Chronic ischaemic heart disease in the elderly

Med Clin (Barc). 2016;146(8):372.e1–372.e10

www.elsevier.es/medicinaclinica

Consensus statement

Chronic ischaemic heart disease in the elderly夽,夽夽 Manuel Martínez-Sellés a,∗ , Ricardo Gómez Huelgas b , Emad Abu-Assi c , Alberto Calderón d , María Teresa Vidán e a Sociedad Espa˜ nola de Cardiología (SEC), Sección de Cardiología Geriátrica, Servicio de Cardiología, Hospital General Universitario Gregorio Mara˜ nón, Universidad Europea y Universidad Complutense, Madrid, Spain b Sociedad Espa˜ nola de Medicina Interna (SEMI), Departamento de Medicina Interna, Hospital Universitario Regional de Málaga, Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud (FIMABIS), Málaga, Spain c Sociedad Espa˜ nola de Cardiología (SEC), Sección de Cardiopatía Isquémica y Cuidados Agudos Cardiovasculares, Servicio de Cardiología y Unidad Coronaria, Hospital Clínico na, Spain Universitario de Santiago de Compostela, Santiago de Compostela, A Coru˜ d Sociedad Espa˜ nola de Médicos de Atención Primaria (SEMERGEN), Centro de Salud Rosa Luxemburgo, San Sebastián de los Reyes, Madrid, Spain e Sociedad Espa˜ nola de Geriatría y Gerontología (SEGG), Servicio de Geriatría, Hospital General Universitario Gregorio Mara˜ nón, Universidad Complutense, Madrid, Spain

a r t i c l e

i n f o

Article history: Received 20 November 2015 Accepted 21 January 2016 Available online 20 June 2016 Keywords: Ischaemic heart disease Elderly Comorbidity

a b s t r a c t It is the aim of this manuscript to take into account the peculiarities and specific characteristics of elderly patients with chronic ischaemic heart disease from a multidisciplinary perspective, with the participation of the Spanish Society of Cardiology (sections of Geriatric Cardiology and Ischaemic Heart Disease/Acute Cardiovascular Care), the Spanish Society of Internal Medicine, the Spanish Society of Primary Care Physicians and the Spanish Society of Geriatrics and Gerontology. This consensus document shows that in order to adequately address these elderly patients a comprehensive assessment is needed, which includes comorbidity, frailty, functional status, polypharmacy and drug interactions. We conclude that in most patients medical treatment is the best option and that this treatment must take into account the above factors and the biological changes associated with ageing. ˜ S.L.U. All rights reserved. © 2016 Elsevier Espana,

Cardiopatía isquémica crónica en el anciano r e s u m e n Palabras clave: Cardiopatía isquémica Anciano Comorbilidad

Este artículo pretende tener en cuenta las peculiaridades y características específicas de los pacientes ancianos con cardiopatía isquémica crónica desde una perspectiva multidisciplinar, con la partici˜ pación de la Sociedad Espanola de Cardiología (secciones de Cardiología Geriátrica y Cardiopatía ˜ Isquémica/Cuidados Agudos Cardiovasculares), la Sociedad Espanola de Medicina Interna, la Sociedad ˜ ˜ Espanola de Médicos de Atención Primaria y la Sociedad Espanola de Geriatría y Gerontología. En este documento de consenso se detalla cómo el abordaje de estos enfermos de edad avanzada exige una valoración integral de la comorbilidad, la fragilidad, el estado funcional, la polifarmacia y las interacciones medicamentosas. Concluimos que en la mayoría de los pacientes el tratamiento médico es la mejor opción y que, a la hora de programarlo, se deben tener en cuenta los factores anteriores y las alteraciones biológicas asociadas al envejecimiento. ˜ S.L.U. Todos los derechos reservados. © 2016 Elsevier Espana,

Rationale 夽 Please cite this article as: Martínez-Sellés M, Gómez Huelgas R, Abu-Assi E, Calderón A, Vidán MT. Cardiopatía isquémica crónica en el anciano. Med Clin (Barc). 2016;146:372.e1–372.e10 夽夽 Consensus document of the Spanish Society of Cardiology (Geriatric Cardiology and Ischaemic Heart/Cardiovascular Acute Care sections), the Spanish Society of Internal Medicine, the Spanish Society of Primary Care Physicians and the Spanish Society of Geriatrics and Gerontology. ∗ Corresponding author. E-mail address: [email protected] (M. Martínez-Sellés). ˜ S.L.U. All rights reserved. 2387-0206/© 2016 Elsevier Espana,

Decision making regarding diagnosis, treatment and care of elderly patients with chronic ischaemic heart disease should combine the influence of heterogeneity among the elderly, the coexistence of multiple comorbidities, frequent in this population, and the polypharmacy associated with it, the functional status in daily life and the biological differences associated with ageing.1 Non-specific symptoms are often found in the elderly such as

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dizziness, fatigue and others that can interfere the with symptoms of ischaemic heart disease and make the differential diagnosis difficult. To all of these, we must add the fact that the care and treatment based on evidence, recommended to us by clinical guidelines, have been established from clinical trials in which the elderly are underrepresented. Because of these, decision-making throughout the whole process requires the completion of a patient-centred plan that also incorporates their wishes and expectations. In this context, the priority may be to maintain patient independence, improve their quality of life and prevent hospital admissions, rather than prolong survival. The good clinical practice guidelines are a good help for doctors facing an up-to-date approach of different diseases. In the last 2 years, a new European Society of Cardiology2 guide and an update of the American Heart Association3 guide have been published in the field of stable ischaemic heart disease. These recommendations emphasize those subgroups that stand out due to their prevalence, impact and specific characteristics. As a result of the progressive ageing of the population, and the advances in the treatment of acute coronary syndrome,4 the number of elderly patients with stable ischaemic heart disease has increased. While the guidelines establish specific recommendations for elderly patients, only one5 out of the 7 major clinical trials comparing revascularization with medical treatment was performed in a population over 75 years of age. In the other 6 trials, the inclusion of subjects over 65 years did not exceed 30%. This lack of data is disturbing, given the specific and peculiar characteristics of this population. The mortality associated with chronic ischaemic heart disease increases with age.6 The development of heart failure7 and the presentation of complications after percutaneous and surgical coronary interventions is more frequent in the elderly.8 In addition, asymptomatic and/or atypical presentations are more common in those over 75 years of age9 and some diagnostic tests may be more complex to perform or have a lower diagnostic yield.10,11 Also the percentage of patients who comply with medical treatment decreases significantly with age,12 not exceeding 33 and 50% before and after revascularization, respectively.13 On the other hand, in the elderly population, the response to aspirin is decreased,14 the efficacy of statins is lower,15 adverse effects are more frequent16 and betablockers are prescribed less frequently and are associated with higher discontinuation,17 and with a worse heart rate control.18,19 The underuse of aspirin and renin-angiotensin system inhibitors has also been documented, more significantly in those over 80 years of age.20 Methodology, receivers, objective and recommendations Prior to the writing of this manuscript, during the months of June to October 2015 interactive searches were conducted in the MEDLINE® database to find the articles related to the care of the elderly with chronic ischaemic heart disease. Search terms included “angina pectoris”, “stable coronary artery disease”, “risk factors”, “anti-ischaemic drugs”, “coronary revascularization”, “elderly”, “chronic ischaemic heart disease”, “comorbidity”, “frailty”, “functional status”, “polypharmacy”, “drug interactions” and “aging”. No specific keywords required as inclusion criteria were used. Reference lists of each article were reviewed in detail to find additional articles. Those studies specifically conducted in the elderly or that provided a subgroup analysis in elderly patients were selected. This consensus document is intended for all healthcare professionals who are involved in caring for elderly patients with chronic ischaemic heart disease. It aims to provide clear guidelines for diagnosis and treatment that take into account the specific characteristics of this population from a multidisciplinary perspective, enabling a comprehensive assessment of elderly patients. Specifically, this manuscript is focused on subjects over 80 years of

age or over 75 years with comorbidity and/or frailty. Future possible updates of this document would be conducted by experts appointed by the scientific societies involved. The recommendations in this document are based on previous scientific evidence, specific for the elderly, regarding measures that improve their survival, symptom control and/or quality of life, taking into account the side effects and risks of the various measures. The fact that all medical societies engaged in the care of these patients are involved in the preparation of this manuscript will facilitate its dissemination, implementation and monitoring, integrating the new evidence. Our recommendation is that this is always done from a multidisciplinary perspective, because otherwise the global approach required by these patients would be lost. For these recommendations to be put into practice close contact between all professionals who diagnose and treat these patients is essential. Epidemiology Chronic ischaemic heart disease encompasses a variety of clinical conditions including stable angina, asymptomatic patients after an acute coronary syndrome, vasospastic angina and microvascular angina. Consequently, its prevalence depends on the highly variable selection criteria used in different studies. As regards symptomatic patients, the Fibrillation and Coronary Heart Disease Observation study has recently been published in Spain (OFRECE),21 which included 8378 individuals and whose objective was to calculate the prevalence of angina among the Spanish general population using the Rose questionnaire as the classification variable. The adjusted prevalence in the overall population was 2.6%, increasing to 7.1% for the population aged 70–79 years. However, in the population aged 80 or older, the prevalence decreased to 5.6%, which could be explained in part by the increased mortality from cardiovascular disease in this population. If the results are compared with 2 previous studies conducted in Spain,22,23 a reduction is observed in the prevalence (7.6 and 3.5% compared to 2.6% of the OFRECE study), which can be explained by the different selection criteria. These data are somewhat lower than those published by the USA Institute of Health, which estimated an angina prevalence of 12–14% in men and 10–12% in women in the 65–84-year-old population.24 Regarding the prevalence of angina among patients with chronic ischaemic heart disease, the most relevant data come from the multinational Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease – CLARIFY –25 European study conducted in 32,724 patients. While there are notable differences between regions, the overall prevalence of angina was 22%, equal to that of the Spanish cohort.26 If we focus on the incidence of angina rather than in its prevalence, the rate goes from 1% per year in the population under 65 years of age up to 4% in the age range of 75–84 years.24 With regard to the incidence of angina as initial symptom, recent data show a reduction in the age range of 70–79 years and those over 80 years versus those under 70 years.27 Finally, with regard to mortality in stable angina, it is highly variable depending on the clinical, functional and anatomical characteristics, ranging from 1.2 to 2.4% per year.28 In general, poor prognostic factors are more common in the population over 65 years of age, therefore, these mortality rates are probably higher in this population group. Diagnosis Clinical and lab test history Coronary heart disease can be difficult to diagnose in the elderly. The clinical presentation is often atypical or manifests as

M. Martínez-Sellés et al. / Med Clin (Barc). 2016;146(8):372.e1–372.e10 Table 1 Severity classification of angina as per Canadian Cardiovascular Society. Class I Class II

Class III

Class IV

No limitation of normal life. Angina only appears when strenuous, rapid or prolonged exertion Slight limitation of physical activity. Angina occurs when walking fast or climbing stairs or slopes, after meals, in cold temperatures, emotional stress, or only during the first hours after waking up Can walk more than one or 2 blocks or climb a flight of stairs Significant limitation of physical activity. Angina occurs when walking one or two blocks on ground level (100–200 m) or climbing a flight of stairs at normal speed and under normal conditions Inability to perform any activity without angina. This may occur at rest

“anginal equivalents” (shortness of breath, back pain, back or shoulder pain, fatigue, tiredness, dizziness, epigastric discomfort) and a high percentage of patients are unable to engage in a level of effort that is compatible with an exercise test. In addition, the high proportion of elderly patients with silent ischaemia should be noted. The case history should be precise, assessing the probability of coronary disease considering the cardiovascular risk profile and referred symptomatology. The Canadian Cardiovascular Society29 system helps to classify the severity of angina and the degree of functional impairment of the patient (Table 1). As a reminder, in all cases of elderly patients with ischaemic heart disease we should ask: -

Number of episodes of angina per week. Use of sublingual nitrates per week. Circumstances and/or activities that trigger angina attacks. Activities no longer performed for this reason (such as getting dressed, walking, climbing a slope, etc.). - Adherence to treatment and recent medication changes that might relate to changes in symptoms.

Physical examination can detect other associated conditions such as valvular heart disease, peripheral and/or central arterial disease, which would help to establish both diagnosis and prognosis. Before performing any tests, the general condition, the presence of comorbidities and quality of life of the patient should be evaluated. If the preliminary assessment indicates that revascularization would not be an acceptable option, further testing should be avoided and, even without establishing a definitive diagnosis, an anti-anginal therapy should be tried.30 With regard to laboratory tests, the following should be performed in the initial assessment: complete blood count (always check the haemoglobin), basic biochemical (serum creatinine and glomerular filtration, ion and lipid profile) and determination of plasma glucose and glycosylated haemoglobin, and, if there is suspicion of thyroid condition, a thyroid hormone test. Liver function tests can also be performed as soon as a statin treatment is started. Most patients should undergo an annual lipid profile, renal function and blood sugar re-evaluation so as to determine the efficacy of the treatment and the occurrence of diabetes mellitus.2 ECG, chest radiography and echocardiography 12-lead ECG should be performed in all patients at the initial visit and in the presence of chest pain. The presence of old necrosis Q waves or repolarization abnormalities indicative of ischaemia would reflect basal coronary disease and support the diagnosis. Repolarization abnormalities without accompanying chest pain are not diagnostic of angina.31 ECG-Holter may be indicated in the case of suspected arrhythmias, or vasospastic angina. The (relatively frequent) presence of arrhythmias or conduction disorders help with

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Table 2 Considerations before requesting a diagnostic test in an elderly patient with chronic ischaemic heart disease. 1. How will the result be used? a. Establishing the diagnosis Is there any effective treatment? Does the patient comorbidity and functionality allow treatment? Does the patient accept such treatment? b. Establishing the prognosis Does the patient want to know? 2. What is the accuracy of the test in this patient? 3. Do the potential consequences of the test justify its cost and inconvenience?

treatment and prognostic stratification.2 Chest radiography should be performed in patients with suspected heart failure, aortic disease and any chest pain under study. It is also indicated if concomitant lung disease is suspected, something very common in the elderly. An echocardiography should be performed in all patients with suspected or confirmed myocardial ischaemia if data on heart failure, previous myocardial infarction, hypertrophic cardiomyopathy or other data of structural heart disease concur. Tests for myocardial ischaemia Before requesting a screening test or invasive test for ischaemia in an elderly patient, the clinician should know how to evaluate and how to interpret and use the results of this evaluation (Table 2). Therefore, we must ask ourselves how we will use the results of the test and whether the actions we take as a result of the findings can help improve the prognosis or quality of life of patients.32 Given the above premises, the elderly patient with symptoms suggestive of coronary disease should be evaluated as the younger one, following risk evaluation algorithms of coronary obstruction and thus obtaining a pre-test probability that will guide us in performing subsequent tests. However, it is important to know that the predictive value of a test is greatly influenced by the prevalence of the disease in this population. For example, we may mistakenly interpret that a negative stress test on an elderly woman at high risk (80% pre-test probability) rules out coronary heart disease, while the post-test probability is 60%. For this reason, these patients with high pre-test probability should be referred for a coronary angiography directly, provided that its implementation does not involve greater risks and revascularization is an option in that particular patient. The stress test can be considered the initial test in suspected myocardial ischaemia. Exercise protocols in the elderly may require treadmill speed and inclination modifications. The presence of arthropathy, anxiety or balance disorders, as well as baseline ECG abnormalities, reduce this test’s efficiency. The sensitivity reaches 84% (compared to 45–50% in younger subjects) due to the increased prevalence of coronary heart disease, but with a lower specificity (∼70% compared to 85–90% in younger patients) due to false positives potentiated by left ventricular hypertrophy and intraventricular conduction disorders. A decline in the ST segment during the test in the absence of accompanying symptoms does not establish per se a definitive diagnosis and requires other diagnostic criteria or other tests.33 The workload achieved is the strongest predictor related to prognosis in the elderly, while chronotropic incompetence during exercise has been linked to both, diagnosis and prognosis.3,4 The occurrence of arrhythmias during exercise tests is more common in the elderly and does not condition per se a worse prognosis.33,34 Stress echocardiography or perfusion study with single-photon emission computed tomography are a valid alternative when a simple stress test is not possible (orthopaedic limitations, intermittent claudication, maladjustment, etc.), not analysable (bundle branch block, ST depression ≥1 mm, pacemaker

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rhythm), or when the treadmill exercise testing is inconclusive. This test has a 90% sensitivity and an 80% specificity.34 Induction of left ventricular dilatation or reducing left ventricular ejection fraction during exercise indicate poor prognosis.35 Pharmacological stress imaging is indicated in patients unable to adequately perform an exercise. The efficiency of these tests is similar to the exercise imaging tests. The drugs used are often dipyridamole, adenosine or dobutamine. Multislice computed tomography and coronary angiography Elderly people have a high prevalence of coronary heart disease and coronary calcifications, so multislice CT is less useful in these patients. Its use would be probably justified in those cases where invasive coronary angiography wants to be avoided in elderly patients. The prognostic value of coronary disease detected by multislice CT is different in the elderly.36 Before performing a coronary angiography in an elderly patient with stable ischaemic heart disease, we would need to consider what to do in case of observing a severe coronary lesion. Will we be able to discern if the said lesion is the cause of the patient’s condition? If it will be susceptible to revascularization? If the patient’s comorbidity will make the test too risky or if the treatment (e.g. placement of a stent) could result in more risks than benefits (e.g. prolonged dual antiplatelet therapy in a patient with a significant bleeding risk). The diagnostic test may be unnecessary if the patient is not interested in treatment, or if this can result in more risks than benefits. Coronary angiography is indicated only for diagnostic purposes when facing a chest pain of uncertain origin with non-invasive, inconclusive testing or when facing severe angina with suspected trunk or 3-vessel disease. It is also justified when a non-invasive test indicates extensive ischaemia in patients with early recurrence of angina after revascularization or in the presence of severe complications such as cardiac arrest, complex arrhythmias or heart failure. Treatment Lifestyle modification Efforts in secondary prevention have to be established according to the life expectancy of the elderly patient. Smoking cessation, increased physical activity, limiting salt intake, the Mediterranean diet, moderation in alcohol consumption and weight control are measures that are more likely to confer an immediate benefit and help control anginal symptoms.37 Light exercise is recommended, depending on the physical condition of the person, including cardiac rehabilitation in patients with heart failure or previous infarction. Exercise helps control cardiovascular risk factors, improving exercise tolerance and myocardial ischaemia itself, it has positive psychological effects and reduces hospitalization and post infarction mortality.2 Heart rate and blood pressure control is useful to reduce angina attacks. Anaemia, hyperthyroidism or infections can be triggers of angina in elderly patients with ischaemic heart disease, so their study, detection and treatment is recommended.

(75–100 mg) is indicated in all cases, provided that the bleeding risk is not high.2 Clopidogrel can be used in patients with intolerance/contraindication to aspirin. Dual antiplatelet therapy is indicated in the first 6–12 months after stent implantation or history of an acute coronary syndrome. The use of antiplatelet drugs concomitantly with an anticoagulant should be individualized, considering the ischaemic and haemorrhagic risk, and the absence of solid scientific evidence. Current clinical guidelines consider that the elderly benefit from lipid-lowering treatments to reduce cardiovascular morbidity and mortality, although they note that the evidence is insufficient for subjects over 80 years of age and that clinical judgement should guide decisions in the very elderly.2 Overall, statin use is not indicated in patients over 80 years of age with severe comorbidity or life expectancy shorter than three years, moderate to severe dementia or significant functional impairment.37 The need for a prolonged period of time in order to obtain benefits with statins casts doubt on their usefulness in patients with a shorter life expectancy. There is no difference in the LDL-C target between the elderly and the younger population (<70 mg/dl). With regard to anti-anginal therapy, short-acting nitrates, in sublingual form, remain the basic treatment for angina attacks. The elderly must be trained regarding their proper use. The use of long-acting nitrates as patches must be accompanied by the recommendation of its withdrawal for a few hours a day to avoid tolerance. There are no specific recommendations on the use of beta-blockers as anti-anginal agents in the elderly. The aim is to achieve a resting heart rate <60 bpm and to reduce tachycardia during exercise. As an alternative to beta blockers, calcium channel blockers, diltiazem or verapamil are used, reserving the dihydropyridine agents as an adjuvant to beta-blockers when an adequate control of angina is not achieved. Ivabradine is a safe drug in elderly patients and is especially useful when beta-blockers are contraindicated, not tolerated or appear insufficient to control symptoms or heart rate, provided that the patient is in sinus rhythm.2 Ranolazine in patients older than 70 years has been associated with more side effects compared to the younger population, although not in a significant way.2 Trimetazidine added to atenolol can improve the threshold until the onset of myocardial ischaemia, but is contraindicated in Parkinson’s disease and movement disorders, which are more common in the elderly. Coronary revascularization There is still controversy about the usefulness of coronary revascularization in stable angina. As in the overall population of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation–COURAGE–study, there was no benefit with revascularization in the pre-established over 65s subgroup.38 In the elderly, consideration of whether to perform a coronary revascularization or not should be taken with caution as intervention and surgery in the elderly carry higher rates of complications. The decision made should aim at not worsening the prognosis or quality of life and, at the same time not deprive the elderly of effective treatment. Comorbidity

Pharmacotherapy Adherence to treatment is usually lower in the elderly. The therapeutic objectives in elderly patients with chronic ischaemic heart disease involve relieving symptoms and reducing the risk of future cardiovascular events, slowing the progression of the disease. Although there are no studies specifically designed for the use of antiplatelet drugs in elderly patients, there is a general consensus on a similar efficacy in preventing cardiovascular events regardless of age. Antiplatelet therapy with aspirin at low doses

Elderly patients with chronic ischaemic heart disease often present with multiple diseases, frailty or geriatric syndromes that limit the therapeutic possibilities and worsen the prognosis.39 More than 50% present with frailty criteria and its occurrence increases mortality 2–4 times.40 Cognitive impairment is also common,41 which can hinder treatment adherence. Depression affects 50% and carries a worse prognosis.42 Hypertension affects most, with orthostatic or postprandial hypertension, masked hypertension and pseudohypertension

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being very frequent.43 Control of hypertension should be considered a priority, given the existing evidence on reducing morbidity and mortality even in very elderly patients.44 Although current guidelines in elderly patients recommend a blood pressure target <150/90 mmHg, or <140/90 mmHg, those very elderly or frail subjects with diabetes or chronic kidney disease will be carefully assessed for tolerance to antihypertensive treatment, and a systolic blood pressure target <160 mmHg5 may be acceptable. In fact, in patients with ischaemic heart disease, some studies warn of the possible existence of a J-curve phenomenon, an increase in coronary events with excessive decreases in blood pressure.45 The results of the International Verapamil SR-Trandolapril Study – INVEST – reinforce the recommendation to avoid a systolic blood pressure <120 mmHg.46 It also seems reasonable to avoid diastolic blood pressures <60 mmHg in elderly patients with coronary artery disease.47 In Spain, the prevalence of diabetes in those over 70 exceeds 30%.48 In the presence of ischaemic heart disease, the prevalence may be even higher.49 Strict glycaemic control in patients with chronic ischaemic heart disease may be associated with increased mortality50 in relation to hypoglycaemia, so current clinical practice guidelines recommend more conservative goals (glycated haemoglobin <8%) in this population51 ; in frail elderly a glycated haemoglobin target <8.5%52 may be reasonable. Kidney failure is also common in the elderly and is a key factor when planning treatment.53 In Spain, heart failure affects 16% of those over 75 years.54 Although the characteristic pattern of cardiac failure associated with ischaemic heart disease is that of depressed left ventricular systolic function, a pattern with preserved systolic function predominates in the elderly (especially in women with hypertension).55 Atrial fibrillation affects 17.7% of the Spanish population over 80 years.56 Elderly patients with atrial fibrillation have a high embolic risk, so they are anticoagulant therapy candidates. Cardiovascular disease is the leading cause of death in patients with chronic obstructive pulmonary disease,57 which worsens the prognosis of ischaemic heart disease.58,59 The use of cardioselective ␤1 beta-blockers (bisoprolol, metoprolol) in these patients is generally safe and have been associated with fewer relapses and lower mortality in observational studies,60 despite that, they are clearly underused.61 On the other hand, the use of respiratory drugs (anticholinergics, long-acting beta2 and inhaled corticosteroid) is safe for heart patients.59

Side effects The elderly are at increased risk of adverse drug effects because they have altered pharmacokinetics and pharmacodynamics typical of ageing, also because of the aforementioned comorbidities (especially hepatic and renal impairment or dementia) and frequent polypharmacy. Tables 3 and 4 list the adverse effects and contraindications of the main drugs used in patients with ischaemic heart disease. Beta-blockers should be used with caution in the elderly due to the increased risk of adverse effects, especially bradycardia and atrioventricular blocks. Atenolol should be avoided if renal failure. Non-dihydropyridine calcium antagonists have a negative inotropic and chronotropic effect, so they should be avoided in patients with systolic dysfunction or conduction disorders. Dihydropyridine agents can be used in patients with angina and hypertension. The adverse effects of nitrates, related to vasodilatation, may limit their use in the elderly and reduce their adherence.62 Ranolazine is generally well tolerated in the elderly, as it lacks haemodynamic effects,63 but it should be used with caution due to the higher incidence of adverse reactions and frequent drug interactions. Its dosage should be adjusted in case of renal failure, and is contraindicated with a glomerular filtration

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rate <30 ml/min/1.73 m2 , as well as in the presence of moderate to severe liver failure. Ivabradine is a particularly well-tolerated drug in the elderly, but should be administered at low doses to prevent symptomatic bradycardia. It is not recommended in cases of severe renal or hepatic failure. Because of its metabolic action, free of haemodynamic effects, trimetazidine is usually well tolerated in the elderly,64 but the occurrence of drug parkinsonism in those over 75 years of age has to be monitored, which is usually reversible after drug withdrawal. The dose should be reduced in patients with a glomerular filtration rate <60 ml/min/1.73 m2 . Advanced age is a risk factor for gastrointestinal bleeding associated with antiplatelet drugs, so the adjuvant treatment with proton-pump inhibitors65 is recommended, although there are doubts about the long-term safety of this treatment.66 While current guidelines67 highlight the benefit of statins in elderly patients in secondary prevention, there is no firm evidence in patients older than 80 years, so it is essential to individually analyze the treatment’s risk/benefit.43 The elderly are at increased risk of adverse effects with statins, although these are rarely serious. The most common are asymptomatic hypertransaminemia and myotoxicity. These adverse effects are dose dependent, so, in the elderly, an intermediate potency statin is recommended. In case of intolerance, pravastatin or fluvastatin can be used instead, which have a lower myotoxicity, or a long-acting statin, such as rosuvastatin, 1–3 times a week.68 The risk of developing myotoxicity is increased with the concomitant use of drugs that inhibit cytochrome P450 (Table 5) and in the presence of renal failure. With the exception of atorvastatin, which does not require dose adjustment in the presence of renal failure, it is recommended to use 50% of the dose of statins, even less in patients with glomerular filtration rate <30 ml/min/1.73 m2 .43 In diabetics, the use of drugs that increase the risk of hypoglycaemia (sulfonylureas, repaglinide, insulin) should be careful. In fact, the use of sulfonylureas has been linked to an increased cardiovascular morbidity and mortality.69 Glibenclamide should be avoided because it is associated with an increased risk of hypoglycaemia and alters ischaemic preconditioning in coronary patients. Metformin is the treatment of choice70 and it is important to adjust its dose to kidney function and monitor potential adverse effects (gastrointestinal intolerance, hyporexia, weight loss, lack of vitamin B12 ).52 DPP-4 inhibitors are effective, safe and well tolerated drugs in the elderly,71 and they have demonstrated their cardiovascular safety in high-risk patients. Unlike saxagliptin,72 sitagliptin and alogliptin are not associated to an increased risk of heart failure and its use seems safe in this population.73 There is little experience with GLP-1 agonists in subjects older than 75 years. They induce significant weight loss and are not associated with hypoglycaemia, but require subcutaneous administration and have frequent gastrointestinal effects, especially in the first weeks of treatment. They are safe drugs from a cardiovascular standpoint,74 and lixisenatide has demonstrated its safety in patients with a history of acute coronary syndrome. Sodium-glucose cotransporter type 2 inhibitors have the advantage of not causing hypoglycaemia, induce weight loss and present a good cardiovascular profile. Empagliflozin has been shown to reduce cardiovascular morbidity and mortality in patients with a history of cardiovascular disease.75 However, there is little experience of use in the elderly, so it must be used carefully, considering its limitations and adverse effects (genital candidiasis, dehydration, hypotension, renal failure). Regarding the interventional treatment, after coronary surgery, octogenarian patients have a postoperative mortality 3–5 times higher than younger subjects, and are exposed to more haemodynamic complications (low cardiac output, myocardial infarction, atrial fibrillation, heart block, heart failure), bleeding (with a higher rate of reoperation for bleeding), neurological complications (stroke, delirium), infectious complications (pneumonia,

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Table 3 Antianginal drugs in chronic ischaemic heart disease: adverse effects and contraindications. Drug

Adverse effects

Contraindications

Comments

BB

Asthenia, dizziness, headache, acral coldness, bradycardia, hypotension, erectile dysfunction, constipation Uncommon: syncope, bronchospasm, hypoglycaemia (in patients treated with insulin or sulfonylureas), hyperglycaemia, depression, sleep disorders, Raynaud’s syndrome Hypotension, headache, dizziness, falls, oedema, facial flushing, nausea NDCCB: constipation, bradycardia

Low blood pressure (SBP < 100 mmHg), sick sinus syndrome, second or third degree AV block, bradycardia (HR basal <60 bpm), acute heart failure, severe bronchial asthma, severe COPD with bronchial hyperreactivity, advanced peripheral arterial occlusion, Raynaud’s syndrome, pheochromocytoma Hypotension, acute heart failure Avoid NDCCB in: heart failure, severe bradycardia (HR < 40 bpm), second or third degree AV block, sick sinus syndrome, arterial hypertension, left ventricular dysfunction

They can be used generally in COPD patients with peripheral arterial disease Avoid atenolol in renal failure Avoid abrupt discontinuation of BB for risk of rebound myocardial ischaemia Non-recommended combinations: NDCCB, MAOI, clonidine, sulpiride

Nitrates

Headache, hypotension, orthostasis, dizziness, falls, flushing, nausea, cyanosis (methemoglobinemia)

Aortic stenosis, hypertrophic cardiomyopathy, hypotension Combination with phosphodiesterase-5 inhibitors (sildenafil)

Ivabradine

Phosphenes, blurred vision, headache, dizziness, bradycardia, first degree AV block, ventricular extrasystolia, atrial fibrillation Uncommon: asthenia, dizziness, syncope, diplopia, nausea, constipation, diarrhoea, urticaria, angioedema QT prolongation, dizziness, headache, nausea, constipation, abdominal pain, hypoglycaemia in patients with diabetes treatment

Bradycardia (HR < 70 bpm), sick sinus syndrome, heart block (sinoatrial, second-third grade AV), pacemaker dependency, atrial fibrillation, hypotension (<90/50 mmHg), myocardial infarction, unstable angina, acute heart failure, severe renal or hepatic failure

Dizziness, fatigue, headache, parkinsonism, sleep disorders (insomnia, somnolence). Abdominal pain, diarrhoea, dyspepsia, nausea and vomiting. Pruritus, urticaria Rare: extrasystoles, tachycardia, falls, hypotension (patients with antihypertensives), flushing, angioedema, agranulocytosis, thrombocytopenia, hepatitis

Parkinson’s disease and other movement disorders (tremor, restless leg syndrome) Severe renal impairment (GFR < 30 ml/min)

Calcium channel blockers NDCCB: nondihydropyridine agents (verapamil, diltiazem)

Ranolazine

Trimetazidine

Prolonged QT or combination with drugs that prolong the QT, ventricular tachycardia, severe renal failure (GFR < 30 ml/min), moderate to severe liver failure, congestive heart failure iii–ivNYHA

Avoid NDCCB association with BB, digoxin and antiarrhythmic agents NDCCB interact with drugs metabolized by cytochrome p450: statins, BB, digoxin, flecainide, theophylline, carbamazepine, midazolam, sulfonylureas, macrolides, rifampin, protease inhibitors, cimetidine, colchicine Chronic use induces tolerance, sympathetic activation and endothelial dysfunction Myocardial ischaemia may rebound if suspended abruptly Interaction with ACE inhibitors, ARBs, l-arginine, folic acid and ascorbic acid Drug interactions (cytochrome P450 3A4): azole antifungals, NDCCB, macrolides, protease inhibitors Avoid concomitant use of drugs that prolong the QT interval: antiarrhythmic agents, cisapride, erythromycin

Adjust dose in renal and hepatic failure Hypoglycaemic effect (may require adjustment of antidiabetic drugs) Drug interactions (cytochrome P450 3A4 and 2D6): azole antifungals, protease inhibitors, macrolides, rifampin, phenytoin, NDCCB, digoxin, simvastatin, antiarrhythmics (except amiodarone), tricyclic antidepressants Reduce dose in renal failure (GFR < 60 ml/min)

NDCCB: Non-Dihydropyridine Calcium Channel Blockers; ARBs: angiotensin (AT1) receptor antagonists II; AV: atrioventricular; BB: beta blockers; COPD: chronic obstructive pulmonary disease; HR: heart rate; GFR: glomerular filtration rate; ACE inhibitors, angiotensin converting enzyme inhibitors ii; MAO: monoamine oxidase inhibitors; IV: intravenous; NYHA: New York Heart Association; SBP: systolic blood pressure.

bacteraemia, mediastinitis, safenectomy infection) and renal failure.76 Percutaneous coronary revascularization has become a routine procedure in elderly patients with chronic high risk angina or not controlled with medical treatment, being considered a

safe and effective procedure in the elderly, even in patients over 85 years,77 while it is true that hospital complications are more frequent in the elderly (death, myocardial infarction, coronary dissection, tachyarrhythmia, stroke, kidney failure, bleeding).78

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Table 4 Drugs indicated in secondary prevention: adverse effects and contraindications. Drug

Adverse effects

Contraindications

Comments

Statins

Myotoxicity (CPK elevation, myalgia, myositis, rhabdomyolysis). Hepatotoxicity (altered liver biochemistry, toxic hepatitis). Diabetes Fatigue, exercise intolerance. Osteoarticular (tendinitis, arthralgia, arthritis) Rare: cognitive impairment, behavioural disorders, insomnia, cataracts, haemorrhagic stroke Gastrotoxicity (dyspepsia, gastritis, ulcer, gastrointestinal bleeding), bleeding, asthma, rhinitis, urticaria, angioedema Rare: headache, dizziness, confusion, tinnitus, deafness, hepatitis, acute renal failure

Chronic liver disease Avoid association with fibrates and drugs that inhibit cytochrome P450 (see Table 3) Use with caution (increased risk of myotoxicity) in: elderly (use intermediate potency statins), renal impairment (reduce dose, except atorvastatin), hypothyroidism and vitamin D deficiency, alcoholism and family or personal history of myopathy Peptic ulcer, bleeding, coagulopathy, severe renal or hepatic failure, asthma, hypersensitivity to NSAIDs

Recommendations: 1. Perform baseline measurement of transaminases; repeat if symptoms of hepatotoxicity 2. Perform CPK determination only if muscle symptoms, myotoxic drugs or family or personal history of myopathy Monitor blood glucose

ACE inhibitors

Cough, angioedema, hypotension, renal failure, dizziness, headache, blurred vision, nausea, diarrhoea, abdominal pain, dysgeusia Rare: hepatotoxicity, cytopenias

Bilateral renal artery stenosis, severe aortic stenosis, hypertrophic cardiomyopathy, idiopathic or hereditary angioedema, hypersensitivity to NSAIDs

ARBs

Cough, angioedema, hypotension, renal failure, asthenia, dizziness Rare: collagenous colitis (telmisartan)

Bilateral renal artery stenosis, severe aortic stenosis, hypertrophic cardiomyopathy, hypersensitivity to ARBs, severe hepatic failure

Acetylsalicylic acid

Interactions: methotrexate; sulfonylureas, insulin (risk of hypoglycaemia); NSAIDs, corticosteroids, antiplatelet agents, anticoagulants, SSRIs (bleeding risk); digoxin (risk of poisoning); diuretics, ACE inhibitors, ARBs (risk of renal failure); phenytoin, valproate (increased levels) Reduce dose in renal failure (control GFR and K) Risk of hypoglycaemia (patients with secretagogues or insulin) Avoid association with lithium, NSAIDs (renal failure) and ARBs (hypotension, renal failure, hyperkalemia) Avoid association with lithium, NSAIDs (renal failure) and ARBs (hypotension, renal failure, hyperkalemia)

NSAIDs: nonsteroidal anti-inflammatory drugs; ARBs: angiotensin AT1 receptor antagonists II; CPK: creatine phosphokinase; GFR: glomerular filtration rate; ACE inhibitors, angiotensin converting enzyme inhibitors II; SSRIs: selective serotonin reuptake inhibitors. Table 5 Statins: differential characteristics and drug interactions. Statin

Lipophilia

CYP metabolism

Pravastatin Rosuvastatin Pitavastatin Fluvastatin Atorvastatin Lovastatin Simvastatin

No No Yes Yes Yes Yes Yes

No 2C9, 2C19 2C9, 2C8 2C9 3A4 3A4 3A4

Drug interactions

LDL reduction (%) with maximum dose

F

PI

AA

A

M

CCB

SSRIs

SNRI

+ + + + + + +

+ + + + + + +

+ + + + + + +

− + + + − − −

− − − − + + +

− − − − + + +

− − − − + + +

− − − − + + +

38 63 41 38 55 41 41

A: amiodarone; AA: azole antifungals; CCB: calcium channel blockers; CYP: cytochrome P450; F: fibrates; PI: protease inhibitors; SNRI: serotonin–norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; LDL: low density lipoproteins; M: macrolides. Adapted from Bitzur et al.68

Geriatric factors Unlike what happens in younger patients, the risk assessment includes a wide range of factors that can influence the results. It is essential to carry out a comprehensive assessment from a biopsychosocial point of view, since elderly patients with chronic ischaemic heart disease often have multiple comorbidities, frailty or geriatric syndromes that limit the therapeutic possibilities and worsen the prognosis. Some very common comorbidities in the elderly, such as aortic stenosis, atrial fibrillation, poorly controlled hypertension, anaemia and thyrotoxicosis, can contribute to worsen myocardial ischaemia. In addition to the risk factors

of coronary heart disease (smoking, hypertension, diabetes), it is essential to consider other risks associated with age, such as the risk of falls, confusion, disability and the need for social support or polypharmacy. Although in ischaemic heart disease an increased risk of cardiovascular mortality usually involves a higher absolute benefit of interventional treatments, in the elderly, there is also an increased risk of iatrogenic complications associated with hospitalization and development of new disability. It is therefore very important to complete the geriatric assessment, including functional evaluation, frailty, cognitive function, social status, life expectancy and the patient’s wishes and guidelines (Table 6) to weigh the risk-benefit ratio and be sure that the competitive risk

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Table 6 Geriatric evaluation factors.

Comorbidity

Frailty

Functional status

Mental state

Polypharmacy

Diagnosis

Prognosis/plan

DM, COPD, renal failure, risk of bleeding, etc. Geriatric syndromes (falls, incontinence) Fried scale Clinical Frailty Scale SPPB

Affect the short- and long-term results Increased risk in diagnostic tests and treatments

Katz index (basic ADLs) Barthel index Lawton index (instrumental ADLs) MMSE MoCA miniCog Depression test ≥5 chronic medications

Risk of more severe coronary disease Increased morbidity and mortality after intervention It does not necessarily mean not performing tests or invasive treatments. It does mean more personalized care Increased risk of complications and death If there is moderate to severe dependence, prioritize actions aimed at obtaining quality of life Independently associated with morbidity and mortality Close monitoring, especially if depression Risk of interactions and nonadherence Risk of adverse effects Sometimes it is necessary to prioritize which drugs are essential for the objective sought

ADLs: activities of daily living; Clinical Frailty Scale: scale from 1 = consistent and 9 = very sick (different deficiencies, diseases and disabilities are included in the evaluation); DM: diabetes mellitus; COPD: chronic obstructive pulmonary disease; Fried scale: evaluates five criteria: unintentional weight loss, easy fatigue, poor physical activity, slow gait and poor muscle strength (the presence of 3 or more indicates frailty); miniCog: Mini-Cognitive Assessment Instrument, very simple test (2 questions and drawing of a clock) for cognitive impairment screening; MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive Assessment; SPPB: Short Physical Performance Battery (evaluates balance, gait speed and ability to rise from a chair).

associated with these geriatric conditions is not greater in predicting prognosis than that associated with the coronary disease itself. One of the main geriatric prognostic factors, essential in decision-making, is the functional ability to perform daily living activities. The functional status can be considered a measure of the overall impact of a patient’s diseases and deficiencies, within their social environment and context. Dependence to perform basic activities of daily living is an independent predictor of mortality in the short and long term, both for hospitalized patients79 as well as for the community elderly.80 These activities are the most basic for self-care and should be evaluated using validated scales, such as the Katz index or the Barthel index, and be sure that the loss of autonomy for the same is established and irreversible, before classifying the elderly as dependent. The objectives of treating a patient with chronic ischaemic heart disease and a moderate degree of dependence must be aimed at controlling symptoms and prevent iatrogenesis, minimizing the side effects of medication and diagnostic tests. Another important factor to individualize and optimize treatment recommendations focused on the patient is knowledge of the degree of frailty. Frailty is a specific geriatric syndrome consisting of a special state of vulnerability associated with age, produced by the decrease in the functional and biological reserve of multiple organs, characterized by a decrease in responsiveness to different stress situations.81 As the individual progresses in the frailty

syndrome, this reserve continues declining, and although there are no obvious symptoms, it will mean that the elderly patient’s disease can produce more serious consequences, with greater functional and cognitive impairment. Different phenotypes or combinations of clinical features that identify frailty in clinical practice have been described. The most widely used is the model described by Fried,82 who, using the Cardiovascular Health Study population, defined five criteria, of which the presence of 3 or more characterized frailty. These criteria include: unintentional weight loss, fatigue, low physical activity, slow gait and decreased grip strength. Elderly individuals with frailty have a higher prevalence of coronary heart disease and a further extension of this on coronary angiography, and have a higher mortality than patients without frailty. The frailty is also associated with an increased risk of death after an acute coronary syndrome without ST elevation, as well as an increased risk of major cardiac adverse events, regardless of age and comorbidity.83 Frailty means a longer hospital stay and higher mortality at 30 days and one year after coronary intervention, as evidenced by the Murali-Krishnan et al. study, in which frailty was measured according to the Canadian Clinical Frailty Scale.84 Gait speed is one of the most discriminative frailty factors and also a predictor of mortality in hospitalized patients with coronary heart disease. In the Purser et al. study,85 using the speed to travel a short distance as a marker of frailty, in patients with multivessel disease or left dominant coronary disease, a speed <0.65 m/s was detected in 50% of the study population and this was associated with a 4-fold increased risk of mortality at 6 months. This association persisted after adjustment for age, sex, cardiac risk factors, comorbidity, disability, cognitive impairment and depression.

Life expectancy Depending on the context of biological and clinical heterogeneity of the elderly, it becomes very difficult for any prognostic index based only on specific disease parameters to accurately predict the risk of long-term mortality. Important aspects such as the previously mentioned functional status and the presence of frailty are not evaluated in the indices that assess prognosis in ischaemic heart disease, and may determine life expectancy in a more decisive way when compared to many specific factors of coronary heart disease. Multiple general prognostic indices have also been developed in recent years, not based on a single disease, to predict the risk of death in the elderly, in different periods of time.86 None of them, however, is perfect, so as to be used in a unique and extensive way in daily clinical practice. In addition, none of them makes an estimate of the individual’s life expectancy, a much more useful parameter when making medical decisions, and easier to understand for patients and families than the risk of death. Until further progress is achieved in this field’s research, allowing us to quantify the specific risk of the patient, we will have to make clinical decisions by completing the information on the specific scales with qualitative life expectancy approaches by sex, race and age, adding comorbidity and functionality data. These latter factors are the strongest and most consistent predictors of mortality in the elderly, therefore, a proper geriatric assessment is essential to properly appreciate them. This approach allows us to, at least, identify the ends of the spectrum, identifying patients with a life expectancy well below the average for their age or, on the contrary, the elderly who do not have a significant comorbidity, are robust and maintain autonomy, and are, therefore, very likely to live longer than average. The time in which the benefit of the evaluated treatment is expected,87 the type of benefit expected, its cost and the patient’s wishes will complete the set of considerations in the complex task of treating an elderly patient with ischaemic heart disease, beyond treating an angina or a coronary lesion in an older patient.

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