Therapy of Heart Failure (Heart Failure with Reduced Ejection Fraction): New Sequencing (Drug Therapy)

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 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 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 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 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 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 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 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 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 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 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 Ejection Fraction As the by John McMurray of the British Heart from the of ARNI, MRA, SGLT2i and blockers, when the for HFrEF. the approach to HF therapy has been a addition 6 of the different drugs doses of before the the above all the drugs within a short of time 2 in low doses the maximally tolerated doses of any of the drugs start with ACEi/ARB followed by beta blocker, MRA, ARNI and SGLT2i to doses at However, the current system that in a patient who has beta and SGLT2i to be initiated ARNI added in weeks is stable and MRA added in the weeks renal function and levels are stable as the specific circumstances the entire therapy within a short of 1 the can be 1 and of HF of HF put forth in of the new are as The not to the known relative of the drugs Even low doses of the drugs significant the of only to the in low is to beneficial effects than dose of a drug important is the long time to the doses of all drugs compared to the very short within which the drugs have beneficial effects in clinical as early as all drugs in low doses in over weeks of HF to be and The may also allow and tolerability can reduce the renal dysfunction associated with ARNI and SGLT2i can the risk of associated with SGLT2i can the risk of early worsening HF with beta-blocker The is to the of the entire of highly effective HF being introduced in a that deaths and hospitalizations for HF with a and tolerable adverse effect