Why is Heart Failure so Important in the 21St Century?

Heart failure (HF) is a common affliction across the globe. As the 21st century unfolds, data from all over the planet suggest that HF increasingly affects us on a global level.1-7 The causes of HF are different in different parts of the world, ranging from hypertension and rheumatic heart disease in developing regions6 to degenerative valvular and myocardial diseases driven by aging populations in Europe and North America.1-3. Curiously, whatever triggers the HF process, it seems that once initiated HF becomes a separate syndrome with an accelerated dire outcome. For example, we were surprised in recent years when examining the results of an acute HF registry in sub-Saharan Africa to learn that short-term rates of readmission and death were similar to rates observed in other regions8 despite patients in the registry being younger, with HF mostly driven by hypertension and with virtually none of the patients having manifestations of ischaemic heart disease. This combination of HF being highly prevalent across the globe and the significant adverse outcome, which seems to be largely independent of age, aetiology, and region, should prompt the global community to invest in tackling this growing epidemic as a major priority, with focus in a few key areas. Significant progress has been made in the treatment of chronic, but not acute, HF with the introduction of medications blocking the renin–angiotensin–aldosterone system (RAAS) and adrenergic system and devices that reduce sudden death and improve left ventricular contractile synchronization.9 Despite these advances, even in the controlled setting of a clinical study, patients with chronic HF have an annual rate of readmission or death of approximately 10% and close to 20% mortality over 2 years10 while those with acute HF have an accelerated disease progression leading to a mortality rate of approximately 10% in the first 6 months after admission.11 Our inability to fully ameliorate these adverse outcomes may relate to our incomplete understanding of HF pathophysiology. This lack of understanding may stem from an historical emphasis on the role of the heart in HF, and a lack of attention to other contributing factors such as the vasculature, lungs, kidneys, liver, gastrointestinal tract, and inflammation,12 suggesting that HF may be a systemic rather than a cardiac disorder. The invariance of outcomes regardless of age, aetiology, or region further supports the systemic nature of HF and suggests that some common systemic pathways mediate the progression of the HF process once established. However, some of these systemic pathways have been discarded after studies of agents blocking them (such as calcium blockers for the vasculature and tumour necrosis factor alpha for inflammation)13 failed to show clinical benefit and we have focused where clinical benefit has been shown. We believe that current data strongly suggest that HF is a systemic disease in which the heart and neurohormonal mechanisms are only responsible for some of its symptoms, progression, and outcomes and we should double our efforts to address other systemic factors such as the role of the lungs, vasculature and inflammation14-17 in order to identify suitable treatment targets furthering our aim to make patients with HF, especially acute HF where no progress was made over the last 30 years, feel better and live longer. As proposed earlier, evidence is accumulating that, once initiated, HF puts patients on a trajectory of high morbidity and mortality, much of it remaining unmodified even with the advent of modern therapy. Therefore, it would seem logical that prevention of HF should become a major therapeutic focus for the 21st century on a global level. With varying levels of success, such efforts have been initiated and implemented in some advanced economies, including early diagnosis and treatment of hypertension, identification and early control of risk factors for ischaemic heart disease, as well as more advanced methods to treat coronary artery disease and degenerative valvular disease early, before myocardial and systemic damage leads to overt HF.9, 18 However, the bulk of the global population continues to benefit only partly from such measures. While prevention and treatment of infectious disease, obstetric complications, and paediatric diseases were made a priority by global charitable funds such as the Bill and Melinda Gates foundation,19 similar efforts in the field of HF prevention in the developing world are lagging. This issue is especially important because in those countries HF affects younger adults, significantly disrupting their ability to provide for their families, thus having huge ramifications beyond the individual for communities as a whole. Given the extremely low price of simple interventions such as hypertension control, antibiotics to prevent rheumatic fever, and smoking and diet counselling, it is imperative that financial resources globally are allocated in a more balanced manner to address all sources of morbidity and mortality globally. Effectively advancing multiple new interventions through early clinical development is crucial to our ability to improve the treatment of HF.20 Reliable methods should be implemented to increase the chances that interventions tested in early development are correctly identified as effective when they are and ineffective when they are not. A main obstacle is that early development of new interventions in HF still relies heavily on surrogate measures, such as changes in haemodynamics or effects on neurohormonal markers, which do not always translate well into improvements of symptoms and outcomes. Examples of interventions that positively affected surrogate outcomes but that failed to improve patient outcomes abound,21-23 and we, of course, do not know how many potentially beneficial interventions were abandoned in the early development phase because they failed to improve surrogate measures—some of which may have been shown to improve symptoms and outcomes if tested in larger studies. In some cases companies have opted to ‘take the risk’ and skip phase II studies altogether, sometimes successfully as was the case with LCZ in chronic systolic HF.10 However, such an approach requires significant resources and limits the number of compounds that can be developed. Other approaches may involve using more complex statistical methods examining the efficacy of interventions across multiple endpoints in early studies.24 These endpoints representing multiple facets of the HF process, including symptom relief, functional status, quality of life, hospital readmissions, end organ damage and death can be combined to determine the overall effects of novel interventions on clinical rather than surrogate outcomes, hopefully reducing the number of subjects needed for proof of concept and increasing the translatability of such early findings to larger definitive studies. Once such potentially effective therapies are identified, it is equally important that they are made available to patients as soon as possible, taking into account effects beyond those on the traditional mortality and to some degree hospital readmissions. Studies have shown that for some patients symptom relief and quality of life may be equally (if not more) important than hospital stays;25 these considerations are largely ignored in the current regulatory framework for approval of interventions in HF. It is therefore equally imperative for regulators to enable more rapid availability of therapies, even if only shown initially to benefit symptoms, early disease recurrence,26 and quality of life, by allowing a more gradual and tiered approval process where initial results in smaller studies suggesting benefit in patient-reported outcomes may lead to conditional approval followed by expansion of indication as information becomes available in larger studies exploring additional endpoints such as readmission and death. Some existing therapies have not been fully explored. For example, a combination of hydralazine and nitrates has been shown to be beneficial in patients with HF;27 however, after the introduction of blockers of the RAAS and adrenergic systems into HF therapy the combination has not been further evaluated in a larger cohort of HF patients. The same comment can be made about digoxin.28 This paucity of research may be because of the drugs' lack of commercial value, so private investment is negligible while publicly-funded research institutions are not equipped to invest large amounts of money into focused HF drug development. Such investments should be made, however, both in this regard and in furthering our understanding of the pathophysiology of HF. In summary, HF is a significant health burden globally that should be prioritized by health authorities, the scientific community and funding sources. We believe that a better understanding of HF pathophysiology, significant investment in its prevention, and smoother, simpler pathways for developing new interventions should be the focus of our efforts in coming years in order to reduce the high human and economical costs incurred by this disease.