Update of treatment in chronic heart failure

Casado Cerrada, Jesús; Gómez del Olmo, Vicente; Manzano, Luis
doi:10.1016/j.medcle.2016.04.024
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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; However&#44; its implementation in routine clinical practice is lower than that of other recommended pharmacological groups&#44; probably due to the excessive suspicion about the development of hyperkalemia in high-risk patients who are receiving ACE inhibitors&#47;ARBs or in those with impaired renal function&#46; In any case&#44; they are indicated in patients with ventricular dysfunction in NYHA class II&#8211;IV or in patients with recent acute myocardial infarction &#40;AMI&#41; who are diabetic or have HFdEF&#44; regardless of their functional class&#46; According to the published results of a substudy of EPHESUS<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a>&#44; which demonstrated a marked reduction in mortality in the first month of treatment&#44; the AA should be initiated in the period right after AMI&#44; before hospital discharge&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Up to date there are no studies that allow us to compare&#44; 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" => "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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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">HF&#58; heart failure&#46;</p>"
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                  \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&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
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1042214.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Nonpharmacological general therapeutic recommendations&#46;</p>"
        ]
      ]
      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" => "<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>"
          "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">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"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "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 "
            "rol" => "short"
          ]
        ]
        "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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