CHAPTER 4 192 DISCUSSION Since the success of the first heart failure therapeutic trial more than 30 years ago, survival of patients with HF have improved substantially. This improvement applies only to the HFrEF phenotype, encompassing about 50% and 60% of hospitalized and ambulatory HF patients, respectively.1–3 At least six therapeutic classes of proven clinical benefit by mortality and morbidity reductions and symptom relief are available for the treatment of chronic HFrEF. These are: (i) angiotensin-converting enzyme inhibitors (ACEi) , (ii) angiotensin-II receptor blockers (ARB), (iii) betablockers (BB), (iv) mineralocorticoid receptor antagonists (MRA), (v) neprilysin inhibitor (ARNI, sacubitril-valsartan) and (vi) sodium-glucose co-transporter 2 inhibitor (SGLT2i).4 Other treatments such as digoxin, ivabradine and vericiguat are available for specific subgroups and these work mainly by reducing risk of HF hospitalization.5–7 Taken together, about 73% reduction in mortality is anticipated with quadruple (BB, MRA, ARNI and SGLT2i) therapy.8 In practice, data from high income regions showed that the largest decline in mortality for HF occurred between 1980 and 2000.9 This coincides with the introduction and uptake of renin-angiotensin system (RAS) antagonists for HF.10 However, improvements in mortality in HF patients subsequently slowed, levelled and more recently, showed a reversed upward trajectory from 201510–12 signaling that incremental benefits from therapeutic development in HFrEF have yet to translate into population survival gains of comparable magnitude in the recent two decades. These stalling mortality rates are not isolated to Europe and North America but also observed in middle-income regions in Asia.13,14 Part of the reluctance or dilemma to use all proven medical treatment for HFrEF and up-titrate to target doses can be attributed to differences in titration strategies and populations seen in the explanatory trials versus those in routine care. The gap in data on safety and efficacy in under-represented subgroups, particularly older persons, women, individuals with comorbidities and organ dysfunction leads to hesitation to apply a one-size-fit-all approach to population in which frailty is common. When it comes to generalizability of HFrEF clinical evidence, the ultimate goal would be to encompass the full spectrum of patients who will receive the treatment post regulatory approval. In this chapter, we will discuss the present state
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