Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence

Abstract

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

Keywords: Angiotensin receptor blocker; Angiotensin receptor-neprilysin inhibitor; Angiotensin-converting enzyme inhibitor; Beta-blocker; Cancer; Cardio-oncology; Heart failure; Mineralocorticoid Receptor antagonist; Sodium-glucose cotransporter 2 inhibitor.

Graphical abstract

The risk factors and pathophysiological pathways of both heart failure and cancer are common. The discipline of cardio-oncology investigates how heart failure and cancer progression are connected: on one hand, the cardiac effects of anti-cancer medications or cancer-derived metabolic byproducts are investigated, whereas on the other hand, the possible effects of heart failure on cancer progression are examined, such as those mediated by maladaptive neuroendocrine activation and factors secreted from the failing heart. Nevertheless, there is a lack of systematic knowledge on how heart failure pharmacotherapies affect new-onset cancer incidence or prevalent cancer outcomes, and whether these effects are mediated through the improvement in cardiac functions. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; MRA, mineralocorticoid receptor antagonist; SGLT2I, sodium-glucose cotransporter 2 inhibitor.

Figure 1

Suggested mechanism of action of the different heart failure pharmacotherapies on cancer cells. A: Adrenaline, NA: noradrenaline, Ang: angiotensinogen, Ang1: angiotensin-I, Ang2: angiotensin-II, ACE: angiotensin-converting enzyme, Aldo: aldosterone, ARB: angiotensin receptor blocker, ACEI: angiotensin-converting enzyme inhibitor, BB: β-blocker, SGLT2I: sodium-glucose cotransporter 2 inhibitor, ß-AR: ß-adrenergic receptor, AT1-R: angiotensin II receptor type 1, SGLT2: sodium-glucose cotransporter 2, MC-R: mineralocorticoid receptor, MRA: mineralocorticoid receptor antagonist, cAMP: cyclic adenosine-monophosphate, EPAC: exchange protein directly activated by cAMP, PKA: protein-kinase A, IP3: inositol-triphosphate, Akt: protein-kinase B, mTOR: mammalian target of rapamycin, Gluc: glucose, TF: transcription factors. Figure created with BioRender.com.

Figure 2

Meta-analyses of clinical studies on the effect of beta-blockers on cancer incidence or outcomes. The number of studies used for overall effect size estimation is marked (n). OS: overall survival, CSS: cancer specific survival, CR: cancer recurrence, DFS: disease-free survival, Obs: observational studies, RCTs: randomized controlled trials. The meta-analyses are referenced in the text. Figure created with BioRender.com.

Figure 3

Meta-analyses of clinical studies on the effect of RAAS inhibitors (angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, or mineralocorticoid receptor antagonists) on cancer incidence or outcomes. The number of studies used for overall effect size estimation is marked (n). OS: overall survival, CSS: cancer specific survival, CR: cancer recurrence, DFS: disease-free survival, Obs: observational studies, RCTs: randomized controlled trials. The meta-analyses are referenced in the text. Figure created with BioRender.com.

Figure 4

Meta-analyses of clinical studies on the effect of sodium-glucose cotransporter 2 inhibitors on cancer incidence or outcomes. The number of studies used for overall effect size estimation is marked (n). OS: overall survival, CSS: cancer-specific survival, CR: cancer recurrence, DFS: disease-free survival, Obs: observational studies, RCTs: randomized controlled trials. The meta-analyses are referenced in the text. Figure created with BioRender.com.

Figure 5

A graphical summary for both the pre-clinical and clinical evidence on the effect of different heart failure pharmacotherapies on cancer. The terms were defined as follows: beneficial: decreases cancer incidence, or improves any patient outcome; neutral: no effect on cancer incidence, or no effect on any patient outcome; harmful: increased incidence or worsening of any patient outcome; conflicting: there are studies showing either benefit or harm on cancer incidence or outcomes. Figure created with BioRender.com.

Figure 6

A graphical summary of future directions for decreasing cancer burden of heart failure from pre-clinical studies to clinical investigations and their meta-analyses. Figure created with BioRender.com.