Heart failure with mid-range ejection fraction
A recent
review assessed patients with mid-range ejection fraction, elaborating on
its epidemiology, pathophysiology, prognosis, and management (see Hsu JJ. JACC: Heart
Failure; 2017; 5 (11): 763). This entity was first codified in 2013 in guidelines from the Am Heart Assn and
European Society of Cardiol. Main points:
--definition:
--HFrEF (heart failure with reduced ejection fraction) is with EF <40 (per AHA), <41 (per ESC)
--HFpEF (preserved EF) is with EF>=50 (both agree)
--HFmEF (mid-range EF) is with EF 40-49 (AHA), or EF 41-49 (ESC).
--epidemiology:
--of the 6.5 million people in the US with HF, about 1.6 million have HFmEF (13-24% of the total), and this has remained pretty steady from 2005-2010, whereas HFpEF has increased from 33 to 39% and HFrEF decreased from 52 to 47%
--clinical characteristics:
--the actual clinical characteristics are a bit fragmentary as they are largely based on older clinical studies that included patients with varying classifications of LVEF (eg, subgroup analysis of patients with LVEF >45%, etc). But a Medicare study had a specific analysis of HF in >40,000 patients, where 14% had HFmEF
--overall HFmEF was clinically more similar to HFpEF: older age, females, comorbidities (hypertension, COPD, diabetes); though there was more similarity with HFrEF with the comorbidity of coronary artery disease
--pathophysiology:
--unclear. ESC attributes it most likely as having simultaneous components of systolic and diastolic dysfunction (ie, both HFrEF and HFpEF). But could also be a transitional stage between the two. of interest, another article (see Tromp J. JACC: Heart Failure. 2017; 5(7): 507) assessed 37 biomarkers and found that those patients with HFrEF had biomarkers mainly related to cardiac stretch, those with HFpEF had biomarkers more related to inflammation, and those with HPmEF had biomarkers related to both stretch and inflammation)
--prognosis:
-- HFrEF has slightly higher mortality rates than HFpEF, with HFmEF in between, but the numbers really are not that different (eg. Canadian study: 30 day and 1 year mortality rates, respectively: HFpEF 5.3%, 22.2%; HFrEF 7.1%, 25.5%; and HFmEF 5.1, 21.3%: so tracks a bit more like HFpEF). The mortality rates for HFrEF increase by about 30% for each 10% reduction in EF.
--more recent studies of HFmEF have found chronic kidney disease, age >85 and COPD were associated with increased mortality
--morbidity rates (eg hospital admissions) are also basically intermediate between HFpEF and HFrEF, though again not really much difference between the groups
Management:
--the management insights basically come from subgroup analysis of the older studies, finding:
--spironolactone (TOPCAT study): there was reduction of HF hospitalizations, with even more benefit in those with EF 45-50% than with higher, leading the AHA to give it a Class IIb recommendation
--candesartan (CHARM-Preserved trial): decreased HF hospitalizations (not found with irbesartan in I-PRESERVE trial, but that latter trial mostly had people with higher EFs).
--no evident benefit from ACE inhibitors or b-blockers
--probably the most useful interventions at this point, lacking better studies, is management of comorbidities.
Commentary:
--per the authors of the above study:
--there is an ongoing study of sacubitril/valsartan in patients with LVEF >45%, which may help to see if neprilysin inhibition helps in HFmEF patients
--it may be important to look at other factors than LVEF itself in determining optimal management, including HF etiology (ischemic, familial, hypertensive), as well as other characteristics of heart function (eg differences in gadolinium enhancement on cardiac MRI). Also, there are technical issues with the stability of LVEF as measured by echocardiography.
--the above management suggestions should be taken with several grains of salt: these were subgroup analyses of bigger studies, and not RCTs comprised of patients solely with HFmEF. and though the post-hoc analyses of ACE-I and b-blockers do not show benefit in patients with HFmEF, there really should be RCTs done since the biomarkers suggest that these patients have some combo of HFrEF and HFpEF.
--It may even be that the defined LVEF cutpoints are incorrect: perhaps those with EF of 40-45 are actually different from those with EF 45-50, that instead of discrete cutpoints there is a continuum, and the response to different meds may mimic the relative component of HFrEF vs HFpEF. And perhaps this therapeutic response can be predicted on an individual patient basis better by looking at some biomarkers (eg, as per the Tromp study, the relative increase of some biomarkers associated with stretch vs inflammation). Perhaps the most useful guide to individual therapy is in fact looking at the biomarkers (which perhaps reflects that individual’s underling etiology for and/or response to their cardiac condition) instead of the LVEF????
--although not mentioned, it is clear that loop diuretics are helpful in controlling symptoms and decreasing hospitalizations (at least in several of my patients with HFmEF)
So, I am bringing up this paper since I have seen several patients with HFmEF, have assumed that this is a combo of systolic and diastolic dysfunction (since both are so common, seems reasonable that many patients do have components of each), but was really unclear what optimal therapy should be. HFrEF responds really well to therapies; HFpEF less well. it probably makes sense to use loop diuretics (eg torsemide) to control acute symptoms, then spironolactone, then an ARB as the next lines of therapy, since they have at least some data supporting longer term benefit, decreasing hospitalizations. And mostly to treat the underlying comorbidities (hypertension, etc) preferentially with meds that help with HFrEF (eg ACE-I/ARBs, b-blockers)
other relevant past blogs:
see http://gmodestmedblogs.blogspot.com/2017/06/spironolactone-helps-heart-failure-with.html , a review of the somewhat controversial TOPCAT study (with probable shenanigans in Russia/Georgia), but did show benefit for spironolactone
see http://gmodestmedblogs.blogspot.com/2017/05/new-heart-failure-guidelines.html for review of the 2017 heart failure treatment guidelines, which endorsed spironolactone for patients with HFpEF, with Grade IIb recommendation, moderate level of evidence
see http://gmodestmedblogs.blogspot.com/2017/07/decreasing-sudden-death-in-heart-failure.html for blog detailing decreased death rates in those with HFrEF over the past 20 years, arguing that the benefit of implanting an ICD may not be justified in patients with EF<35%
--definition:
--HFrEF (heart failure with reduced ejection fraction) is with EF <40 (per AHA), <41 (per ESC)
--HFpEF (preserved EF) is with EF>=50 (both agree)
--HFmEF (mid-range EF) is with EF 40-49 (AHA), or EF 41-49 (ESC).
--epidemiology:
--of the 6.5 million people in the US with HF, about 1.6 million have HFmEF (13-24% of the total), and this has remained pretty steady from 2005-2010, whereas HFpEF has increased from 33 to 39% and HFrEF decreased from 52 to 47%
--clinical characteristics:
--the actual clinical characteristics are a bit fragmentary as they are largely based on older clinical studies that included patients with varying classifications of LVEF (eg, subgroup analysis of patients with LVEF >45%, etc). But a Medicare study had a specific analysis of HF in >40,000 patients, where 14% had HFmEF
--overall HFmEF was clinically more similar to HFpEF: older age, females, comorbidities (hypertension, COPD, diabetes); though there was more similarity with HFrEF with the comorbidity of coronary artery disease
--pathophysiology:
--unclear. ESC attributes it most likely as having simultaneous components of systolic and diastolic dysfunction (ie, both HFrEF and HFpEF). But could also be a transitional stage between the two. of interest, another article (see Tromp J. JACC: Heart Failure. 2017; 5(7): 507) assessed 37 biomarkers and found that those patients with HFrEF had biomarkers mainly related to cardiac stretch, those with HFpEF had biomarkers more related to inflammation, and those with HPmEF had biomarkers related to both stretch and inflammation)
--prognosis:
-- HFrEF has slightly higher mortality rates than HFpEF, with HFmEF in between, but the numbers really are not that different (eg. Canadian study: 30 day and 1 year mortality rates, respectively: HFpEF 5.3%, 22.2%; HFrEF 7.1%, 25.5%; and HFmEF 5.1, 21.3%: so tracks a bit more like HFpEF). The mortality rates for HFrEF increase by about 30% for each 10% reduction in EF.
--more recent studies of HFmEF have found chronic kidney disease, age >85 and COPD were associated with increased mortality
--morbidity rates (eg hospital admissions) are also basically intermediate between HFpEF and HFrEF, though again not really much difference between the groups
Management:
--the management insights basically come from subgroup analysis of the older studies, finding:
--spironolactone (TOPCAT study): there was reduction of HF hospitalizations, with even more benefit in those with EF 45-50% than with higher, leading the AHA to give it a Class IIb recommendation
--candesartan (CHARM-Preserved trial): decreased HF hospitalizations (not found with irbesartan in I-PRESERVE trial, but that latter trial mostly had people with higher EFs).
--no evident benefit from ACE inhibitors or b-blockers
--probably the most useful interventions at this point, lacking better studies, is management of comorbidities.
Commentary:
--per the authors of the above study:
--there is an ongoing study of sacubitril/valsartan in patients with LVEF >45%, which may help to see if neprilysin inhibition helps in HFmEF patients
--it may be important to look at other factors than LVEF itself in determining optimal management, including HF etiology (ischemic, familial, hypertensive), as well as other characteristics of heart function (eg differences in gadolinium enhancement on cardiac MRI). Also, there are technical issues with the stability of LVEF as measured by echocardiography.
--the above management suggestions should be taken with several grains of salt: these were subgroup analyses of bigger studies, and not RCTs comprised of patients solely with HFmEF. and though the post-hoc analyses of ACE-I and b-blockers do not show benefit in patients with HFmEF, there really should be RCTs done since the biomarkers suggest that these patients have some combo of HFrEF and HFpEF.
--It may even be that the defined LVEF cutpoints are incorrect: perhaps those with EF of 40-45 are actually different from those with EF 45-50, that instead of discrete cutpoints there is a continuum, and the response to different meds may mimic the relative component of HFrEF vs HFpEF. And perhaps this therapeutic response can be predicted on an individual patient basis better by looking at some biomarkers (eg, as per the Tromp study, the relative increase of some biomarkers associated with stretch vs inflammation). Perhaps the most useful guide to individual therapy is in fact looking at the biomarkers (which perhaps reflects that individual’s underling etiology for and/or response to their cardiac condition) instead of the LVEF????
--although not mentioned, it is clear that loop diuretics are helpful in controlling symptoms and decreasing hospitalizations (at least in several of my patients with HFmEF)
So, I am bringing up this paper since I have seen several patients with HFmEF, have assumed that this is a combo of systolic and diastolic dysfunction (since both are so common, seems reasonable that many patients do have components of each), but was really unclear what optimal therapy should be. HFrEF responds really well to therapies; HFpEF less well. it probably makes sense to use loop diuretics (eg torsemide) to control acute symptoms, then spironolactone, then an ARB as the next lines of therapy, since they have at least some data supporting longer term benefit, decreasing hospitalizations. And mostly to treat the underlying comorbidities (hypertension, etc) preferentially with meds that help with HFrEF (eg ACE-I/ARBs, b-blockers)
other relevant past blogs:
see http://gmodestmedblogs.blogspot.com/2017/06/spironolactone-helps-heart-failure-with.html , a review of the somewhat controversial TOPCAT study (with probable shenanigans in Russia/Georgia), but did show benefit for spironolactone
see http://gmodestmedblogs.blogspot.com/2017/05/new-heart-failure-guidelines.html for review of the 2017 heart failure treatment guidelines, which endorsed spironolactone for patients with HFpEF, with Grade IIb recommendation, moderate level of evidence
see http://gmodestmedblogs.blogspot.com/2017/07/decreasing-sudden-death-in-heart-failure.html for blog detailing decreased death rates in those with HFrEF over the past 20 years, arguing that the benefit of implanting an ICD may not be justified in patients with EF<35%
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