Editor comments: focus on heart failure and cardiomyopathies Free

Sarcopenia, body mass index, and outcomes in heart failure

Sarcopenia is a predominantly age-related process that is a result of loss of skeletal muscle mass and function that leads to decreased physical ability. Here, Konishi et al., evaluated in a retrospective fashion the impact of sarcopenia on mortality among 942 patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) patient older than 65 years of age. Prevalence of sarcopenia was similar in the two HF groups but similarly associated with 1-year mortality in all multivariable-adjusted models.¹

In contrast, the relationship between body weight and mortality is not linear. Several observational studies have shown a J-curved or U-shaped relationship between body mass index (BMI) and death, giving rise to a phenomenon called the obesity paradox. The obesity paradox has also been observed in HF patients which overweight and at least mildly obese patients with HF often have a better prognosis, during the short-term, compared with lean HF patients.²

However, most of the studies have enrolled HFrEF or HFpEF patients while whether obesity paradox is present also in patients with HF and mid-range ejection fraction (HFmrEF) has never been addressed so far. Likewise, little evidence exists about the relationship between BMI and HF aetiology.

In this issue, Gentile et al.³ explored the prognostic value of BMI in 5155 patients with either ischaemic or non-ischaemic HF across the whole spectrum of LVEF. The vast majority of patients had HFrEF while 18% had HFmrEF and 19% HFpEF. Patients were further stratified according to the World Health Organization classification of BMI. Among these categories, the authors found that only underweight was significantly associated with an increased risk of 5 years of all-cause mortality. In the subgroup analyses, underweight was an independent predictor of mortality in all subgroups of patients, including HFmrEF. In contrast, both overweight and mild-to-moderate obesity were associated with better outcomes but only in non-ischaemic HF.

Temporal trends and predictors of in-hospital death in patients hospitalized for heart failure

Despite the great progress in its treatment, HF remains one of the main causes of hospitalization in several countries and is associated with high rates of morbidity and mortality.⁴ Among patients hospitalized for HF, in-hospital mortality is reported to vary from 2.0% to 12.0% and mortality at 1-year post-discharge from 13.3% to 30.5%. In this issue of the journal, Keller et al.,⁵ analysing 4 539 140 hospitalizations due to HF, investigated trends in incidence, case fatality rate, patient characteristics, and adverse in-hospital events of patients hospitalized for HF in Germany. They reported an increase in the annual rate of primary HF hospitalizations from 380.9 in 2005 to 539.4 per 100 000 population in 2016. Despite this increase in hospitalization, the in-hospital case fatality rate decreased from 11.1% to 8.1 and the rate of major adverse cardiovascular and cerebrovascular events decreased from 12.7% to 10.3%. Older age and cancer were independent predictors of in-hospital death.

Impact of sex-specific target dose in chronic heart failure

Guidelines recommend equal target doses for women and men. Recently, these recommendations have been challenged as a research suggested that women with HFrEF may reach optimal treatment effect at half of the guideline-recommended dose with respect to men.⁶

In the current study, Veenis et al.⁷ used the CHECK-HF cross-sectional observational cohort, which included 10 910 HF patients from 34 participating Dutch centres, to study the impact of sex-specific target dose in HFrEF patients. The authors found that there were significant but relatively small differences in drug dose between men and women, the latter less often received renin-angiotensin-system inhibitors but more often b-blockers than men. Furthermore, the study looked at the implementation of a hypothetical sex-specific target dosing schedule (50% of the guideline-recommended target dose) and found that more women were adequately treated and identified a subgroup that was overdosed with increased risk of side-effects and intolerance. This study confirmed the importance of moving towards personalized medicine in HF and suggested that future HF clinical trials must have prespecified gender analysis to determine optimal doses for all genders.

MyoVasc study: a prospective cohort study investigating development and progression of heart failure

Despite the enormous progress in the treatment and management of HF patients, there are still unmet needs such as the limited knowledge about the natural history of HF across LVEF, the lack of effective preventive strategies for HFrEF, or specific medical therapies for patients with HFpEF.⁸

In the current issue, Göbel et al.⁹ presented the rationale, design, and baseline characteristics of the MyoVasc, a prospective, observational, cohort study, investigating the development, and progression of HF in a cohort of subjects enrolled from the University Medical Centre Mainz, Germany. From January 2013 to April 2018, 3289 subjects have been enrolled. Of these, 1741 were overt HF subjects, with HFpEF as the prevalent phenotype (37.1%), whereas 19.7% were HFrEF and 23% were HFmrEF. In addition, 1253 individuals were not HF patients (considered as stage A/B following the American guidelines). The primary aim of the study was the improvement of the understanding of the patho-mechanisms of HF across the full spectrum of clinical presentation.

Prevalence and determinants of the precursor stages of heart failure

The increasing prevalence of risk conditions (e.g. hypertension, diabetes) leads to an increased number of persons at risk of HF, categorized as HF Stage A, according to the American guidelines. Overt HF, categorized as HF Stage C or D, is associated with poor prognosis, but also preclinical stages of HF, HF Stage B, has an increased risk of hospitalization and mortality. The early recognition and improved treatment of risk conditions may delay the progression of HF and optimize tailored preventive interventions.¹⁰

In the current issue, Morbach et al.¹¹ assessed the prevalence of HF precursor stages in a representative sample of near 5000 residents of the City of Wurzburg, aged 30–79 years with who no medical history of HF. Patients were grouped into A–D stages of HF according to American guidelines and the whole sample was divided in a derivation cohort (2473 patients) and validation cohort (2492 patients).

In the derivation cohort, 42% of participants were in Stage A and 17% were in Stage B while only seven patients had structural heart disease with symptoms (Stage C). Interestingly, they also identified a substantial proportion of participants (31%) with structural heart disease who had no risk factors (called Stage B-not-A) Compared to individuals in Stage B with A criteria, B-not-A were younger, more often women, and had left ventricular dilation as the predominant B qualifying criterion. These findings were confirmed in the internal validation cohort, in which 9% were found to be in Stage B-not-A. Given the higher prevalence of patients in Stages A and B, this study highlighted the importance of screening at-risk asymptomatic patients for HF and shed a light on a group of patients who lacked established HF risk factors and therefore would have been missed by conventional primary prevention.

Integrating natriuretic peptides and diastolic dysfunction to predict adverse events in high-risk asymptomatic subjects

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is produced within myocytes and released into the circulation during increases in the ventricular and atrial pressures with an association between NT-proBNP levels and subclinical cardiac structural abnormalities.¹² Therefore, NT-proBNP could represent a useful diagnostic marker for detecting subclinical cardiac impairment in patients with HF in Stage A or B.

In the current issue, Gori et al.¹³ explored the value of predicting new-onset HF and death by combining diastolic dysfunction (DD; E/E1 >15) and NT-proBNP values in an asymptomatic population at risk of AHA HF Stages A and B.

The authors identified four risk categories by combining DD (present/absent) and NT-proBNP values (high/low), with the group (DD/high NT-proBNP) conveying the worse prognosis compared to the control group. These results highlighted how the combination between natriuretic peptides and diastolic dysfunction may aid in the early and correct identification of patients who are at increased risk of incident HF and death and thus may be suitable candidates for more stringent preventive strategies.

Management of cardiac amyloidosis

Cardiac amyloidosis (CA) is caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells or transthyretin (TTR) amyloidosis (ATTR), a liver-synthesized protein previously called prealbumin that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein. ATTR can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of ATTRwt (wild-type transthyretin protein), previously called senile CA. The ATTR amyloid protein can infiltrate other organs, most often the autonomic and peripheral nervous systems, but cardiac involvement, when present, is the principal determinant of survival. The management and diagnosis of cardiac amyloid are challenging and, in most cases, require a careful evaluation of these patients by a multi-disciplinary team.¹⁴

In the present review, Aimo et al.¹⁵ provide a useful guide to clinicians treating patients with CA formulating 10 main questions and answers based on the evidence available as well as their clinical experience. In brief, the authors point out that the cardiac-specific treatment of all forms of amyloidosis involves mainly volume (diuretics/salt restriction) and arrhythmia management. Neurohormonal antagonists typically used in HF often lead to hypotension (due to autonomic dysfunction and the presence of a small left ventricular cavity with an inability to augment stroke volume in response to vasodilation), and beta-blockers often exacerbate brady-arrhythmias. Pacemakers are frequently needed due to a high prevalence of conduction disease (particularly in ATTR amyloidosis) while implantable cardioverter-defibrillators can be effective in patients with a reasonable prognosis (>1 year) and with a history of exertional syncope or non-sustained or sustained VT. Anticoagulation should be given for any atrial arrhythmia and might be considered in patients in sinus rhythm but an enlarged and dysfunctional left atrium.

Cost-effectiveness of dapagliflozin and of sacubitril-valsartan

After several years without positive data for new pharmacotherapies, the impressive results of the PARADIGM-HF trial in 2014, the DAPA-HF trial in 2019 and more recently the EMPEROR-Reduced trial led to the inclusion of the angiotensin receptor neprilysin inhibitor (ARNi) sacubitril-valsartan and the sodium-glucose cotransporter 2 (SGLT2) inhibitors into the armamentarium of medications available for HFrEF.¹⁶ With the exception of loop diuretics, all of these therapies have been shown in randomized controlled trials to improve symptoms, reduce hospitalizations, and/or prolong survival.

In this issue of the journal, Savira et al.¹⁷ assessed the cost-effectiveness of dapagliflozin in patients with HFrEF while Perera et al.¹⁸ explored the cost-effectiveness of the use of sacubitril-valsartan vs. enalapril in acute decompensated HF. In both studies, the main outcome was ‘the incremental cost-effectiveness ratio (ICER) per quality-adjusted lifeyear (QALY) gained’ and the economic value of the intervention was assessed according to the Australian healthcare perspective. Using this approach, the authors calculated that over a lifetime horizon the addition of dapagliflozin would prevent 88 acute HF hospitalizations and yield an additional 416 years of life and 288 QALYs. This means an ICER of €7600 per QALY gained well below the threshold of approximately € 22,300 to € 33,500 per QALY that is commonly considered as cost-effective for a (new) technology or treatment by the UK’s National Institute for Health and Care Excellence (NICE).

Compared to enalapril, sacubitril-valsartan was estimated to cost an additional AU$7464 per person, but lead to 0.127 years of life saved and 0.096 quality-adjusted life-years gained (discounted) over a lifetime analysis. These equated to incremental cost-effectiveness ratios of €49 202 making the sacubitril-valsartan not cost-effective in the management of acute decompensated HF.

Adverse events with sacubitril/valsartan in the real world

In the PARADIGM-HF trial, sacubitril/valsartan demonstrated a reduction in the composite end point of cardiovascular death or hospitalization for worsening HF compared with enalapril. Despite its success, the trial design triggered concerns with the use of a run-in phase which potentially underestimated side-effects. Furthermore, a single clinical trial with its recognized limitations and methodological bias is not sufficient to fully evaluate the safety profile of drugs, especially in the detection of rare, unexpected, and delayed adverse events (AEs). In this context the use of spontaneous reporting systems (SRSs) represents a valuable source for post-marketing surveillance, allowing early identification of possible safety signals occurring in the real world, including a multifaceted scenario of patients with comorbidities and polypharmacotherapy.

Here, Gatti et al.,¹⁹ using US Food and Drug Administration adverse event reporting system, characterized the safety profile of sacubitril/valsartan. The extracted AEs were ranked in term of clinical priority level to identify and prioritize potential preventive measures. Sudden cardiac death was the only designated medical event with strong clinical priority, but increased reporting emerged for several cardiovascular adverse events, including renal failure, hyperkalaemia, and angioedema. Notably, sudden cardiac death occurred early after sacubitril/valsartan administration, with concomitant drugs known for pro-arrhythmic potential (e.g. amiodarone, escitalopram, mirtazapine, and loop diuretics) in 26.2% of records.

Conflict of interest: none declared.

This editorial refers to the current Journal issue

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