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4 December 2017

Residual risk of heart failure: how to address this global epidemic?

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco Heart failure affects more than 26 million people worldwide 1, and poses a huge economic burden to society. In 2012, the annual costs of heart failure management were estimated at $108 billion, although this is likely to be an underestimate of the true burden due to an aging, rapidly expanding and industrializing global population 2. This cost is largely driven by the need for repeated hospitalization. Indeed, a recent US analysis illustrates this; about one in five patients was readmitted within 30 days of the index hospitalization, one in three readmitted within 60 days, and nearly half readmitted within 90 days 3, higher than that for other cardiovascular complications including acute myocardial infarction (AMI) and coronary artery bypass surgery 4. Additionally, these patients are likely to have multiple co-morbidities, for example, including diabetes, hypertension and atrial fibrillation all of which are costly to manage. Recent estimates from a US payer perspective indicate that patients with heart failure are likely to accrue a minimum of $34,000 in annual hospitalization costs 3.

In developed countries, AMI is one of the main events precipitating the development of heart failure 5. For example, the Cardiovascular Disease in Norway study showed that one in eight patients with an AMI subsequently was hospitalized or died because of heart failure over a 3-year follow-up period 6. Thus, there is a high residual risk for development of heart failure following the acute event.

What strategies can reduce this residual risk of heart failure? The EMPA-REG OUTCOME® trial 7 showed that empagliflozin added to standard of care reduced the risk of cardiovascular outcomes, specifically defined as a composite of cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. Empagliflozin also improved other heart failure outcomes, including hospitalization for heart failure. These findings have prompted some to propose that selective inhibition of the sodium glucose cotransporter 2 may have future application for prevention of heart failure beyond the diabetes setting 8. However, as the effect of empagliflozin on heart failure outcomes was evident very early and sustained throughout the trial, it is likely that this is not driven by effects on atherosclerosis ; the mechanims have yet to be elucidated.

Statins are clearly effective in reducing acute coronary events 9, and thus should in theory have a beneficial effect on the development of heart failure. Yet conclusive evidence to support this proposal is lacking from prospective placebo-controlled statin trials (10,11). Could other lipid or lipoprotein factors have relevance ?

There is some evidence to suggest that levels of triglycerides, a marker for triglyceride-rich lipoproteins and their remnants, may be implicated. One study implicated the triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) as a predictor for new-onset heart failure in patients with coronary heart disease 12. Furthermore, in post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan, levels of triglycerides were predictive of mortality and heart failure rehospitalization beyond conventional risk factors 13.

This month’s Focus report 14 provides further evidence linking elevated triglycerides with increased risk for heart failure. In two prospective Danish studies, higher triglycerides were associated with higher risk for heart failure, by 69% at levels of 2-2.99 mmol/L (176-263 mg/dl), and more than 250% in individuals with nonfasting triglycerides ?5 mmol/L (?440 mg/dl). In contrast, stepwise increases in LDL-C were not associated with increased risk for heart failure. Based on their findings, the authors argue that targeting elevated triglycerides may offer potential for reducing the residual risk of developing heart failure. Indeed, attention is being redirected to this strategy for reducing major cardiovascular events in high risk patients. Three ongoing studies – REDUCE-IT with AMR101 (NCT01492361), STRENGTH with EpaNova (NCT02104817) and PROMINENT with pemafibrate (NCT03071692) - are evaluating this hypothesis. It appears that the tide has truly turned in favour of targeting elevated triglycerides ; we await with much anticipation the findings of these trials.

1. Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev 2017;3:7-11.
2. Cook C, Cole G, Asaria P et al. The annual global economic burden of heart failure. Int J Cardiol. 2014;171:368-76.
3. Kilgore M, Patel HK, Kielhorn A et al. Economic burden of hospitalizations of Medicare beneficiaries with heart failure. Risk Manag Healthc Policy 2017;10:63-70.
4. Readmissions and deaths-national. 2016. Available from:
5. Nieminen MS, Brutsaert D, Dickstein K et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006;27:2725–36.
6. Sulo G, Igland J, Vollset SE et al. Heart failure complicating acute myocardial infarction; burden and timing of occurrence: a nation-wide analysis including 86 771 patients from the Cardiovascular Disease in Norway (CVDNOR) Project. J Am Heart Assoc 2016;51.
7. Fitchett D, Zinman B, Wanner C et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016;37:1526–34.
8. Martens P, Mathieu C, Verbrugge FH. Promise of SGLT2 inhibitors in heart failure: diabetes and beyond. Curr Treat Options Cardiovasc Med 2017;19:23.
9. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61.
10. Gissi-HF Investigators , Tavazzi L, Maggioni AP et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231-9.
11. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61 2.
12. Yunke Z, Guoping L, Zhenyue C. Triglyceride-to-HDL cholesterol ratio. predictive value for CHD severity and new-onset heart failure. Herz 2014;39:105-10.
13. Greene SJ, Vaduganathan M, Lupi L et al. Prognostic significance of serum total cholesterol and triglyceride levels in patients hospitalized for heart failure with reduced ejection fraction (from the EVEREST Trial). Am J Cardiol 2013;111:574-81.
14. Varbo A, Nordestgaard BG. Nonfasting triglycerides, low-density lipoprotein cholesterol, and heart failure risk. Two cohort studies of 113 554 individuals. Arterioscler Thromb Vasc Biol 2017; DOI: 10.1161/ATVBAHA.117.310269.