Challenges in predicting heart failure readmission: focus on heart rate






Michael BÖHM,MD
University Hospital of Saarland
Department of Internal Medicine III
Cardiology, Angiology, and Intensive Care Medicine
Homburg/Saar
GERMANY

Challenges in predicting heart failure readmission: focus on heart rate


by M. Böhm, Germany



Chronic heart failure is characterized by a high readmission rate, in particular in patients with advanced syndrome. Shortly after discharge, neuroendocrine activation is particularly evident, resulting in elevated heart rate and low blood pressure. Both of these vital signs are closely associated with high morbidity and mortality. The open question is whether early treatment to achieve heart rate reduction with an If-channel inhibitor like ivabradine could reduce the high readmission rate. As heart rate is associated with hospital admissions and mortality, this approach is worthwhile to study in a prospectively randomized trial.

Medicographia. 2015;37:197-201 (see French abstract on page 201)



Despite intensive multidrug therapy, patients with heart failure are often readmitted to hospital, resulting in an annual rehospitalization rate for heart failure in the United States of 1 million patients per year.1 Despite evidence-based treatments, often initiated in the hospital, these individuals face high postdischarge mortality and rehospitalization rates: 15% and 30%, respectively, within 60 to 90 days.2-4 Mechanistically, during this vulnerable phase, an excess of neuroendocrine activation likely contributes to the high event rate. To take one example, the escape phenomenon of the renin-angiotensin-aldosterone system (RAAS) provides the basis for a combined inhibitor therapy for heart failure5-7 in stable patients, but such therapy during the postdischarge vulnerable phase has failed to show benefits.8,9 The treatment of these patients is limited due to the fact that they quite often have low blood pressure and high heart rates, preventing physicians from treating with adequate doses of neuroendocrine antagonists.10

Association of heart rate and blood pressure

Elevated heart rates in heart failure increase oxygen consumption11 and might reduce cardiac contractility due to the inverse force-frequency relationship in vitro12,13 and in vivo.14 In patients with stable heart failure with a heart rate above 70 beats per minute (bpm) included in the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial), heart rate was associated with an increased risk of cardiovascular death and heart failure hospitalizations,15 which translates into a 3% increase in risk for every 1-bpm increase from baseline heart rate and 15% increase in risk for every 5-bpm increase. Consistently, heart rate reduction with ivabradine in stable patients with heart failure was able to reduce the composite outcome of cardiovascular death and heart failure hospitalization in individuals with a heart rate above 70 bpm16 and even cardiovascular death and total mortality in the subgroup of patients with a heart rate above 70 bpm.17 For the postdischarge phase, there are no data on treatment effects of heart rate reduction. However, a substudy for the EVEREST trial (Efficacy of Vasopressin antagonism in hEart failuRE: outcome Study with Tolvaptan) has shown that early after discharge, a heart rate above 75 bpm was associated with an increase in mortality, while heart rate at admission showed no association (Figure 1).18 Furthermore, in a large hospital registry, the threshold heart rate for an increased risk was 70 to 80 bpm in determining 30-day and 1-year cardiovascular death.19 This observation provides the basis for the hypothesis that heart rate reduction early after discharge might improve outcome. However, this has to be closely examined in prospective randomized trials.


Figure 1
Figure 1. Baseline heart rate (left) and 1-week postdischarge heart rate (right) in patients acutely admitted for acute heart failure.

In particular, heart rate 1-week postdischarge is strongly predictive of death after acute hospitalization for heart failure.
Abbreviation: Q, quartile.
After reference 18: Greene et al. JACC Heart Fail. 2013;1:488-496. © 2013, American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.



After discharge from heart failure hospitalization, undertreatment of patients with β-blockers and angiotensin-converting enzyme (ACE) inhibitors occurs—in particular, in high-risk patients with presumably low blood pressure (Figure 2)— and this does not change over the year following discharge.20





Therefore, early initiation (even in hospital) of heart rate–reducing therapies such as ivabradine, which is not accompanied by blood pressure reduction,16 might lead to a higher proportion of patients receiving evidence-based treatment, which includes heart rate reduction, in the year after discharge. In the long run, this could improve outcomes.

Heart rate–reducing therapy after discharge

The problem in the treatment of the postdischarge vulnerable patient is that about 15% to 25% of patients present with low blood pressure (ie, <120 mm Hg), which puts them at a particularly high risk for poor outcomes.10,21,22 Interestingly, in SHIFT, high heart rates and low blood pressure, in particular the combination thereof, further increased event rates in heart failure patients.23 In this heart failure population at particularly high risk, the heart rate reducer ivabradine showed no heterogeneity of treatment effects whether blood pressure was low or high.23 Furthermore, ivabradine treatment in stable patients did not reduce blood pressure, but even slightly increased it.16,17

Patients with low blood pressure are more likely to suffer from multiple cardiovascular and noncardiovascular comorbidities.<10 In the SOLVD (Studies Of Left Ventricular Dysfunction) population, the cumulative load of comorbidities was accompanied by a strong increase in cardiovascular morbidity and mortality.24 Also, in SHIFT, there was no heterogeneity of the treatment effects in the elderly,25 in patients with particularly severe heart failure or low ejection fraction,26 impairment of renal function,27 intensive treatment with mineralocorticoid antagonists,28 chronic obstructive pulmonary disease,29 or left bundle branch block.30


Figure 2
Figure 2. Drug treatment at hospital discharge in patients with chronic heart failure.

These numbers document the risk paradox indicating that those patients with high and average risk
have lower treatment intensity while the same patients exhibit an increased risk concerning 1-year
mortality with or without cerebrovascular events.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
Data from reference 20: Lee et al. JAMA. 2005;294:1240-1247.



Though still to be proven whether heart rate reduction is safe in this condition, in the critically ill patient, like in patients with multiple organ dysfunction syndrome, high heart rate was related to poor outcome.31 Thus, one ongoing trial is looking at the effect of heart rate reduction with ivabradine in septic shock.32 The association of heart rate and outcome also holds true in acutely admitted patients with hypertensive crisis.33

Early experiences with patients in cardiogenic shock provide evidence that this drug has potential to be applicable in critical cardiac disease34 and, thus, also in patients in a fragile postdischarge situation. Again, the treatment effect from lowering heart rate has to be carefully examined in prospective randomized trials to validate these hypotheses-generating associations.

Perspectives and future research
While the effect of heart rate reduction is established and such treatment has been introduced in the heart failure guidelines of the European Society of Cardiology35 in stable heart failure patients, data on the postdischarge situation are not available. Reduction in rehospitalization for heart failure is a crucial goal in heart failure treatment, because hospitalizations markedly worsen the prognosis in heart failure patients.36-38 Interestingly, ivabradine was shown not only to reduce those heart failure hospitalizations occurring as first events, but also recurrent hospitalizations, with a similar risk reduction as for first events for patients on ivabradine compared with placebo.39 Thus, a prospective trial in postdischarge patients is needed to show whether heart rate reduction—in particular, in vulnerable patients with low blood pressure early after discharge, in the context of guideline-based therapies for heart failure— might improve clinical outcomes in patients with this disabling condition.

Practical considerations
Despite some deficits in scientific knowledge, heart rate measurement is a very simple tool to predict future outcomes in chronic heart failure patients. Since heart rate is related to cardiovascular death and heart failure hospitalization in stable patients,15,17,23 it is also predictive of outcome early at discharge.9,18,19 Heart rate is also closely associated with symptoms, being in turn associated with outcomes.40

Therefore, the determination of heart rate in accordance with well-being of the patients at discharge might provide important information helping clinicians to identify those at high risk for future complications. Those patients would require special attention, such as uptitration of the doses of heart failure medications and initiation of ivabradine to reduce heart rate when heart rate stays above 70 bpm. Heart rate should be calculated as in clinical trials, by an electrocardiogram (ECG) following sufficient rest time and, as recommended by guidelines, in the sitting position, counting heart beats for 30 seconds and then multiplying the value by 2.41 Altogether, high heart rate has been identified as a risk marker and in heart failure has been determined to be a modifiable risk factor for outcomes that are amenable to heart rate–reducing therapy. In chronic heart failure, the normal or beneficial heart rate is to be newly defined as below 70 bpm.42

References
1. Blecker S, Paul M, Taksler G, Ogedegbe G, Katz S. Heart failure–associated hospitalizations in the United States. J Am Coll Cardiol. 2013;61:1259- 1267.
2. Gheorghiade M, Abraham WT, Albert NM, et al; OPTIMIZE-HF Investigators and Coordinators. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA. 2006; 296:2217-2226.
3. Blair JE, Zannad F, Konstam MA, et al; EVEREST Investigators. Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program. J Am Coll Cardiol. 2008;52:1640-1648.
4. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol. 2013;61: 391-403.
5. Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011; 364:11-21.
6. McMurray JJ, Ostergren J, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771.
7. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675.
8. Gheorghiade M, Böhm M, Greene SJ, et al; ASTRONAUT Investigators and Coordinators. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA. 2013;309:1125-1135.
9. Maggioni AP, Greene SJ, Fonarow GC, et al; ASTRONAUT Investigators and Coordinators. Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial. Eur Heart J. 2013;34:3117-3127.
10. Gheorghiade M, Vaduganathan M, Ambrosy A, et al. Current management and future directions for the treatment of patients hospitalized for heart failure with low blood pressure. Heart Fail Rev. 2013;18:107-122.
11. Colin P, Ghaleh B, Monnet X, Hittinger L, Berdeaux A. Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther. 2004;308:236-240.
12. Böhm M, La Rosée K, Schmidt U, Schulz C, Schwinger RH, Erdmann E. Forcefrequency relationship and inotropic stimulation in the nonfailing and failing human myocardium: implications for the medical treatment of heart failure. Clin Investig. 1992;70:421-425.
13. Mulieri LA, Hasenfuss G, Leavitt B, Allen PD, Alpert NR. Altered myocardial force-frequency relation in human heart failure. Circulation. 1992;85:1743-1750.
14. Hasenfuss G, Holubarsch C, Hermann HP, Astheimer K, Pieske B, Just H. Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J. 1994;15:164-170.
15. Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376: 886-894.
16. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.
17. Böhm M, Borer J, Ford I, et al. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol. 2013;102:11-22.
18. Greene SJ, Vaduganathan M, Wilcox JE, et al; EVEREST Trial Investigators. The prognostic significance of heart rate in patients hospitalized for heart failure with reduced ejection fraction in sinus rhythm: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial. JACC Heart Fail. 2013;1:488-496.
19. Habal MV, Liu PP, Austin PC, et al. Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure. Circ Heart Fail. 2014;7:12-20.
20. Lee DS, Tu JV, Juurlink DN, et al. Risk-treatment mismatch in the pharmacotherapy of heart failure. JAMA. 2005;294:1240-1247.
21. Meredith PA, Ostergren J, Anand I, et al. Clinical outcomes according to baseline blood pressure in patients with a low ejection fraction in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) Program. J Am Coll Cardiol. 2008;52:2000-2007.
22. Cheng RK, Horwich TB, Fonarow GC. Relation of systolic blood pressure to survival in both ischemic and nonischemic systolic heart failure. Am J Cardiol. 2008;102:1698-1705.
23. Komajda M, Böhm M, Borer JS, et al; SHIFT Investigators. Efficacy and safety of ivabradine in patients with chronic systolic heart failure according to blood pressure level in SHIFT. Eur J Heart Fail. 2014;16:810-816.
24. Böhm M, Pogue J, Kindermann I, Pöss J, Koon T, Yusuf S. Effect of comorbidities on outcomes and angiotensin converting enzyme inhibitor effects in patients with predominantly left ventricular dysfunction and heart failure. Eur J Heart Fail. 2014;16:325-333.
25. Tavazzi L, Swedberg K, Komajda M, et al; SHIFT Investigators. Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights from the SHIFT study. Eur J Heart Fail. 2013;15:1296-1303.
26. Borer JS, Böhm M, Ford I, et al; SHIFT Investigators. Efficacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study). Am J Cardiol. 2014;113:497-503.
27. Voors AA, van Veldhuisen DJ, Robertson M, et al; on behalf of the SHIFT Investigators. The effect of heart rate reduction with ivabradine on renal function in patients with chronic heart failure: an analysis from SHIFT. Eur J Heart Fail. 2014 Feb 7. Epub ahead of print. doi:10.1002/ejhf.59.
28. Borer JS, Böhm M, Ford I, et al; SHIFT Investigators. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J. 2012;33:2813-2820.
29. Tavazzi L, Swedberg K, Komajda M, et al; SHIFT Investigators. Clinical profiles and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety analysis of SHIFT study. Int J Cardiol. 2013;170:182-188.
30. Reil JC, Robertson M, Ford I, et al. Impact of left bundle branch block on heart rate and its relationship to treatment with ivabradine in chronic heart failure. Eur J Heart Fail. 2013;15:1044-1052.
31. Hoke RS, Müller-Werdan U, Lautenschläger C, Werdan K, Ebelt H. Heart rate as an independent risk factor in patients with multiple organ dysfunction: a prospective, observational study. Clin Res Cardiol. 2012;101:139-147.
32. Nuding S, Ebelt H, Hoke RS, et al. Reducing elevated heart rate in patients with multiple organ dysfunction syndrome by the If (funny channel current) inhibitor ivabradine: MODIfY trial. Clin Res Cardiol. 2011;100:915-923.
33. Al Bannay R, Böhm M, Husain A. Heart rate differentiates urgency and emergency in hypertensive crisis. Clin Res Cardiol. 2013;102:593-598.
34. De Santis V, Vitale D, Santoro A, et al. Ivabradine: potential clinical applications in critically ill patients. Clin Res Cardiol. 2013;102:171-178.
35. McMurray JJ, Adamopoulos S, Anker SD, et al; Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14:803-869.
36. Solomon SD, Dobson J, Pocock S, et al; Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Investigators. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116:1482-1487.
37. Liao L, Allen LA, Whellan DJ. Economic burden of heart failure in the elderly. Pharmacoeconomics. 2008;26:447-462.
38. Abrahamsson P, Swedberg K, Borer JS, et al. Risk following hospitalization in stable chronic systolic heart failure. Eur J Heart Fail. 2013;15:885-891.
39. Borer JS, Böhm M, Ford I, et al; SHIFT Investigators. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J. 2012;33:2813-2820.
40. Ekman I, Chassany O, Komajda M, et al. Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J. 2011;32:2395-2404.
41. Palatini P, Benetos A, Grassi G, et al; European Society of Hypertension. Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting. J Hypertens. 2006;24:603-610.
42. Palatini P. Need for a revision of the normal limits of resting heart rate. Hypertension. 1999;33:622-625.



Keywords: heart failure; heart rate reduction; If-channel inhibitor; ivabradine; postdischarge; rehospitalization