherosclerosis and preserved LV function. In SCAD patients with hypertension, a combination therapy consisting of an ACE inhibitor and a DHP CCB, such as perindopril/amlodipine in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trial and benazepril/amlodipine in the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, is preferred. In contrast, adding an angiotensin II receptor antagonist (ARB) to an ACE inhibitor was associated with more adverse events, without an increase in benefit.
Hence, ARB treatment may be an alternative therapy for patients with SCAD when ACE inhibition is indicated but not tolerated. There are, however, no clinical outcome studies showing a beneficial effect of ARB in SCAD.
Aldosterone blockade with spironolactone or eplerenone is recommended for use in post-MI patients without significant renal dysfunction or hyperkalaemia, who are already receiving therapeutic doses of an ACE inhibitor and a β-blocker, have an LVEF ≤40% and have either diabetes or heart failure.
7.3 Other Drugs
7.3.1 Analgesics. The use of selective cyclooxygenase-2 (COX-2) inhibitors and traditional non-selective non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased risk for CV events in recent clinical trials in arthritis and cancer prevention and are not recommended. In patients at increased CV risk in need of pain relief, it is therefore recommended to commence with acetaminophen or aspirin at the lowest efficacious dose, especially for short-term needs.
If adequate pain relief requires the use of NSAIDs, these agents should be used in the lowest effective doses and for the shortest possible duration. In patients with atherosclerotic vascular disease—and in SCAD in particular—NSAID treatment should, when this is indicated for other reasons, be combined with low-dose aspirin to ensure effective platelet inhibition.
7.4 Strategy
Figure 4 summarizes the medical management of SCAD patients. This common strategy might be adjusted according to patient comorbidities, contra-indications, personal preference and drug costs. The medical management consists of a combination of at least a drug for angina relief plus drugs to improve prognosis, as well as use of sublingual nitroglycerin for chest pain management. It is recommended that either a β-blocker or a CCB to a short-acting nitrate be added as first-line treatment to control heart rate and symptoms. If the symptoms are not controlled, it is advised to switch to the other option (CCB or β-blocker) or to combine a β-blocker and a DHP CCB. The combination of a heart-lowering CCB with a β-blocker is not advised. Other anti-anginal drugs might be used as a second-line treatment when symptoms are not satisfactorily controlled. In selected patients with intolerance or contra-indications to both β-blockers and CCBs, second-line drugs can be used as a first-line treatment. The event prevention is optimally achieved by the prescription of antiplatelet agents and statins. In selected patients, the use of ACE inhibitors or ARBs can be considered.
(Enlarge Image)
Figure 4.
Medical management of patients with stable coronary artery disease. ACEI = angiotensin converting enzyme inhibitor; CABG = coronary artery bypass graft; CCB = calcium channel blockers; CCS = Canadian Cardiovascular Society; DHP = dihydropyridine; PCI = percutaneous coronary intervention.
Data for diabetics.
if intolerance, consider clopidogrel
7.5 Treatment of Particular Forms of SCAD
7.5.1 Microvascular Angina. All patients with microvascular angina should achieve optimal coronary risk factor control. Symptomatic treatment is empirical because of the limited knowledge of its causes. Furthermore, the results of available therapeutic trials cannot be accepted as conclusive because of variable patient selection, small sample size, inadequate design and lack of demonstration of clinical improvement of microvascular disease.
Traditional anti-ischaemic drugs are the first step in medical treatment. Short-acting nitrates can be used to treat anginal attacks, but often they are only partially effective. β-Blockers seem a rational approach because the dominant symptom is effort-related angina; they were indeed found to improve symptoms in several studies and should constitute the first choice of therapy, particularly in patients with evidence of increased adrenergic activity (e.g. high heart rate at rest or during low-workload exercise).
Calcium antagonists and long-acting nitrates have shown variable results in clinical trials and are more helpful when used in addition to β-blockers in the case of insufficient control of symptoms. Calcium antagonist, however, can be first-line therapy in patients with a significant variable threshold of effort angina. In patients with persisting symptoms despite optimal anti-ischaemic drug therapy, several other treatments have been proposed. ACE inhibitors (and possibly ARBs) may improve microvascular function by counteracting the vasoconstrictor effects of angiotensin II; they have improved symptoms and exercise results in small trials and can be helpful, particularly in patients with hypertension or diabetes mellitus. α-Adrenergic antagonists may decrease sympathetic-mediated vasoconstriction and may be considered in individual patients, although clinical benefits have usually been disappointing. Improvement of exercise capacity has been observed in a small trial with nicorandil. Improvement of anginal symptoms, probably mediated primarily by improvement of endothelial function, has been reported with statins and with oestrogen replacement treatment. In patients with angina refractory to various combinations of the previous medications, other forms of treatment can be proposed. Xanthine derivatives (aminophylline, bamiphylline) can be added to anti-ischaemic treatment to reduce angina by adenosine receptor blockade; adenosine is indeed a major mediator of cardiac ischaemic pain (see Table 29). New anti-ischaemic drugs such as ranolazine or ivabradine have shown good effects in some patients with microvascular angina. Finally, in case of refractory angina, additional interventions may be discussed (see section 9 on refractory angina).
In patients with microvascular angina, the susceptibility of symptoms to medical treatment is extremely variable and experimentation of different drug combinations, is needed before establishing satisfactory symptom control.
7.5.2 Treatment of Vasospastic Angina. All patients with vasospastic angina should achieve optimal coronary risk factor control, in particular through smoking cessation and aspirin. A drug-related cause (e.g. cocaine or amphetamines) should be systemically researched and managed if detected. Chronic preventive treatment of vasospastic angina is mainly based on the use of CCBs. Average doses of these drugs (240–360 mg/day of verapamil or diltiazem, 40–60 mg/day of nifedipine) usually prevent spasm in about 90% of patients. Long-acting nitrates can be added in some patients to improve the efficacy of treatment and should be scheduled to cover the period of the day in which ischaemic episodes most frequently occur, in order to prevent nitrate tolerance. β-Blockers should be avoided, as they might favour spasm by leaving α-mediated vasoconstriction unopposed by β-mediated vasodilation.
In about 10% of cases, coronary artery spasm is refractory to standard vasodilator therapy, although refractoriness is usually limited to brief periods in most patients. Very high doses of calcium antagonists and nitrates usually prevent transient ischaemic episodes in these critical periods. In the very rare patients in whom even this treatment is insufficient, the addition of anti-adrenergic drugs like guanethidine or clonidine might be helpful. PCI with stent implantation at the site of spasm (even in the absence of significant stenosis), as well as chemical or surgical sympathectomy, have also been reported but are not recommended. Because of the high prevalence of silent ischaemic episodes and possible arrhythmias, 24-hour ambulatory ECG monitoring can be used to verify the treatment efficiency.
Implantation of an automatic cardioverter defibrillator or of a pacemaker is indicated in patients with ischaemia-related life-threatening tachyarrhythmias or bradyarrhythmias, respectively, when coronary spasm presents a poor or uncertain response to medical therapy.
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