Update of treatment in chronic heart failure | Medicina Clínica (English Edition)

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First, we have evidence that the implementation of pharmacological measures is still insufficient.<a class="elsevierStyleCrossRef" href="#bib0190">4</a> The cause of this underuse lies mainly in the complexity of treatment, which requires the combination of various drugs progressively staggered, whose side effects require close monitoring, especially during the period of staggering the doses. Another reason is the limited representativeness of the patients assessed in clinical trials with respect to those assisted in “real life”. In this regard, it should be noted that most clinical trials exclude older patients, who represent in daily practice the largest population of patients with HF, as it happens with patients with preserved ejection fraction (HFpEF).The purposes of HF treatment are to relieve symptoms, prevent hospitalization and improve survival. The procedure includes a number of general recommendations (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), pharmacological treatment and non-pharmacological treatment (surgical and ventricular assist devices [VADs]). This article is intended as an update of current pharmacological therapeutic strategies for chronic HF, focusing on the latest guidelines published by the European<a class="elsevierStyleCrossRef" href="#bib0195">5</a> and American<a class="elsevierStyleCrossRef" href="#bib0200">6</a> societies as well as in new evidence and therapeutic targets that may be useful in clinical practice.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Drug treatment of systolic heart failureAngiotensin-converting enzyme inhibitorsIndicationsThe angiotensin converting enzyme (ACE) inhibitor drugs have been the mainstay of treatment for heart failure with depressed ejection fraction (HFdEF) for nearly 25 years, with a mortality reduction during the first year of approximately 23%.<a class="elsevierStyleCrossRefs" href="#bib0205">7,8</a> They are indicated in all patients with HFdDF, in any functional class, including asymptomatic ventricular dysfunction, except intolerance or contraindication. Until recently it was believed they should be the first drug group to be used, being beta-blockers (BBs) subsequently associated, once achieved the maximum or tolerated dosage. However, CIBIS III study has shown that the benefit is similar if the therapeutic sequence begins with BB, being ACE inhibitors subsequently associated.<a class="elsevierStyleCrossRef" href="#bib0215">9</a> Probably more beneficial is the co-administration of ACE inhibitors and BB at moderate doses than only one of these drugs at optimal doses. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> describes most frequently used drugs.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Practical recommendations for useBefore initiating treatment with an ACE inhibitor, kidney function and blood ions should be checked, as well as using the lowest dose of diuretics, or even temporarily withdraw for 24 or 48h, in order to minimize deterioration of renal function that ACE inhibitors may cause. In any case, there is evidence that some deterioration of renal function at treatment onset with an ACE inhibitor does not involve deterioration in prognosis.<a class="elsevierStyleCrossRef" href="#bib0220">10</a> Initially, especially in patients with low systolic blood pressure (BP), treatment will be administered in supine position at night. ACE inhibitors should not be withdrawn simply because of a low systolic BP that hardly causes symptoms or significant deterioration of renal function. Frequently, once the dose of ACE inhibitor has been gradually increased, BP increases as a result of the improvement in cardiac output. The staggered administration starting with the recommended baseline dose, will be doubled every 2 weeks up to the target dose or the maximum tolerated dose. The adverse events will be monitored 7–14 days after each dose increased, by controlling the BP and determination of renal function and ions. Once the maintenance dose is reached controls will be performed quarterly. Contraindications and criteria for drug reduction or withdrawal are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.β-BlockersIndicationsBBs, as well as ACE inhibitors, provide a solid benefit in HFdEF, and their use is recommended in all functional classes, including asymptomatic ventricular dysfunction, unless contraindication or intolerance. It is estimated that its administration in patients who were previously taking ACE inhibitors, reduces mortality in the first year by about 30%. As discussed above, the sequential treatment regimen in the HFdEF can start with the use of BBs, instead of ACE inhibitors as traditionally recommended. BBs have priority when other circumstances warrant their use, such as the existence of angina, or high heart rate (HR), especially if atrial fibrillation. However, in this regard, it is worth noting the recent publication of a meta-analysis where the effectiveness of BBs in patients with HF and atrial fibrillation has been questioned.<a class="elsevierStyleCrossRef" href="#bib0225">11</a><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the BB drugs used in the HFdEF. It should be noted that other BBs have not proven therapeutic benefit and may worsen disease progression. Therefore, the benefit of BBs, unlike what happens with ACE inhibitors, are not due to a class effect, and only the recommended should be used.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Practical recommendations for useBefore starting the treatment it should be verified that the patient is clinically stable and congestive symptoms have been controlled. In patients prone to hypotension (BP<100mmHg) BBs and ACE inhibitors should be administered at different times of day and the dose of diuretics and other antihypertensives should be adjusted. Treatment will be initiated at the lowest possible doses and will be doubled every 2 weeks up to the optimal or tolerated dose. After 7–14 days of each dosage modification, adverse effects will be assessed by monitoring the presence of congestive symptoms, HR and BP. In general, there is an excessive and unjustified apprehension to adverse effects of BBs, which is the main reason for underuse. BB tolerance, even in elderly patients, following the recommendations for use, is usually excellent. In some cases there may be a slight worsening of symptoms in the first 4–10 weeks. In general, it is not sufficient reason for treatment discontinuation, and it can be controlled by adjusting the dose of other antihypertensive drugs. A very important aspect usually due to BB underuse is the presence of a low HR as a result of previous use of digoxin, especially in patients with atrial fibrillation. Taking into account that digoxin has not been shown to increase survival, its use will never be an obstacle to the administration of BBs. Therefore, if HR <70lpm in patients treated with digoxin, this drug will be progressively reduced or withdrawn when starting BB administration. Another important recommendation is that in an episode of acute exacerbation of HF, with obvious congestive symptoms in a patient previously treated with BBs, BBs should not be reduced or withdrawn, and diuretics administration should be intensified.Angiotensin II receptor antagonistsIndicationsCurrently the indications of the angiotensin II receptor antagonists or angiotensin receptor blockers (ARBs) are as follows:As an alternative to ACE inhibitors in patients intolerant to them, usually by coughing or, less commonly, angioedema. In these cases the benefit is estimated in a magnitude similar to ACE inhibitors and, consequently, they should be indicated in all functional classes, including asymptomatic patients. This benefit is primarily supported by two studies, one conducted with valsartan (Val-Heft)<a class="elsevierStyleCrossRef" href="#bib0230">12</a> and another with candesartan (CHARM).<a class="elsevierStyleCrossRef" href="#bib0235">13</a>Patients who remain symptomatic (NYHA class II–IV) despite being treated with ACE inhibitors and BBs, and with no indication or the use of aldosterone antagonists (AAs) is contraindicated. This indication increases the risk of serious adverse effects such as renal failure, hyperkalemia or severe hypotension. Therefore, it is restricted to symptomatic patients despite appropriate treatment as described and guidelines provide it with a 2a indication. From a physiological point of view, possibly the most effective way to block the renin-angiotensin-aldosterone system (RAAS) is by associating ACE inhibitors, ARBs and AA. However, by the even higher risk of side effects mentioned, this triple treatment has been considered contraindicated until there is sufficient evidence to justify its use.Practical recommendations for useIn general, side effects are similar to those of ACE inhibitors, except for cough and angioedema, whose incidence is much lower, and the same recommendations will be followed in terms of dosage schedule, monitoring, staggering, dose reduction and contraindications (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).Aldosterone antagonistsIndicationsThe following studies: RALES<a class="elsevierStyleCrossRef" href="#bib0240">14</a>, EPHESUS<a class="elsevierStyleCrossRef" href="#bib0245">15</a> and EMPHASIS<a class="elsevierStyleCrossRef" href="#bib0250">16</a> have provided sufficient scientific evidence, with respect to reducing mortality. Therefore, today the AAs are granted the highest level of recommendation in the clinical guidelines. However, its implementation in routine clinical practice is lower than that of other recommended pharmacological groups, probably due to the excessive suspicion about the development of hyperkalemia in high-risk patients who are receiving ACE inhibitors/ARBs or in those with impaired renal function. In any case, they are indicated in patients with ventricular dysfunction in NYHA class II–IV or in patients with recent acute myocardial infarction (AMI) who are diabetic or have HFdEF, regardless of their functional class. According to the published results of a substudy of EPHESUS<a class="elsevierStyleCrossRef" href="#bib0255">17</a>, which demonstrated a marked reduction in mortality in the first month of treatment, the AA should be initiated in the period right after AMI, before hospital discharge.Up to date there are no studies that allow us to compare, in similar clinical situations, spironolactone versus eplerenone. In spironolactone-intolerant patients, due to side effects related to non-mineralocorticoid receptor blockade (mainly gynecomastia), it is reasonable replaced by eplerenone. Some authors suggest that spironolactone, because of its longer half-life, induce hyperkalemia more frequently than eplerenone.<a class="elsevierStyleCrossRef" href="#bib0260">18</a> However, there are still no convincing studies having confirmed this hypothesis.Practical recommendations for useBefore starting treatment with AAs, kidney function and ions should be evaluated, which should have lower serum creatinine levels 2.5mg/dl (or FGe <30ml/m) and lower serum potassium 5mEq/l to be prescribed. It should be noted that the benefit of spironolactone is its favorable effect on cardiac and vascular remodeling, and not in its diuretic effect. Therefore, the doses used should be “non diuretic” i.e. 12.5–50mg a day. In monitoring the treatment, it is advisable to measure serum creatinine and potassium within the first 5–7 days after treatment onset, especially in patients who are also receiving ACE inhibitors or ARBs, with further maintenance control monthly, and finally quarterly.DiureticsIndicationsIt is the drugs of choice for control of congestive symptoms, despite the lack of scientific evidence to support their benefit in reducing mortality. The dose to be prescribed should be the minimum dose of diuretic that maintains a normal extracellular volume, since in case of poor volume control, either by excess or by default, it may condition the prescription of other drugs such as ACE inhibitors/ARBs or BBs (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Practical recommendations for useThe use of loop diuretics is best in decompensation for being most effective. Once euvolemia is obtained we can use thiazide diuretics for maintenance. In the phase of decompensation, daily ideal intravenous dose should be 2.5 times the oral dose the patient used to receive before decompensation, and it will be adjusted according to the diuretic response and the impact on BP, renal function and serum electrolytes. A proper diuretic response is when weight reduction is 0.5–1kg/day or a negative fluid balance 500–1000ml/day. In the maintenance phase it is very helpful for the patient to weight daily and is recommended to make slight modifications on the diuretic dose depending on weight changes. Monitoring the kalemia should be particularly close when loop diuretics are associated with thiazides (hypokalemia) or potassium-sparing diuretics (hyperkalemia). It is also important to remember that diuretics activate the RAAS. Therefore, and if possible, they should be prescribed combined with an ACE inhibitor or ARB.Frequently, the patient develops resistance to the effect of loop diuretics (commonly understood as the existence of congestion despite at least 80mg furosemide daily). It is appropriate, in these cases, using different strategies to overcome this obstacle. One of these strategies is the association of diuretics with different mechanisms of action, such as thiazides or potassium-sparing diuretics. To opt for one or the other, potassium excretion in the urine is useful, because when this is below 50mEq/l, a thiazide may be associated, and when it is over 50mEq/l with a AA.<a class="elsevierStyleCrossRef" href="#bib0265">19</a> Another commonly accepted strategy is to administer furosemide in continuous infusion (usually 10mg/h after an initial bolus of furosemide 80mg and staggering the doses depending on the response). However, the DOSE study results<a class="elsevierStyleCrossRef" href="#bib0270">20</a> showed that continuous infusion of furosemide did not offer advantages over bolus administration in patients hospitalized from decompensated HF. Therefore, we strongly recommend the first strategy in loop diuretic-resistant patients.IvabradineThis is the last drug that has joined the pharmacological armamentarium of patients with heart failure and is recommended in clinical guidelines. Its pharmacological effect is the reduction of heart rate in patients in sinus rhythm, not being indicated in patients with atrial fibrillation.<a class="elsevierStyleCrossRef" href="#bib0275">21</a> Therefore, the best indication would be in patients with heart failure and systolic dysfunction who are in sinus rhythm with a HR over 70lpm (in Spain its use has been authorized for HR over 75lpm), and who remain with symptoms despite treatment with ACE inhibitors/ARBs, BBs and AAs. They can also be used as an alternative to the BBs when these cannot be used. The baseline dose should be 5mg/12h (2.5mg/12h in the elderly), and it may be increased if necessary to 7.5mg/12h after 2 weeks in case of good tolerance. If bradycardia occurs it will be necessary to reduce the dose, and if this continues we will stop treatment.DigoxinDigoxin improves symptoms and reduces hospitalization in patients with ventricular dysfunction and atrial fibrillation, but survival does not increase.<a class="elsevierStyleCrossRef" href="#bib0280">22</a> Its beneficial effect lies in the control of ventricular rate, but it should be noted that it is only able to control it at rest. It is also worth noting the results of a recent meta-analysis, where it is revealed that prescribing digoxin is not harmless, and may be associated with an increased risk of mortality, particularly in patients with atrial fibrillation and no HF.<a class="elsevierStyleCrossRef" href="#bib0285">23</a> Nonetheless, currently, its use is accepted in those patients who, regardless of the existence or not of atrial fibrillation, are symptomatic despite taking ACE inhibitors, BBs, AAs and diuretics. Digoxin is not indicated in the acute management of patients with decompensation in sinus rhythm, or in cases of mitral stenosis in sinus rhythm. The optimal digoxin dose is that necessary to maintain serum levels ranging 0.5–0.8ng/ml, since higher concentrations are associated with increased toxicity with no higher benefit. It is advisable to start with low doses (0.125mg/48h), adjusting the dose according to their serum levels. In patients with renal failure the baseline dose will be lower, and possible interactions with other drugs will always be taken into account.Pharmacological treatments of heart failure with preserved ejection fractionApproximately half of patients with HF have preserved EF. The definition of preserved EF is slightly different in the different studies that have addressed this condition, but it is generally understood as the EF being over 40–50%. What is beyond any doubt is that its prevalence increases with age of patients to become the predominant form in the elderly.<a class="elsevierStyleCrossRefs" href="#bib0180">2,24</a> Patients with HFpEF have a survival similar to that of patients with HFdEF, estimating 50% mortality after 5 years in both groups.<a class="elsevierStyleCrossRef" href="#bib0295">25</a> However, until a few years ago there were hardly any randomized studies to evaluate the treatment of this type of ventricular dysfunction. While it is true that recently several clinical trials have been focused on the usefulness of different pharmacological groups in patients with HFpEF, the results are not very encouraging (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>) and there are still many gaps to complete information. Consequently, treatment recommendations are largely speculative and are mainly based on pathophysiological criteria, being HR control and BP the 2 cornerstones.<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>HR control Whether or not the patient is in sinus rhythm or atrial fibrillation, proper control of HR at rest (60–75lpm) and during mild-moderate exertion (<100–120lpm) is a major therapeutic goal. In this regard, the medication of choice will be the BBs for their ability to control the HR both at rest and under exertion. If beta-blockers are contraindicated or are not tolerated, calcium antagonists (verapamil or diltiazem) can be used. When control is not achieved with these drugs, and the patient is in atrial fibrillation, digital or amiodarone will be associated Although ivabradine is a good drug to control the HR, it should be noted that its use is restricted to patients with systolic dysfunction and sinus rhythm.BP control The optimal BP should be less than or equal to 130/80mmHg. Currently, there are no consistent evidence that allow us to decide the most appropriate antihypertensive drug. In general, drugs that have shown benefit in HFdEF (ACE inhibitors/ARBs, BBs) will be used. If BP cannot be controlled with HF standard medication, amlodipine and/or doxazosin might be associated.In addition to these basic considerations regarding the control of HR and BP, the following measures should be considered:In general, the same recommendations discussed for the HFdEF with respect to ACE inhibitors/ARBs, BBs, AAs and diuretics should be followed. Taking into account that patients with HFpEF are usually hypertensive, generally they tolerate these drugs better. Therefore, the dose staggering might be faster.The dose of diuretics should be the minimum necessary to control congestive symptoms. An excess of diuretics make it difficult to implement other drugs and may alter ventricular filling and cardiac output as a result of excessive preload reduction.Unlike HFdEF, verapamil or diltiazem are not contraindicated. Apart from these drugs and the BBs the only antiarrhythmic recommended is amiodarone. However, it is possible that other antiarrhythmic contraindicated in systolic dysfunction for reducing ventricular contractility may be administered in patients with HFpEF.In cases with symptomatic coronary heart disease, myocardial revascularization procedures should be considered. However, in our experience, the vast majority of HFpEF cases occurring in older people, specifically in women, are not accompanied by convincing findings of ischemic heart disease.Other drug groupsIn addition to the mentioned drugs, which currently constitute the fundamental basis of HF treatment, other drugs of great value in clinical practice should be taken into account.Antiplatelet and anticoagulation. Initially all patients with diabetes mellitus or evidence of atherosclerotic lesion (coronary, cerebral or peripheral) should be on antiplatelet agents. As for anticoagulation, the firmly established indications are: atrial fibrillation, previous embolic event, intracavitary thrombus and metal prosthesis. In the absence of these conditions there are doubts about the benefit of anticoagulation, since anticoagulation in patients in sinus rhythm with severe ventricular systolic dysfunction (EF<20%) is very controversial.Statins. Statins are indicated in patients with heart failure whose etiology is ischemic heart disease, or any other etiology whenever lipid profile is susceptible to lipid-lowering therapy.Inotropics. Currently there are several drugs (amrinone, milrinone, vesnarinone, dobutamine) that share the ability to increase myocardial contractility. However, no evidence is available on such drugs reducing morbidity and mortality, and their adverse effects, potentially serious, force to restrict their use to extreme situations.Intravenous iron. In patients with HFdEF administering intravenous iron has been shown to improve functional status and exercise capacity when there is iron deficiency, regardless of the presence or not of anemia.<a class="elsevierStyleCrossRef" href="#bib0335">33</a>Future strategiesNeprilysin inhibition. Neprilysin is a neutral endopeptidase that degrades different endogenous vasoactive peptides, including natriuretic peptides. Therefore, its inhibition increases the concentration of these and other peptides, offsetting the existing neurohormonal activation in heart failure and responsible for vasoconstriction, sodium retention and maladaptive remodeling. The recent PARADIGM-HF study has shown how the combined inhibition of RAAS and neprilysin with the drug LCZ696 (molecule of dual action with neprilysin- sacubitril- and ARBs-valsartan-inhibitor effect) in patients with symptomatic HF (NYHA II–IV) and reduced EF is higher than enalapril in reducing mortality (20% in cardiovascular mortality and 16% in overall mortality) and hospitalizations from HF.<a class="elsevierStyleCrossRef" href="#bib0340">34</a> The strength of the results of this landmark study has laid the groundwork for a renewed optimism in the field of research into new therapeutic targets in HF.Conflict of interestThe authors report no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:3 [ "identificador" => "sec0010" "titulo" => "Drug treatment of systolic heart failure" "secciones" => array:7 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Angiotensin-converting enzyme inhibitors" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Indications" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Practical recommendations for use" ] ] ] 1 => array:3 [ "identificador" => "sec0030" "titulo" => "β-Blockers" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Indications" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Practical recommendations for use" ] ] ] 2 => array:3 [ "identificador" => "sec0045" "titulo" => "Angiotensin II receptor antagonists" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Indications" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Practical recommendations for use" ] ] ] 3 => array:3 [ "identificador" => "sec0060" "titulo" => "Aldosterone antagonists" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Indications" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Practical recommendations for use" ] ] ] 4 => array:3 [ "identificador" => "sec0075" "titulo" => "Diuretics" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "Indications" ] 1 => array:2 [ "identificador" => "sec0085" "titulo" => "Practical recommendations for use" ] ] ] 5 => array:2 [ "identificador" => "sec0090" "titulo" => "Ivabradine" ] 6 => array:2 [ "identificador" => "sec0095" "titulo" => "Digoxin" ] ] ] 2 => array:2 [ "identificador" => "sec0100" "titulo" => "Pharmacological treatments of heart failure with preserved ejection fraction" ] 3 => array:2 [ "identificador" => "sec0105" "titulo" => "Other drug groups" ] 4 => array:2 [ "identificador" => "sec0110" "titulo" => "Future strategies" ] 5 => array:2 [ "identificador" => "sec0115" "titulo" => "Conflict of interest" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-06-11" "fechaAceptado" => "2015-06-16" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Casado Cerrada J, Gómez del Olmo V, Manzano L. Actualización en las estrategias terapéuticas de la insuficiencia cardiaca crónica. Med Clin (Barc). 2015;145:545–550." ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "HF: heart failure." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Training and self care \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Provide clear, practical and simple information to the patient and his family on HF Teach prevent or avoid precipitating factors and know the symptoms and signs of decompensation Insist on therapy adherence Through structured educational measures readmissions to hospital can drop by 30% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weight, intake, diuresis control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Daily weight, intake and diuresis control in unstable patients and twice a week in stable patients Gaining weight over 2kg in three days is usually due to fluid retention \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diet \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Poor in salt and fat free Diets very restrictive in sodium (<2g/d) are poorly tolerated and are only recommended in decompensation or when very high doses of diuretics are required. In stable patients lower restriction (<3g/d) is recommended \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Physical exercise \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Daily, regular and moderate physical activity in patients with stable HF In episodes of decompensation, rest is recommended during the first days \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tobacco and alcohol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alcohol can have a negative inotropic effect and is associated with increased blood pressure and risk of arrhythmias Advise, support and motivate the patient to stop smoking is recommended because it is a known risk factor for cardiovascular disease \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042214.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Nonpharmacological general therapeutic recommendations." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Absolute contraindications: creatinine >3mg/dl (creatinine >2.5mg/dl in a single determination is a relative contraindication); systolic blood pressure <80mmHg; Kalemia >5.5mEq/l. Dose reduction or drug withdrawal: increased creatinine >50% of baseline creatinine or >3mg/dl; Kalemia >5.5mEq/l. Asymptomatic hypotension is no reason for dose reduction." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Initial dose (orally) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Optimal maintenance dose \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Captopril \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.25mg/8h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50mg/8h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Enalapril \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10mg/12h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Perindopril \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4mg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lisinopril \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20mg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ramipril \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.25mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg/12h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Quinapril \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20mg/12h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Trandolapril \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4mg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042216.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Use of angiotensin converting enzyme inhibitor drugs in chronic heart failure." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Contraindications: bronchial asthma; serious chronic obstructive pulmonary disease (if mild, it is a relative contraindication); systolic blood pressure <85mmHg; heart rate <60lpm; second or third degree atrioventricular block, breast disease; PR >0.24s. Dose reduction or drug withdrawal: symptomatic bradycardia; symptomatic hypotension; hypoperfusion." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Initial dose (orally) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Optimal maintenance dose \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Carvedilol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.125mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25mg/12h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bisoprolol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.25mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10mg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metoprolol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.5mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">200mg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nebivolol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.25mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10mg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042212.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Use of β-blockers in chronic heart failure." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Initial dose (orally) (mg/day) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Maximum dose (mg/day) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Furosemide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20–40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">160–200 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Torasemide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5–10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40–80 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chlorthalidone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50–100 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hydrochlorothiazide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50–100 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indapamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Spironolactone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.5–25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042213.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Use of diuretics in chronic heart failure." ] ] 4 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "EF: ejection fraction; HR: hazard ratio; HF: heart failure; 95% CI: 95% confidence interval." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Methods \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Objectives \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Results \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PEP-CHF<a class="elsevierStyleCrossRef" href="#bib0300">26</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double-blind study in 850 outpatients aged >70 with EF >50%, randomized to receive perindopril 4mg/d versus placebo with 2 year-followup \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Evaluates the effect of perindopril in reducing overall mortality and hospitalization from HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Certain benefit with perindopril was observed, but both the selection and the number of episodes was lower than the anticipated, which shrugged off power to the study \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Enalapril in HFpEF<a class="elsevierStyleCrossRef" href="#bib0305">27</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind study in 71 patients with EF >50%, clinically stable, randomized to 20mg/d of enalapril versus placebo, with 12 month-followup \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Evaluate the effects of enalapril in improving exercise capacity and arterial distensibility \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No benefit of enalapril versus placebo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">I-PRESERVE<a class="elsevierStyleCrossRef" href="#bib0310">28</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double-blind study of 4128 randomized patients to irbesartan 300mg/d versus placebo in patients admitted to hospital with EF >45%, with 49.5 month-followup \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Evaluates the effect of irbesartan in the combined primary endpoint of overall mortality or hospitalization from cardiovascular causes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No benefit of irbesartan versus placebo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CHARM-PRESERVED<a class="elsevierStyleCrossRef" href="#bib0315">29</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind study in 3023 patients with EF >40%, randomized to candersatan 32mg/d versus placebo, with 36.6 month-followup \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Evaluates the effect of candesartan in the combined primary endpoint of cardiovascular mortality or hospitalization from HF causes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Candesartan showed no reduction in the primary endpoint, but showed a moderate impact in reducing secondary objective of hospitalization from HF (230 versus 279, p=0.017) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RELAX<a class="elsevierStyleCrossRef" href="#bib0320">30</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind study of 216 patients with EF >50% clinically stable, randomized to sildenafil 20mg 3 times a day versus placebo for 12 weeks followed by 60mg 3 times daily for another 12 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It investigates the effect of inhibiting phosphodiesterase-5 with sildenafil in functional improvement and exercise capacity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No benefit of sildenafil versus placebo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RAAM-PEF<a class="elsevierStyleCrossRef" href="#bib0325">31</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind study in 44 stable patients with EF >50%, randomized to eplerenone 50mg/d versus placebo, with 6 month-followup \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It evaluates the effects of eplerenone in improving exercise capacity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Eplerenone did not improve exercise capacity, although it had beneficial effects on diastolic function \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TOPCAT<a class="elsevierStyleCrossRef" href="#bib0330">32</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double blind study in 3445 patients with symptomatic EF >45%, randomized to spironolactone 15–45mg/d versus placebo, with 3.3 year-followup \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It evaluates the effect of spironolactone in the combined primary endpoint of cardiovascular mortality, sudden death or hospitalization from heart failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Spironolactone showed no benefit on the combined primary endpoint, but it did in the secondary objective of reducing hospitalization from HF (206 versus 245; HR 0.83; 95% CI 0.69–0.99, p=0.04) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042215.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Drugs specifically evaluated in patients with heart failure and preserved ejection fraction." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0175" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.A. 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Diagnosis and treatment

Update of treatment in chronic heart failure

Actualización en las estrategias terapéuticas de la insuficiencia cardiaca crónica

Jesús Casado Cerradaa,

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jmanuel.casado@salud.madrid.org

Corresponding author.

, Vicente Gómez del Olmob, Luis Manzanob

a Servicio de Medicina Interna, Hospital Universitario de Getafe, Getafe, Madrid, Spain

b Unidad de Insuficiencia Cardiaca y Riesgo Vascular, Servicio de Medicina Interna, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Heart failure &#40;HF&#41; is considered the great epidemic today in cardiovascular disease&#44; affecting more than 23 million people worldwide&#44; and with an expected increased prevalence around 25&#37; in the year 2030&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> In Spain more than 80&#37; of diagnosed cases occur in patients aged over 65&#44; and its prevalence reaches 10&#37; in the population over 70&#44; representing the leading cause of hospitalization in this group&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Despite advances in treatment&#44; morbidity and mortality remain too high&#44; with a median survival of 5 years following the onset of the first clinical symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> The fact that the extent expected has not been reduced is due to various causes&#46; First&#44; we have evidence that the implementation of pharmacological measures is still insufficient&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a> The cause of this underuse lies mainly in the complexity of treatment&#44; which requires the combination of various drugs progressively staggered&#44; whose side effects require close monitoring&#44; especially during the period of staggering the doses&#46; Another reason is the limited representativeness of the patients assessed in clinical trials with respect to those assisted in &#8220;real life&#8221;&#46; In this regard&#44; it should be noted that most clinical trials exclude older patients&#44; who represent in daily practice the largest population of patients with HF&#44; as it happens with patients with preserved ejection fraction &#40;HFpEF&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The purposes of HF treatment are to relieve symptoms&#44; prevent hospitalization and improve survival&#46; The procedure includes a number of general recommendations &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; pharmacological treatment and non-pharmacological treatment &#40;surgical and ventricular assist devices &#91;VADs&#93;&#41;&#46; This article is intended as an update of current pharmacological therapeutic strategies for chronic HF&#44; focusing on the latest guidelines published by the European<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a> and American<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> societies as well as in new evidence and therapeutic targets that may be useful in clinical practice&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Drug treatment of systolic heart failure</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Angiotensin-converting enzyme inhibitors</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Indications</span><p id="par0020" class="elsevierStylePara elsevierViewall">The angiotensin converting enzyme &#40;ACE&#41; inhibitor drugs have been the mainstay of treatment for heart failure with depressed ejection fraction &#40;HFdEF&#41; for nearly 25 years&#44; with a mortality reduction during the first year of approximately 23&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">7&#44;8</span></a> They are indicated in all patients with HFdDF&#44; in any functional class&#44; including asymptomatic ventricular dysfunction&#44; except intolerance or contraindication&#46; Until recently it was believed they should be the first drug group to be used&#44; being beta-blockers &#40;BBs&#41; subsequently associated&#44; once achieved the maximum or tolerated dosage&#46; However&#44; CIBIS III study has shown that the benefit is similar if the therapeutic sequence begins with BB&#44; being ACE inhibitors subsequently associated&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> Probably more beneficial is the co-administration of ACE inhibitors and BB at moderate doses than only one of these drugs at optimal doses&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> describes most frequently used drugs&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Practical recommendations for use</span><p id="par0025" class="elsevierStylePara elsevierViewall">Before initiating treatment with an ACE inhibitor&#44; kidney function and blood ions should be checked&#44; as well as using the lowest dose of diuretics&#44; or even temporarily withdraw for 24 or 48<span class="elsevierStyleHsp" style=""></span>h&#44; in order to minimize deterioration of renal function that ACE inhibitors may cause&#46; In any case&#44; there is evidence that some deterioration of renal function at treatment onset with an ACE inhibitor does not involve deterioration in prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> Initially&#44; especially in patients with low systolic blood pressure &#40;BP&#41;&#44; treatment will be administered in supine position at night&#46; ACE inhibitors should not be withdrawn simply because of a low systolic BP that hardly causes symptoms or significant deterioration of renal function&#46; Frequently&#44; once the dose of ACE inhibitor has been gradually increased&#44; BP increases as a result of the improvement in cardiac output&#46; The staggered administration starting with the recommended baseline dose&#44; will be doubled every 2 weeks up to the target dose or the maximum tolerated dose&#46; The adverse events will be monitored 7&#8211;14 days after each dose increased&#44; by controlling the BP and determination of renal function and ions&#46; Once the maintenance dose is reached controls will be performed quarterly&#46; Contraindications and criteria for drug reduction or withdrawal are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">&#946;-Blockers</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Indications</span><p id="par0030" class="elsevierStylePara elsevierViewall">BBs&#44; as well as ACE inhibitors&#44; provide a solid benefit in HFdEF&#44; and their use is recommended in all functional classes&#44; including asymptomatic ventricular dysfunction&#44; unless contraindication or intolerance&#46; It is estimated that its administration in patients who were previously taking ACE inhibitors&#44; reduces mortality in the first year by about 30&#37;&#46; As discussed above&#44; the sequential treatment regimen in the HFdEF can start with the use of BBs&#44; instead of ACE inhibitors as traditionally recommended&#46; BBs have priority when other circumstances warrant their use&#44; such as the existence of angina&#44; or high heart rate &#40;HR&#41;&#44; especially if atrial fibrillation&#46; However&#44; in this regard&#44; it is worth noting the recent publication of a meta-analysis where the effectiveness of BBs in patients with HF and atrial fibrillation has been questioned&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the BB drugs used in the HFdEF&#46; It should be noted that other BBs have not proven therapeutic benefit and may worsen disease progression&#46; Therefore&#44; the benefit of BBs&#44; unlike what happens with ACE inhibitors&#44; are not due to a class effect&#44; and only the recommended should be used&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Practical recommendations for use</span><p id="par0035" class="elsevierStylePara elsevierViewall">Before starting the treatment it should be verified that the patient is clinically stable and congestive symptoms have been controlled&#46; In patients prone to hypotension &#40;BP<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mmHg&#41; BBs and ACE inhibitors should be administered at different times of day and the dose of diuretics and other antihypertensives should be adjusted&#46; Treatment will be initiated at the lowest possible doses and will be doubled every 2 weeks up to the optimal or tolerated dose&#46; After 7&#8211;14 days of each dosage modification&#44; adverse effects will be assessed by monitoring the presence of congestive symptoms&#44; HR and BP&#46; In general&#44; there is an excessive and unjustified apprehension to adverse effects of BBs&#44; which is the main reason for underuse&#46; BB tolerance&#44; even in elderly patients&#44; following the recommendations for use&#44; is usually excellent&#46; In some cases there may be a slight worsening of symptoms in the first 4&#8211;10 weeks&#46; In general&#44; it is not sufficient reason for treatment discontinuation&#44; and it can be controlled by adjusting the dose of other antihypertensive drugs&#46; A very important aspect usually due to BB underuse is the presence of a low HR as a result of previous use of digoxin&#44; especially in patients with atrial fibrillation&#46; Taking into account that digoxin has not been shown to increase survival&#44; its use will never be an obstacle to the administration of BBs&#46; Therefore&#44; if HR &#60;70<span class="elsevierStyleHsp" style=""></span>lpm in patients treated with digoxin&#44; this drug will be progressively reduced or withdrawn when starting BB administration&#46; Another important recommendation is that in an episode of acute exacerbation of HF&#44; with obvious congestive symptoms in a patient previously treated with BBs&#44; BBs should not be reduced or withdrawn&#44; and diuretics administration should be intensified&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Angiotensin II receptor antagonists</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Indications</span><p id="par0040" class="elsevierStylePara elsevierViewall">Currently the indications of the angiotensin II receptor antagonists or angiotensin receptor blockers &#40;ARBs&#41; are as follows&#58;As an alternative to ACE inhibitors in patients intolerant to them&#44; usually by coughing or&#44; less commonly&#44; angioedema&#46; In these cases the benefit is estimated in a magnitude similar to ACE inhibitors and&#44; consequently&#44; they should be indicated in all functional classes&#44; including asymptomatic patients&#46; This benefit is primarily supported by two studies&#44; one conducted with valsartan &#40;Val-Heft&#41;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> and another with candesartan &#40;CHARM&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a>Patients who remain symptomatic &#40;NYHA class II&#8211;IV&#41; despite being treated with ACE inhibitors and BBs&#44; and with no indication or the use of aldosterone antagonists &#40;AAs&#41; is contraindicated&#46; This indication increases the risk of serious adverse effects such as renal failure&#44; hyperkalemia or severe hypotension&#46; Therefore&#44; it is restricted to symptomatic patients despite appropriate treatment as described and guidelines provide it with a 2a indication&#46; From a physiological point of view&#44; possibly the most effective way to block the renin-angiotensin-aldosterone system &#40;RAAS&#41; is by associating ACE inhibitors&#44; ARBs and AA&#46; However&#44; by the even higher risk of side effects mentioned&#44; this triple treatment has been considered contraindicated until there is sufficient evidence to justify its use&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Practical recommendations for use</span><p id="par0055" class="elsevierStylePara elsevierViewall">In general&#44; side effects are similar to those of ACE inhibitors&#44; except for cough and angioedema&#44; whose incidence is much lower&#44; and the same recommendations will be followed in terms of dosage schedule&#44; monitoring&#44; staggering&#44; dose reduction and contraindications &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Aldosterone antagonists</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Indications</span><p id="par0060" class="elsevierStylePara elsevierViewall">The following studies&#58; RALES<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a>&#44; EPHESUS<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a> and EMPHASIS<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> have provided sufficient scientific evidence&#44; with respect to reducing mortality&#46; Therefore&#44; today the AAs are granted the highest level of recommendation in the clinical guidelines&#46; 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in similar clinical situations&#44; spironolactone versus eplerenone&#46; In spironolactone-intolerant patients&#44; due to side effects related to non-mineralocorticoid receptor blockade &#40;mainly gynecomastia&#41;&#44; it is reasonable replaced by eplerenone&#46; Some authors suggest that spironolactone&#44; because of its longer half-life&#44; induce hyperkalemia more frequently than eplerenone&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a> However&#44; there are still no convincing studies having confirmed this hypothesis&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Practical recommendations for use</span><p id="par0070" class="elsevierStylePara elsevierViewall">Before starting treatment with AAs&#44; kidney function and ions should be evaluated&#44; which should have lower serum creatinine levels 2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl &#40;or FGe &#60;30<span class="elsevierStyleHsp" style=""></span>ml&#47;m&#41; and lower serum potassium 5<span class="elsevierStyleHsp" style=""></span>mEq&#47;l to be prescribed&#46; It should be noted that the benefit of spironolactone is its favorable effect on cardiac and vascular remodeling&#44; and not in its diuretic effect&#46; Therefore&#44; the doses used should be &#8220;non diuretic&#8221; i&#46;e&#46; 12&#46;5&#8211;50<span class="elsevierStyleHsp" style=""></span>mg a day&#46; In monitoring the treatment&#44; it is advisable to measure serum creatinine and potassium within the first 5&#8211;7 days after treatment onset&#44; especially in patients who are also receiving ACE inhibitors or ARBs&#44; with further maintenance control monthly&#44; and finally quarterly&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Diuretics</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Indications</span><p id="par0075" class="elsevierStylePara elsevierViewall">It is the drugs of choice for control of congestive symptoms&#44; despite the lack of scientific evidence to support their benefit in reducing mortality&#46; The dose to be prescribed should be the minimum dose of diuretic that maintains a normal extracellular volume&#44; since in case of poor volume control&#44; either by excess or by default&#44; it may condition the prescription of other drugs such as ACE inhibitors&#47;ARBs or BBs &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Practical recommendations for use</span><p id="par0080" class="elsevierStylePara elsevierViewall">The use of loop diuretics is best in decompensation for being most effective&#46; Once euvolemia is obtained we can use thiazide diuretics for maintenance&#46; In the phase of decompensation&#44; daily ideal intravenous dose should be 2&#46;5 times the oral dose the patient used to receive before decompensation&#44; and it will be adjusted according to the diuretic response and the impact on BP&#44; renal function and serum electrolytes&#46; A proper diuretic response is when weight reduction is 0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>kg&#47;day or a negative fluid balance 500&#8211;1000<span class="elsevierStyleHsp" style=""></span>ml&#47;day&#46; In the maintenance phase it is very helpful for the patient to weight daily and is recommended to make slight modifications on the diuretic dose depending on weight changes&#46; Monitoring the kalemia should be particularly close when loop diuretics are associated with thiazides &#40;hypokalemia&#41; or potassium-sparing diuretics &#40;hyperkalemia&#41;&#46; It is also important to remember that diuretics activate the RAAS&#46; Therefore&#44; and if possible&#44; they should be prescribed combined with an ACE inhibitor or ARB&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Frequently&#44; the patient develops resistance to the effect of loop diuretics &#40;commonly understood as the existence of congestion despite at least 80<span class="elsevierStyleHsp" style=""></span>mg furosemide daily&#41;&#46; It is appropriate&#44; in these cases&#44; using different strategies to overcome this obstacle&#46; One of these strategies is the association of diuretics with different mechanisms of action&#44; such as thiazides or potassium-sparing diuretics&#46; To opt for one or the other&#44; potassium excretion in the urine is useful&#44; because when this is below 50<span class="elsevierStyleHsp" style=""></span>mEq&#47;l&#44; a thiazide may be associated&#44; and when it is over 50<span class="elsevierStyleHsp" style=""></span>mEq&#47;l with a AA&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a> Another commonly accepted strategy is to administer furosemide in continuous infusion &#40;usually 10<span class="elsevierStyleHsp" style=""></span>mg&#47;h after an initial bolus of furosemide 80<span class="elsevierStyleHsp" style=""></span>mg and staggering the doses depending on the response&#41;&#46; However&#44; the DOSE study results<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> showed that continuous infusion of furosemide did not offer advantages over bolus administration in patients hospitalized from decompensated HF&#46; Therefore&#44; we strongly recommend the first strategy in loop diuretic-resistant patients&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Ivabradine</span><p id="par0090" class="elsevierStylePara elsevierViewall">This is the last drug that has joined the pharmacological armamentarium of patients with heart failure and is recommended in clinical guidelines&#46; Its pharmacological effect is the reduction of heart rate in patients in sinus rhythm&#44; not being indicated in patients with atrial fibrillation&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> Therefore&#44; the best indication would be in patients with heart failure and systolic dysfunction who are in sinus rhythm with a HR over 70<span class="elsevierStyleHsp" style=""></span>lpm &#40;in Spain its use has been authorized for HR over 75<span class="elsevierStyleHsp" style=""></span>lpm&#41;&#44; and who remain with symptoms despite treatment with ACE inhibitors&#47;ARBs&#44; BBs and AAs&#46; They can also be used as an alternative to the BBs when these cannot be used&#46; The baseline dose should be 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h &#40;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h in the elderly&#41;&#44; and it may be increased if necessary to 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h after 2 weeks in case of good tolerance&#46; If bradycardia occurs it will be necessary to reduce the dose&#44; and if this continues we will stop treatment&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Digoxin</span><p id="par0095" class="elsevierStylePara elsevierViewall">Digoxin improves symptoms and reduces hospitalization in patients with ventricular dysfunction and atrial fibrillation&#44; but survival does not increase&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> Its beneficial effect lies in the control of ventricular rate&#44; but it should be noted that it is only able to control it at rest&#46; It is also worth noting the results of a recent meta-analysis&#44; where it is revealed that prescribing digoxin is not harmless&#44; and may be associated with an increased risk of mortality&#44; particularly in patients with atrial fibrillation and no HF&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> Nonetheless&#44; currently&#44; its use is accepted in those patients who&#44; regardless of the existence or not of atrial fibrillation&#44; are symptomatic despite taking ACE inhibitors&#44; BBs&#44; AAs and diuretics&#46; Digoxin is not indicated in the acute management of patients with decompensation in sinus rhythm&#44; or in cases of mitral stenosis in sinus rhythm&#46; The optimal digoxin dose is that necessary to maintain serum levels ranging 0&#46;5&#8211;0&#46;8<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#44; since higher concentrations are associated with increased toxicity with no higher benefit&#46; It is advisable to start with low doses &#40;0&#46;125<span class="elsevierStyleHsp" style=""></span>mg&#47;48<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; adjusting the dose according to their serum levels&#46; In patients with renal failure the baseline dose will be lower&#44; and possible interactions with other drugs will always be taken into account&#46;</p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Pharmacological treatments of heart failure with preserved ejection fraction</span><p id="par0100" class="elsevierStylePara elsevierViewall">Approximately half of patients with HF have preserved EF&#46; The definition of preserved EF is slightly different in the different studies that have addressed this condition&#44; but it is generally understood as the EF being over 40&#8211;50&#37;&#46; What is beyond any doubt is that its prevalence increases with age of patients to become the predominant form in the elderly&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#44;24</span></a> Patients with HFpEF have a survival similar to that of patients with HFdEF&#44; estimating 50&#37; mortality after 5 years in both groups&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a> However&#44; until a few years ago there were hardly any randomized studies to evaluate the treatment of this type of ventricular dysfunction&#46; While it is true that recently several clinical trials have been focused on the usefulness of different pharmacological groups in patients with HFpEF&#44; the results are not very encouraging &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41; and there are still many gaps to complete information&#46; Consequently&#44; treatment recommendations are largely speculative and are mainly based on pathophysiological criteria&#44; being HR control and BP the 2 cornerstones&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HR control</span> Whether or not the patient is in sinus rhythm or atrial fibrillation&#44; proper control of HR at rest &#40;60&#8211;75<span class="elsevierStyleHsp" style=""></span>lpm&#41; and during mild-moderate exertion &#40;&#60;100&#8211;120<span class="elsevierStyleHsp" style=""></span>lpm&#41; is a major therapeutic goal&#46; In this regard&#44; the medication of choice will be the BBs for their ability to control the HR both at rest and under exertion&#46; If beta-blockers are contraindicated or are not tolerated&#44; calcium antagonists &#40;verapamil or diltiazem&#41; can be used&#46; When control is not achieved with these drugs&#44; and the patient is in atrial fibrillation&#44; digital or amiodarone will be associated Although ivabradine is a good drug to control the HR&#44; it should be noted that its use is restricted to patients with systolic dysfunction and sinus rhythm&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">BP control</span> The optimal BP should be less than or equal to 130&#47;80<span class="elsevierStyleHsp" style=""></span>mmHg&#46; Currently&#44; there are no consistent evidence that allow us to decide the most appropriate antihypertensive drug&#46; In general&#44; drugs that have shown benefit in HFdEF &#40;ACE inhibitors&#47;ARBs&#44; BBs&#41; will be used&#46; If BP cannot be controlled with HF standard medication&#44; amlodipine and&#47;or doxazosin might be associated&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In addition to these basic considerations regarding the control of HR and BP&#44; the following measures should be considered&#58;In general&#44; the same recommendations discussed for the HFdEF with respect to ACE inhibitors&#47;ARBs&#44; BBs&#44; AAs and diuretics should be followed&#46; Taking into account that patients with HFpEF are usually hypertensive&#44; generally they tolerate these drugs better&#46; Therefore&#44; the dose staggering might be faster&#46;The dose of diuretics should be the minimum necessary to control congestive symptoms&#46; An excess of diuretics make it difficult to implement other drugs and may alter ventricular filling and cardiac output as a result of excessive preload reduction&#46;Unlike HFdEF&#44; verapamil or diltiazem are not contraindicated&#46; Apart from these drugs and the BBs the only antiarrhythmic recommended is amiodarone&#46; However&#44; it is possible that other antiarrhythmic contraindicated in systolic dysfunction for reducing ventricular contractility may be administered in patients with HFpEF&#46;In cases with symptomatic coronary heart disease&#44; myocardial revascularization procedures should be considered&#46; However&#44; in our experience&#44; the vast majority of HFpEF cases occurring in older people&#44; specifically in women&#44; are not accompanied by convincing findings of ischemic heart disease&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Other drug groups</span><p id="par0140" class="elsevierStylePara elsevierViewall">In addition to the mentioned drugs&#44; which currently constitute the fundamental basis of HF treatment&#44; other drugs of great value in clinical practice should be taken into account&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Antiplatelet and anticoagulation&#46;</span> Initially all patients with diabetes mellitus or evidence of atherosclerotic lesion &#40;coronary&#44; cerebral or peripheral&#41; should be on antiplatelet agents&#46; As for anticoagulation&#44; the firmly established indications are&#58; atrial fibrillation&#44; previous embolic event&#44; intracavitary thrombus and metal prosthesis&#46; In the absence of these conditions there are doubts about the benefit of anticoagulation&#44; since anticoagulation in patients in sinus rhythm with severe ventricular systolic dysfunction &#40;EF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>20&#37;&#41; is very controversial&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Statins&#46;</span> Statins are indicated in patients with heart failure whose etiology is ischemic heart disease&#44; or any other etiology whenever lipid profile is susceptible to lipid-lowering therapy&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Inotropics&#46;</span> Currently there are several drugs &#40;amrinone&#44; milrinone&#44; vesnarinone&#44; dobutamine&#41; that share the ability to increase myocardial contractility&#46; However&#44; no evidence is available on such drugs reducing morbidity and mortality&#44; and their adverse effects&#44; potentially serious&#44; force to restrict their use to extreme situations&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Intravenous iron&#46;</span> In patients with HFdEF administering intravenous iron has been shown to improve functional status and exercise capacity when there is iron deficiency&#44; regardless of the presence or not of anemia&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Future strategies</span><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Neprilysin inhibition&#46;</span> Neprilysin is a neutral endopeptidase that degrades different endogenous vasoactive peptides&#44; including natriuretic peptides&#46; Therefore&#44; its inhibition increases the concentration of these and other peptides&#44; offsetting the existing neurohormonal activation in heart failure and responsible for vasoconstriction&#44; sodium retention and maladaptive remodeling&#46; The recent PARADIGM-HF study has shown how the combined inhibition of RAAS and neprilysin with the drug LCZ696 &#40;molecule of dual action with neprilysin- sacubitril- and ARBs-valsartan-inhibitor effect&#41; in patients with symptomatic HF &#40;NYHA II&#8211;IV&#41; and reduced EF is higher than enalapril in reducing mortality &#40;20&#37; in cardiovascular mortality and 16&#37; in overall mortality&#41; and hospitalizations from HF&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a> The strength of the results of this landmark study has laid the groundwork for a renewed optimism in the field of research into new therapeutic targets in HF&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors report no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Drug treatment of systolic heart failure"
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                  "titulo" => "Practical recommendations for use"
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          "titulo" => "Pharmacological treatments of heart failure with preserved ejection fraction"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Casado Cerrada J&#44; G&#243;mez del Olmo V&#44; Manzano L&#46; Actualizaci&#243;n en las estrategias terap&#233;uticas de la insuficiencia cardiaca cr&#243;nica&#46; Med Clin &#40;Barc&#41;&#46; 2015&#59;145&#58;545&#8211;550&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Training and self care&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Provide clear&#44; practical and simple information to the patient and his family on HF<br>Teach prevent or avoid precipitating factors and know the symptoms and signs of decompensation<br>Insist on therapy adherence<br>Through structured educational measures readmissions to hospital can drop by 30&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weight&#44; intake&#44; diuresis control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Daily weight&#44; intake and diuresis control in unstable patients and twice a week in stable patients<br>Gaining weight over 2<span class="elsevierStyleHsp" style=""></span>kg in three days is usually due to fluid retention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Poor in salt and fat free<br>Diets very restrictive in sodium &#40;&#60;2<span class="elsevierStyleHsp" style=""></span>g&#47;d&#41; are poorly tolerated and are only recommended in decompensation or when very high doses of diuretics are required&#46; In stable patients lower restriction &#40;&#60;3<span class="elsevierStyleHsp" style=""></span>g&#47;d&#41; is recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Physical exercise&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Daily&#44; regular and moderate physical activity in patients with stable HF<br>In episodes of decompensation&#44; rest is recommended during the first days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tobacco and alcohol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alcohol can have a negative inotropic effect and is associated with increased blood pressure and risk of arrhythmias<br>Advise&#44; support and motivate the patient to stop smoking is recommended because it is a known risk factor for cardiovascular disease&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Absolute contraindications&#58; creatinine &#62;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dl &#40;creatinine &#62;2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl in a single determination is a relative contraindication&#41;&#59; systolic blood pressure &#60;80<span class="elsevierStyleHsp" style=""></span>mmHg&#59; Kalemia &#62;5&#46;5<span class="elsevierStyleHsp" style=""></span>mEq&#47;l&#46; Dose reduction or drug withdrawal&#58; increased creatinine &#62;50&#37; of baseline creatinine or &#62;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#59; Kalemia &#62;5&#46;5<span class="elsevierStyleHsp" style=""></span>mEq&#47;l&#46; Asymptomatic hypotension is no reason for dose reduction&#46;</p>"
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Initial dose &#40;orally&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Optimal maintenance dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Captopril&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Enalapril&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Perindopril&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lisinopril&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ramipril&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Quinapril&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Trandolapril&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1042216.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Use of angiotensin converting enzyme inhibitor drugs in chronic heart failure&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Contraindications&#58; bronchial asthma&#59; serious chronic obstructive pulmonary disease &#40;if mild&#44; it is a relative contraindication&#41;&#59; systolic blood pressure &#60;85<span class="elsevierStyleHsp" style=""></span>mmHg&#59; heart rate &#60;60<span class="elsevierStyleHsp" style=""></span>lpm&#59; second or third degree atrioventricular block&#44; breast disease&#59; PR &#62;0&#46;24<span class="elsevierStyleHsp" style=""></span>s&#46; Dose reduction or drug withdrawal&#58; symptomatic bradycardia&#59; symptomatic hypotension&#59; hypoperfusion&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Initial dose &#40;orally&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Optimal maintenance dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Carvedilol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;125<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bisoprolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Metoprolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">200<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nebivolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1042212.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Use of &#946;-blockers in chronic heart failure&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Initial dose &#40;orally&#41; &#40;mg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Maximum dose &#40;mg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Furosemide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20&#8211;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">160&#8211;200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Torasemide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#8211;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chlorthalidone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&#8211;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hydrochlorothiazide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&#8211;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Indapamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Spironolactone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;5&#8211;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1042213.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Use of diuretics in chronic heart failure&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at5"
            "detalle" => "Table "
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">EF&#58; ejection fraction&#59; HR&#58; hazard ratio&#59; HF&#58; heart failure&#59; 95&#37; CI&#58; 95&#37; confidence interval&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Methods&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Objectives&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PEP-CHF<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double-blind study in 850 outpatients aged &#62;70 with EF &#62;50&#37;&#44; randomized to receive perindopril 4<span class="elsevierStyleHsp" style=""></span>mg&#47;d versus placebo with 2 year-followup&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Evaluates the effect of perindopril in reducing overall mortality and hospitalization from HF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Certain benefit with perindopril was observed&#44; but both the selection and the number of episodes was lower than the anticipated&#44; which shrugged off power to the study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Enalapril in HFpEF<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind study in 71 patients with EF &#62;50&#37;&#44; clinically stable&#44; randomized to 20<span class="elsevierStyleHsp" style=""></span>mg&#47;d of enalapril versus placebo&#44; with 12 month-followup&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Evaluate the effects of enalapril in improving exercise capacity and arterial distensibility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No benefit of enalapril versus placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleSmallCaps">I</span>-PRESERVE<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double-blind study of 4128 randomized patients to irbesartan 300<span class="elsevierStyleHsp" style=""></span>mg&#47;d versus placebo in patients admitted to hospital with EF &#62;<span class="elsevierStyleHsp" style=""></span>45&#37;&#44; with 49&#46;5 month-followup&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Evaluates the effect of irbesartan in the combined primary endpoint of overall mortality or hospitalization from cardiovascular causes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No benefit of irbesartan versus placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CHARM-PRESERVED<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind study in 3023 patients with EF &#62;40&#37;&#44; randomized to candersatan 32<span class="elsevierStyleHsp" style=""></span>mg&#47;d versus placebo&#44; with 36&#46;6 month-followup&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Evaluates the effect of candesartan in the combined primary endpoint of cardiovascular mortality or hospitalization from HF causes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Candesartan showed no reduction in the primary endpoint&#44; but showed a moderate impact in reducing secondary objective of hospitalization from HF &#40;230 versus 279&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RELAX<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind study of 216 patients with EF &#62;50&#37; clinically stable&#44; randomized to sildenafil 20<span class="elsevierStyleHsp" style=""></span>mg 3 times a day versus placebo for 12 weeks followed by 60<span class="elsevierStyleHsp" style=""></span>mg 3 times daily for another 12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It investigates the effect of inhibiting phosphodiesterase-5 with sildenafil in functional improvement and exercise capacity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No benefit of sildenafil versus placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RAAM-PEF<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind study in 44 stable patients with EF &#62;50&#37;&#44; randomized to eplerenone 50<span class="elsevierStyleHsp" style=""></span>mg&#47;d versus placebo&#44; with 6 month-followup&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It evaluates the effects of eplerenone in improving exercise capacity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eplerenone did not improve exercise capacity&#44; although it had beneficial effects on diastolic function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TOPCAT<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double blind study in 3445 patients with symptomatic EF &#62;45&#37;&#44; randomized to spironolactone 15&#8211;45<span class="elsevierStyleHsp" style=""></span>mg&#47;d versus placebo&#44; with 3&#46;3 year-followup&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It evaluates the effect of spironolactone in the combined primary endpoint of cardiovascular mortality&#44; sudden death or hospitalization from heart failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spironolactone showed no benefit on the combined primary endpoint&#44; but it did in the secondary objective of reducing hospitalization from HF &#40;206 versus 245&#59; HR 0&#46;83&#59; 95&#37; CI 0&#46;69&#8211;0&#46;99&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Drugs specifically evaluated in patients with heart failure and preserved ejection fraction&#46;</p>"
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Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2016.04.024

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