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Table of Contents
EDITORIAL
Year : 2021  |  Volume : 11  |  Issue : 2  |  Page : 44-49

Therapy of heart failure (heart failure with reduced ejection fraction): New sequencing (drug therapy)


Department of Cardiology, Krishna Institute of Medical Sciences, Secunderabad, Telangana, India

Date of Submission05-Feb-2021
Date of Acceptance16-Feb-2021
Date of Web Publication03-May-2021

Correspondence Address:
Dr. Dayasagar Rao Vala
Krishna Institute of Medical Sciences, Secunderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jicc.jicc_8_21

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How to cite this article:
Lokre A, Vala DR. Therapy of heart failure (heart failure with reduced ejection fraction): New sequencing (drug therapy). J Indian coll cardiol 2021;11:44-9

How to cite this URL:
Lokre A, Vala DR. Therapy of heart failure (heart failure with reduced ejection fraction): New sequencing (drug therapy). J Indian coll cardiol [serial online] 2021 [cited 2021 May 17];11:44-9. Available from: https://www.joicc.org/text.asp?2021/11/2/44/315268



Historically, the mainstay of treatment for chronic heart failure (HF) had long been diuretics and digitalis, a cardiac glycoside, which formed the older class of inotropic agents, as recorded in William Withering's document over 200 years ago.[1] Digoxin remained so for a long time until the turn of the 20th century when the digitalis investigation group demonstrated in a placebo-controlled, randomized trial that there was no mortality benefit with digoxin use and since, it ceased to be the panacea for all HFs.[2] However, the modern history of therapy for HF starts with the introduction of vasodilatation as an effective treatment modality with survival advantage in patients with HF with reduced ejection fraction (HFrEF).[1] Over the years, more than 150 trials with various drugs ushered in the current era of evidence based standard of care for HF.[3] Currently, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), beta blockers, mineralocorticoid receptor antagonists (MRA), the combination of ARB with neprilysin inhibitor (ARNI) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i) can be considered the five pillars of modern guideline-directed medical therapy (GDMT) for HF according to John McMurray of the British Heart Foundation.[4] Of note, both ARNI and SGLT2i have only been discovered in the last decade. Digoxin, Ivabradine, diuretics, and the combination of hydralazine with Isosorbide dinitrate have, now, been relegated to use only in specific circumstances in the management of chronic HF.


  Hydrazine-Nitrate Top


The journey of HF therapy began with the V-HeFT I study in 1986, with the rationale that the reversal of the vasoconstriction (seen in the pathophysiology of HF) would reduce the preload and afterload to the left ventricle (LV), and thus, improve the performance of the ventricle and increase the cardiac output resulting in improved hemodynamics effecting improved survival. In chronic congestive heart failure (CHF) patients with impaired cardiac function, when a combination of hydralazine and isosorbide dinitrate, as compared with either placebo or prazosin, was added to the standard treatment regimen of digoxin and diuretics, it reduced mortality by 36% at 3 years of follow-up with a significant mortality benefit evident from as early as 1 year. This was the introduction of the concept of vasodilatation as an effective treatment for HF. However, by the time, this study was concluded, the ACEi, Captopril had already, been approved for treatment of HF. Furthermore, the numbers were small to start with and there was a significant proportion (>20%) of discontinuation because of adverse effects. Furthermore, the study could not give any data on outcomes beyond 3 years.[5]


  Angiotensin-Converting Enzyme Inhibitors Top


CONSENSUS was the first (1987) study which brought ACEi into limelight as a highly effective medical therapy for HF. Enalapril reduced overall mortality by 40% in severe CHF (NYHA Class IV) patients at 6 months on top of the then GDMT, including diuretics, Digoxin, and other vasodilators. However, the favorable effect on mortality was found only for death due HF but no significant benefit was found for sudden cardiac death (SCD). The property of first dose hypotension (leading to discontinuation) and a change of the protocol to start with a lower first dose were initiated from this study. The development of renal dysfunction and hyperkalaemia with ACEi use was noted. Of note, the average follow-up period was extremely short (6 months). Furthermore, beyond 12 months, the sample size was too small for any meaningful interpretation.[6]

SOLVD-treatment trial followed (1991) and reinforced the findings of CONSENSUS in NYHA classes II and III of HFrEF showing a relative risk reduction (RRR) of 16% for cardiovascular (CV) death and 22% for death attributed to HF at more than 3 years' follow-up. However, the mortality benefit was not seen after 2 years, and the CV benefit was essentially due to hospitalizations for HF (HHF).[7]

These two trials firmly established the role of ACEi in the management of HF. However, the above two trials did not show any significant reduction of SCD.

V HEFT II trial (1991) showed that Enalapril was superior to the combination of hydralazine and isosorbide dinitrate when added to the background therapy of Digoxin and diuretics, with an RRR of 28% for mortality after 2 years. For the first time, a mortality benefit was demonstrated with respect to SCD, especially in NYHA Classes I and II, suggesting that the benefits of ACEi may be reflective of an additional nonvasodilatory mechanism. However, more improvement was noticed in the exercise performance and LV function in the nonspecific vasodilator (Hydralzine-Nitrate) arm. The study, thus, suggested that in view of the different physiological effects of the two drug regimens, using a combination of both might be beneficial. This study remains the only major head to head comparison of ACEi and Hydralazine-Nitrate combination till date.[8]

SOLVD-Prevention trial (1992) ushered in the concept of prevention of HF (as opposed to treatment till then) with the use of ACEi. Enalapril, given to subjects with asymptomatic LV dysfunction with ejection fraction (EF) <0.35, who were not on any treatment for HF, reduced the incidence of HF and related hospitalizations and also showed a trend toward reduction of death due to CV causes at the end of, approximately, 3 years. However, a significant reduction in mortality was not demonstrable. The RRR of total and CV mortality were smaller in this “Prevention” trial than the SOLVD-Treatment trial.[9]


  Angiotensin Receptor Blockers Top


Val-HeFT trial (2001) proved the value of ARB in HF; a 13% RRR in the combined endpoint of mortality and morbidity including EF and NYHA class was seen with Valsartan compared to a placebo when added to the background therapy. However, the study demonstrated a trend toward an increase in the endpoint of mortality and morbidity with the use of ARB along with both ACEi and beta-blockers. The increase of EF although was less prominent than the previous trials with ACEi, and there was no significant reduction in all-cause death on statistical analysis. Since the overall uses of ARB were similar to ACEi, they were generally reserved for the use in cases of ACEi-induced cough.[10]


  Beta-Blockers Top


Beta-blockers were initially considered counterproductive because of withdrawal of the compensatory sympathetic activity which was a part of the HF pathophysiology.

US Carvedilol Study Group showed, convincingly, for the first time, in 1996, that the beta blocker, Carvedilol not only reduced HHF but also afforded survival benefit. Carvedilol, added to the standard background medical therapy including an ACEi, diuretics and digoxin, demonstrated a staggering 65% RRR in mortality which prompted an early termination of the trial (in <2 years). This study proved that suppression of the deleterious sympathetic overactivity with the use of beta-blockers was beneficial contrary to the earlier belief. However, since carvedilol has an additional intrinsic sympathetic activity and acts atypically, the study could only be considered as hypothesis-generating for the use of other beta-blockers. Furthermore, since the follow-up period was very short, it precluded extrapolation of the results to long-term outcomes.[11]

MERIT HF trial (1999) demonstrated a 34% reduction in all-cause mortality (38% in the subgroup with NYHA III/IV symptoms), 41% lesser SCD, and 49% lesser deaths from worsening HF when long-acting metoprolol (succinate) was added to optimum background therapy in symptomatic HFrEF. The NNT was as low as 27 patients treated for 1 year. Notably, almost all (96%) the patients had mild-to-moderate HF (NYHA II/III) and since this subgroup of patients is at a higher risk of dying due to SCD (likely due to ventricular fibrillation) rather than worsening pump failure, there was a more predominant mortality benefit with beta-blocker use in SCD reduction as a proportion of the total mortality. Thus, the study could not be extrapolated to severe HF patients (NYHA IV). The results were in close agreement with the CIBIS II trial with Bisoprolol. Interestingly, there was lesser blood pressure reduction with Metoprolol XL compared to placebo which is reflective of the improved hemodynamics and LV remodelling. The study, however, was not designed to allow a subgroup analysis of idiopathic dilated cardiomyopathy and also excluded patients younger than 40 years of age.[12]

CIBIS II trial (1999) with Bisoprolol in symptomatic (NYHA III/IV) HFrEF (<35%) was stopped early because of the significant 34% reduction of all-cause mortality comprised of 42% reduction of SCD and a nonsignificantly lower rate of death due to pump failure – thus suggestive of a predominant anti-arrhythmic effect of bisoprolol (CIBIS I(1994) trial had failed to show a statistically significant mortality benefit, although it showed improvement in functional class with a significant reduction in HHF). However, only stable patients were included in the study, and the role of beta-blockers in nonambulatory NYHA IV patients remained to be defined. Furthermore, the study population was a decade younger than those usually seen in the general population. The role of beta-blockers in post-MI situation also needed to be defined further.[13]

COPERNICUS trial (2001) was the first to evaluate the role of beta blockers in patients with severe HF (NYHA IV) and severe LV dysfunction (EF <25%) and showed a 35% RRR in death with addition of Carvedilol to the then standard medical therapy including ACEi and diuretics. However, it must be remembered that all agents blocking the β1 receptors cannot be considered to be equally effective in providing mortality benefit as Carvedilol has additional α receptor blocking effect which helps further block the deleterious effects of the sympathetic nervous system activation in HF. Also important to note is that patients with symptomatic hypotension, those on intravenous inotropic agents/vasodilators were excluded, and so, should also be excluded in the clinical practice when treatment with beta-blockers is being administered.[14]


  Mineralocorticoid Receptor Antagonists Top


RALES trial (1999) was the first study to prove the role of MRA in HFrEF. Spironolactone, added to the background therapy (including ACEi) in severe HF (NYHA III/IV) due to LV dysfunction (EF <35%) reduced the mortality by additional 30%-reduction of deaths due to HF as well as to SCD was significant. The 35% reduction in hospitalization for HF was thought to reflect the salutary effects of the MRA on myocardial and vascular fibrosis. However, the role of MRA in less severe HF and in post-MI situations remained to be established.[15]

EMPHASIS-HF trial (2011) demonstrated the benefits of Eplerenone, an MRA, in HFrEF (EF <35%) with mild symptoms (NYHA II) when added to standard medical therapy. The trial was stopped prematurely because of the significant 37% reduction in CV death or HHF at 21 months, albeit at a higher risk of significant hyperkalaemia. The earlier stoppage may have overestimated the benefit. The results of the study may not be applicable to patients with mild symptoms (NYHA I/II).[16]


  Angiotensin Receptor Blocker with Neprilysin Inhibitor Top


PARADIGM-HF trial (2014) ushered in a new era in the therapy of symptomatic HFrEF with the introduction of the combination of a new molecule, Saccubitril, a neprilysin inhibitor with Valsartan, an ARB (ARNI/LCZ696), which, when added to the background optimal medical therapy in symptomatic (NYHA II-IV) HFrEF (<40%) patients, resulted in 20% RRR in CV death or HHF when compared with Enalapril therapy (control group). The trial was stopped early because of the overwhelming benefit in the ARNI group. However, the study design included a prolonged run-in period with 10 mg or more of Enalapril to test for tolerability before shifting to ARNI which is the intended design to simulate shifting from the ACEi or ARB to ARNI in clinical practice. However, the specific study population may not be completely identified with the real world scenario because of the strict inclusion and exclusion criteria; the real world data may be needed before the results are extrapolated to a wider population.[17]

The recent PIONEER HF trial (2019) evaluated the role of ARNI in HFrEF patients presenting with acute decompensated HF (ADHF) who were started on ARNI within 1–10 days of presentation before discharge from the hospital, after initial stabilisation. There was a 29% RRR in NT pro BNP levels versus the use of Enalapril, evident as early as the end of 1st week. This trial introduced the concept of early initiation of ARNI in ADHF as there was a reduction in the rate of rehospitalization for HF at the end of 8 weeks when ARNI was initiated in-hospital. This study also put forth the requirements for in-hospital initiation of ARNI and worked with the low dose in contrast to the highest tolerable doses used in the PARADIGM-HF study. However, the trial did not study the clinical outcomes which is a major drawback.[18]


  Sodium-Glucose Co-Transporter 2 Inhibitors Top


EMPAREG trial (2015) evaluated the effect of a new antidiabetic drug, Empagliflozin (an SGLT2i) for its CV mortality and morbidity when given along with the standard medical therapy in patients of Type 2 diabetes mellitus (DM) at high CV risk. It was a randomized, double-blind trial with participation of over 40 countries. The study showed a 14% reduction in CV death, MI or Stroke with Empagliflozin (the primary outcome). Notably, this group also showed statistically significant 38%, 35%, and 32% RRRs in CV death, HHF, and all-cause mortality, respectively. This paved the way for SGLT2i becoming a part of the standard of care of HF medical therapy. However, these benefits were observed in a population of Type 2 diabetics with established CV disease and may not be extrapolated to other patient populations.[19]

CANVAS and CANVAS-R trials (2017) together evaluated canagliflozin compared to placebo in over 10000 patients with Type 2 DM and high risk for CV disease and found that canagliflozin use reduced the composite of CV death, MI and stroke by 14% along with significant renal benefits. A nearly doubled risk of distal foot/toe amputations found with canagliflozin use was still very low in absolute numbers. The total number of adverse events seen in the trial was modest, and thus, the conclusions made could be false positive. The effects in nondiabetic population needed further testing in other trials.[20]

DAPA HF trial (2019) was a placebo controlled randomized trial in HFrEF patients with NYHA II-IV symptoms using Dapagliflozin in addition to the standard background therapy which included beta-blockers (96%), ACE I (56%)/ARB (>25%), MRA (>70%), and guideline directed device therapy. There was a 26% reduction in the composite of CV death or worsening HF with similar findings irrespective of the diabetic status-the first study to demonstrate the efficacy of SGLT2i in the nondiabetic population, thus making them a part of standard of care for HFrEF patients. Their study population was different from the previous trials with SGLT2i in that the participants here were at a higher risk of HHF and death from CV causes and many of them had chronic kidney disease of stage 3 or worse. However, owing to the strict inclusion and exclusion criteria, the findings may not be generalizable to the entire HFrEF population. Furthermore, notable is that in the study population, the use of ARNI, which is known to favorably affect the course and prognosis, in the background medical therapy was very low (approximately 10%).[21]

The recently concluded EMPEROR-REDUCED trial (published August 29, 2020) demonstrated the benefit of empagliflozin in HFrEF patients (EF <40%) in NYHA Class II-III irrespective of the presence or absence of diabetes. Empagliflozin use led to a 25% RRR in CV death or HHF (led by the 31% RRR of HHF) and a reduced annual rate of decline in estimated glomerular filtration rate (including lesser serious renal adverse outcomes) in patients already on GDMT including beta blockers (90%), ACEi/ARB (70%) or ARNI (19%–20%) and MRA (70%). The 'number needed to treat' to prevent one primary event was just 19. The study was notable for the nearly 50% nondiabetic patients, nearly half the population having Stage 3 or worse chronic kidney disease, nearly 1:1 prevalence of HF subjects with ischaemic and nonischaemic aetiologies and the robust background medical therapy of the subjects. The population differed from that of DAPA-HF trial because of the worse LV function (Over 70% subjects had EF <30%) with nearly 80% subjects showing elevated natriuretic peptides. However, the use of ARNI, which has recently been considered to have a significant beneficial effect on HF prognosis, in the background medical therapy, was only about 20%; nonetheless, there was a 36% RRR in those on ARNI on subgroup analysis. The RRR in mortality was only modest (8%).[22]


  Digoxin Top


After centuries of use in the treatment of symptomatic HF with LV dysfunction, The Digitalis Investigation Group formally studied the effects of digoxin on mortality and hospitalization in a placebo controlled, randomized, double-blind trial (DIG trial) in 1997. The subjects had HF with an EF of <0.45 and were on a background therapy with diuretics and ACEi. Digoxin versus placebo, added to the background therapy, did not reduce the mortality; however there was a 28% RRR in HHF, thus determining the more appropriate role for digoxin in the management of HF.[2]


  Ivabradine Top


SHIFT trial (2010) compared Ivabradine, the funny sodium channel inhibitor at sinus node, to placebo, in patients of NYHA II-IV HF with EF <0.35, with the resting heart rate r70/min, on optimal medical therapy, with respect to CV death or HHF. There was a reduction in the resting heart rates and an 18% RRR in the composite of CV death and HHF with Ivabradine, although, the CV mortality-a secondary endpoint, was not significantly reduced. The drug was associated with a small risk of symptomatic bradycardia. This opened up a new approach to the management of HF patients who were intolerant to or were already on the maximally tolerated doses of beta-blockers with inadequately controlled heart rates and having recurrent HF related hospital admissions.[23]


  Heart Failure with Preserved Ejection Fraction Top


Despite the decades of research and the plethora of drugs evaluated in HF, there is still no medical therapy for “HF with Preserved EF” with any proven mortality benefit. Various drugs like Candesartan (CHARM),[24] Nebivolol (SENIORS),[25] Spironolactone (TOPCAT)[26] and Digoxin (DIG)[2] did show reductions in HHF but none of these afforded any survival advantage. Thus, ARB and Spironolactone have received a Class IIb recommendation from the ACC/AHA in HF with Preserved EF (HFpEF) for reduction of HHF.[27] Even ARNI (PARAGON-HF) failed to reduce mortality.[28] As for SGLT2i, EMPEROR-Preserved[29] and DELIVER[30] trials are ongoing studies with Empagliflozin and Dapagliflozin respectively, in HFpEF.[27]


  Current Guidelines on the Sequence of Initiating the Various Heart Failure Therapies in Heart Failure with Reduced Ejection Fraction Top


As per the latest paper by John McMurray of the British Heart Foundation from the University of Glasgow, ARNI, MRA, SGLT2i and Beta blockers, when combined, form the “Foundation therapy” for HFrEF. Whereas the conventional approach to HF therapy has been a gradual addition (typically around 6 months) of the different drugs targeting maximal doses of each before adding the next one, the above publication recommends starting all the 4 drugs within a short span of time (about 2 months) in low doses without targeting the maximally tolerated doses of any of the drugs initially. Traditionally, physicians start with ACEi/ARB followed by beta blocker, MRA, ARNI and lastly SGLT2i while uptitrating to maximal doses at each step. However, the current system recommends that in a patient who has achieved euvolemia, beta blocker and SGLT2i to be initiated first, ARNI added in 1–2 weeks if BP is stable and MRA added in the next 1–2 weeks if renal function and potassium levels are stable (Individualization as per the specific circumstances advised)-thus introducing the entire foundation therapy within a short span of 1 month; the uptitration can be pursued thereafter [Figure 1] and [Figure 2].
Figure 1: Traditional sequencing of HF drugs

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Figure 2: Proposed/New Rapid sequencing of HF drugs

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The explanations put forth in support of the new sequencing are as follows:

  1. The traditional sequence does not necessarily conform to the known relative efficacies of the available drugs
  2. Even low doses of the drugs afford significant benefits, whereas the escalation of dosage adds only marginally to the efficacies, whereas initiating multimodal treatment, even in low dose, is likely to exert greater beneficial effects than maximal dose of a single drug
  3. Another important factor is the unacceptably long time required to achieve the target doses of all 4 drugs compared to the very short periods within which the drugs have shown beneficial effects in clinical trials, sometimes, as early as 30 days. Adding all four drugs in low doses in rapid succession over few weeks allows multiple pathways of HF to be targeted simultaneously and rapidly
  4. The proposed method may also allow better safety and tolerability profile-SGLT2i can reduce the renal dysfunction associated with ACEi/ARB/ARNI; ARNI and SGLT2i can minimise the risk of hyperkalemia associated with MRA; SGLT2i can mitigate the risk of early worsening HF with beta-blocker initiation.


The proposed sequence is expected to maximize the possibility of the entire armamentarium of highly effective HF therapies being introduced rapidly in a manner that minimizes deaths and hospitalizations for HF with a safe and tolerable adverse effect profile.[31]



 
  References Top

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Sacks CA, Jarcho JA, Curfman GD. Paradigm shifts in heart-failure therapy – A timeline. N Engl J Med 2014;371:989-91.  Back to cited text no. 1
    
2.
Garg R, Gorlin R, Smith T, Yusuf S. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group (DIG). NEJM 1997;336:525-33.  Back to cited text no. 2
    
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Owens AT, Brozena SC, Jessup M. New management strategies in heart failure. Circ Res 2016;118:480-95.  Back to cited text no. 3
    
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Nicole Lou. Entresto data support wider reach of 'Fifth Pillar' HF drug – benefits observed beyond HF patients with reduced EF. MedPage Today. Available from: https://www.medpagetoday.com/meetingcoverage/aha/83401. [Last accessed on 2019 Nov 17]  Back to cited text no. 4
    
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Cohn JN, Archibald DG, Ziesche S, Smith R, Anand I, Dunkman WB, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure (V-HeFT I). NEJM 1986;314:1547-52.  Back to cited text no. 5
    
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The Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure (CONSENSUS). NEJM 1987;316:1429-35.  Back to cited text no. 6
    
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The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure (SOLVD-treatment). NEJM 1991;325:293-302.  Back to cited text no. 7
    
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Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. A comparison of enalapril with hydralazine–isosorbide dinitrate in the treatment of chronic congestive heart failure (V-HeFT II). NEJM 1991;325:303-10.  Back to cited text no. 8
    
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The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions (SOLVD-Prevention). NEJM 1992;327:685-91.  Back to cited text no. 9
    
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Cohn JN, Tognoni G. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure (Val-HeFT). NEJM 2001;345:1667-75.  Back to cited text no. 10
    
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Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55.  Back to cited text no. 11
    
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Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-07.  Back to cited text no. 12
    
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CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999;353:9-13.  Back to cited text no. 13
    
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Packer M, Coats AJ, Fowler MB, Roecker EB, Katus HA, Krum H, et al. Effect of carvedilol on survival in severe chronic heart failure (COPERNICUS). NEJM 2001;344:1651-8.  Back to cited text no. 14
    
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Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez E, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure (RALES). NEJM 1999;341:709-17.  Back to cited text no. 15
    
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Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms (EMPHASIS-HF). NEJM 2011;364:11-21.  Back to cited text no. 16
    
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McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). NEJM 2014;371:993-1004.  Back to cited text no. 17
    
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Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, et al. Angiotensin–neprilysin inhibition in acute decompensated heart failure (PIONEER-HF). NEJM 2019;380:539-48.  Back to cited text no. 18
    
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Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPAREG). NEJM 2015;373:2117-28.  Back to cited text no. 19
    
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Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS). NEJM 2017;377:644-57.  Back to cited text no. 20
    
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McMurray JJ, Solomon SD, Inzucchi SE, K&#s248;ber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA HF). NEJM 2019;381:1995-2008.  Back to cited text no. 21
    
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Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure (EMPEROR-REDUCED). NEJM 2020;383:1413-24.  Back to cited text no. 22
    
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Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875-85.  Back to cited text no. 23
    
24.
Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-preserved trial. Lancet 2003;362:777-81.  Back to cited text no. 24
    
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van Veldhuisen DJ, Cohen-Solal A, Böhm M, Anker SD, Babalis D, Roughton M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol 2009;53:2150-8.  Back to cited text no. 25
    
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Pitt B, Pfeffer MA, Assman SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction (TOPCAT). NEJM 2014;370:1383-92.  Back to cited text no. 26
    
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Pfeffer MA, Shah AM, Borlaug BA. Heart failure with preserved ejection fraction in perspective. Circ Res 2019;124:1598-617.  Back to cited text no. 27
    
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EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure with Preserved Ejection Fraction (EMPEROR-Preserved). Available from: https://clinicaltrials.gov/ct2/show/NCT03057951. [Last accessed on 2021 Apr 13].  Back to cited text no. 29
    
30.
An International, Double-Blind, Randomised, Placebo-Controlled Phase III Study to Evaluate the Effect of Dapagliflozin on Reducing CV Death or Worsening Heart Failure in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF) (DELIVER). Available from: https://clinicaltrials.gov/ct2/show/NCT03619213. [Last accessed on 2021 Mar 9].  Back to cited text no. 30
    
31.
McMurray JJ, Packer M. How should we sequence the treatments for heart failure and a reduced ejection fraction? A redefinition of evidence based medicine. Circulation. 2021;143:875–877. [doi: 10.1161/CIRCULATIONAHA.120.052926]  Back to cited text no. 31
    


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