HF medication prescription and overall survival
Potential predictors of mortality are presented in Table 4. Older age at
device implant, renal dysfunction, CRTD implant (rather than ICD), and
VA episodes during F/U were associated with increased overall mortality.
Analysis of HF medications showed that combined treatment with all 3 HF
medication groups (p=0.0047) and treatment with AngA per se (p 0.028),
regardless of dose, were significantly associated with reduced mortality
(Table 4).
In a univariate analysis the following parameters were significantly
associated with overall mortality: age (HR 1.06; 95% CI1.04-1.09;
p=0.0001), renal dysfunction (HR 1.63; 95% CI1.03-2.56; p=0.037), CRTD
(versus ICD) (HR 1.67; 95% CI1.03-2.71; p=0.036), VA during F/U (HR
2.76; 95% CI 1.474-4.967, p=0.001) and AngA treatment ( HR 0.55; 95%
CI 0.31-0.97; p=0.039).
In Cox multivariable survival analysis including patients’ age, gender,
renal function, HF medication treatment, and VA occurrence during F/U,
AngA treatment (but not BB or MRA) was significantly associated with
reduced mortality (HR 0.515; 95% CI 0.285-0.929; p=0.028); while age
(HR 1.06; 95% CI 1.038-1.093; p=0.0001); renal disease (HR 1.728; 95%
CI 1.070-2.792; p=0.025); and VA during F/U (HR 2.672; 95% CI
1.429-4.999; p=0.002) were significantly associated with increased
mortality (Table 5).
Kaplan-Myer overall survival analysis according to HF medication groups
showed reduced mortality among patients with AngA (p=0.036) without
significant impact of BB or MRA (Figure 3). Interestingly, Kaplan-Myer
overall survival curves for the combination of all 3 HF medication
groups diverged for improvement with combined treatment after 4 years
(curve not shown). Kaplan-Myer overall survival curves by incident VA
(as a competing event) revealed increased mortality in patients with VA
(Figure 4).
Discussion
This study, including 186 HF patients implanted with a primary
prevention ICD or CRTD and meticulously followed in the device clinic,
evaluated the impact of guideline-based HF medications on incident VA
and total mortality. During the median F/U period of 3.8 years, 28% of
the patients had VA and 41.4% died. On the whole, although most of the
patients were prescribed with the appropriate HF medications
(> 80% for BB and AngA and 60% for MRA), the doses were
low. The median dose of HF medications in the current study was 25% of
target dose for all 3 medication groups with less than 20% of patients
treated by >50% target dose. We found that treatment with
lower doses of BBs and increased heart rates were both significantly and
independently associated with increased VA, while DM was associated with
reduced VA incidence. We also found that treatment with AngA was
significantly associated with reduced overall mortality, while VA and
renal dysfunction were associated with increased mortality.
The incidence of VA in the current study is comparable to previously
published studies. In the SCD-HeFT primary prevention trial which had a
similar F/U period, the incidence of appropriate ICD shocks was 21.5%
(26). The estimated annual incidence of VA in our study of 7.4% is
similar to the 7.2% annual appropriate shock incidence in the DEFINITE
primary prevention trial (27). Notably, the patients’ devices in the
current study were routinely programmed via prolonged VA detection
periods to enable spontaneous termination of short VAs, as well as
device intervention for relatively fast VAs. Thus, only long and fast
VAs were included in the current study. Importantly, these clinically
relevant VAs do not equal sudden cardiac death, as they might still end
spontaneously (28-30). Nevertheless, these VAs do have a significant
impact on overall mortality, as was shown in the current study and as
supported by several prior studies establishing the benefit of ICD
implant (26,27,31-34).
In the current study the dosage of BB, rather than their mere use, was
associated with VA reduction. The importance of aiming for target doses
was previously studied, revealing increased deaths and/or HF
hospitalizations among HF patient treated by < 50% target
dose of BB and ACE-I (7,20,24). The importance of HF medication dosage
was further emphasized in the DANISH trial where optimal medical
therapy, with medication prevalence of >90% for BB and AA
and 60% for MRA (similar to current study) and doses that were
increased to target doses whenever possible, were suggested to obviate
the survival benefit of an ICD (16). Lastly, a recent meta-analysis
including six pivotal randomized trials of DCM patients, showed a
significant survival benefit of ICD plus medical therapy compared with
medical therapy alone, but this survival benefit was lost in trials
where >50% of patients were treated via combination of BB,
AngA, and MRA with doses reaching guideline target doses (14). On the
whole, our study suggests that HF medication dosage in general and BB
dose specifically, is important for reducing VA in advanced HF patients
implanted with an ICD or CRTD.
Potential mechanisms for antiarrhythmic effects of BB include their
anti-sympathetic effect resulting in reduced heart rates and increased
heart rate variability, direct anti-arrhythmic effect, reducing
intra-cellular Ca within cardiac cells, improving cardiac function,
reducing cardiac ischemia and more (35,36). In the current study,
reduced BB doses were associated with increased VA even when adjusting
for heart rate. Therefore, BBs may have an anti-arrhythmic effect beyond
decreasing heart rate per se. This result is in line with previous
trials (37-39), which show that although increased heart rates are
associated with worst outcomes in HF patients, increasing BB dose
regardless of baseline heart rates is associated with an improved
combined outcome of all-cause mortality and HF hospitalizations.
Accordingly, we as others (37-39), suggest that BB dose up-titration
regardless of baseline heart rate should be considered for VA prevention
(as long as symptomatic or excessive bradycardia is absent).
Low dosing of all HF recommended medications was one of main findings in
the current study. Low dosing was noticed in multiple HF studies and
registries (17-20,24), acknowledging this is a universal problem. For
example, in the CHAMP-HF registry including 3500 HF patients with
reduced EF from 150 medical centers, less than 25% of patients received
target dose of any HF medication and only 1% received target dose of
all 3 HF family medications (17,18). Similarly, only a minority of
patients in the Asian (19) and pan-European (24) registries received
target doses of any HF medication. Low dose HF medications could result
from inadequate medical surveillance, non-referral to specialized HF
clinic, or otherwise impacted by various ’obstacles’ such as low blood
pressure or heart rate, co morbidities, and medication-related side
effects preventing one from achieving target doses. In the current
study, patients with and without VA had similar co morbidities, with HTN
in most patients and heart rates between 70-80 bpm in both groups.
Hence, we suggest that the lower BB dosage among patients with VA is not
related to sicker patients who cannot tolerate increased BB doses but
rather suboptimal medical surveillance. This corroborates with the
limited number of study patients who were followed in the HF clinic
(enjoying better adherence to treatment). Indeed, in reality many
ICD/CRTD candidates are referred to an EP clinic by their general
cardiologists or GPs for device implantation without HF consultation and
with inadequate HF medical treatment. Thus, we suggest that all HF
patients and especially those referred to device implant undergo HF
specialist consultation, aiming to achieve HF medication target doses.
Importantly, this approach is strongly supported by both EP and HF
guidelines advocating ICD or CRTD implant only after confirmation of
optimal HF medical treatment (21-23).
Strengths and Limitations
Our study has several limitations including: a) its retrospective
nature; b) single center data; c) the overall low doses of
guideline-based medications, resulting in possible underestimation of
medication effect; d) discharge prescriptions may not equal true medical
treatment over time, although most patients remain treated with their
discharge recommendations; e) most study patients were included prior to
2016 and thus were not treated with angiotensin receptor/neprilysin
inhibitors (ARNI). Thus, our study did not evaluate impact of ARNI,
which is a pivot HF medication in recent years; f) data on cause of
death is missing. The study also has several strengths including the
meticulous retrieval of VA events and the in-depth manual evaluation of
discharge medication dose analyzed as the proportion of guideline
recommendations.
Conclusion:
In this single center retrospective cohort of CHF patients implanted
with an ICD/CRTD for primary prevention, we found a relatively high
prevalence of HF guideline-recommended medication treatment albeit with
low doses. Reduced BB doses were associated with an increased VAs which
in turn are associated with increased mortality, while treatment with
AngA was associated with reduced overall mortality. Specialized HF
consultation is therefore advocated for these patients referred for
primary prevention ICD/CRTD to improve their medical treatment and
outcomes.
References
- CBIS II Authors. The Cardiac Insufficiency Bisoprolol Study II
(CIBISII): a randomized trial. Lancet 1999; 353:9–13.
- MERIT-HF Investigators. Effect of metoprolol CR/XL in chronic heart
failure: metoprolol CR/XL randomized intervention trial in congestive
heart failure (MERIT-HF). Lancet 1999; 353:2001–2007.
- Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival
in severe chronic heart failure. N Engl J Med 2001;
344:1651–8.
- The SOLVD Investigators. Effect of enalapril on survival in patients
with reduced left ventricular ejection fractions and congestive heart
failure. N Engl J Med 1991; 325:293–302.
- The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
Effect of ramipril on mortality and morbidity of survivors of acute
myocardial infarction with clinical evidence of heart failure.
Lancet . 1993;342(1):821–8.
- Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor
blocker valsartan in chronic heart failure. N Engl J Med 2001;
345:1667–75.
- Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus
low-dose losartan on clinical outcomes in patients with heart failure
(HEAAL study): a randomized, double-blind trial. Lancet 2009;
374:1840–8.
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on
morbidity and mortality in patients with severe heart failure. N
Engl J Med 1999; 341: 709-717.
- Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with
systolic heart failure and mild symptoms. N Engl J Med 2011;
634: 11-21.
- Solomon SD, Wang D, Finn P, et al. Effect of candesartan on
cause-specific mortality in heart failure patients: the Candesartan in
Heart failure Assessment of Reduction in Mortality and morbidity
(CHARM) program. Circulation 2004; 110: 2180-2183.
- Domanski MJ, Exner DV, Borkow CB, et al. Effect of angiotensin
converting enzyme inhibitors on sudden cardiac death in patients
following acute MI. JACC 1999; 33: 568-604.
- Al_Gobaru M, El Khatib C, Pillon F, et al. B-blockers for the
prevention of sudden cardiac death in heart failure patients. BMC
cardioVasc Disord 2013; 13: 52.
- Bapoje SR, Bohia A, Hokanson JE, et al. Effect of mineralocorticoid
receptor antagonsists on risk of sudden cardiac death in patients with
LV dysfunction. Circ heart dail 2013; 6: 166-173.
- Luni FK, Singh H, Khan AR, et al. Mortality effect of ICD in primary
prevention nonischemic cardiomyopathy: A meta analysis of randomized
controlled trials. J Cardiovascul Electrophysiol 2017; 28: 538-543.
- Shen L, Jhund PS, Petrie MC, et al. Declining risk of sudden death in
heart failure. N Engl J Med 2017; 377: 41-52.
- Kober L, Thine JJ, Nielsen JC, et al. Defibrillator implantation in
patients with nonischemic systolic heart failure (DANISH). N Engl J
Med 2016; 375: 1221-1230.
- Greene SJ, Butler J, Albert NM, et al. Medication therapy for heart
failure with reduced ejection fraction. The CHAMP-HF registry. JACC
2018; 72: 351-366.
- Greene SJ, Fonarow GC, Devore AD, et al. Titration of medical therapy
for heart failure patients with reduced ejection fraction. JACC 2019;
73: 2365-2383.
- Teng TH, Tromp J, Tay WT, et al. ASIAN-HF investigators. Prescribing
patterns of evidence-based heart failure pharmacotherapy and outcomes
in the ASIAN-HF registry: a cohort study. Lancet Glob Health 2018; 6:
e1008–18.
- Komajda M, Cowie MR, Tavazzi L, et al. on behalf of the QUALIFY
Investigators. Physicians’ guideline adherence is associated with
better prognosis in outpatients with heart failure with reduced
ejection fraction: the QUALIFY international registry. European J of
Heart Fail 2017; 19: 1414-1423.
- Epstein AE, Darbar D, Di Marco JP, et al. 2012 ACC/AHA/HRS focused
update of the 2008 guidelines for device-based therapy of cardiac
rhythm abnormalities. Circ 2012; 126: 1786-1800.
- Brignole M, Aurucchio A, Baron-Esquivias G, et al. 2013 ESC guidelines
on cardiac pacing and cardiac resynchronization therapy. European
Heart J 2013; 34: 2281-2329.
- Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the
diagnosis and treatment of acute and chronic heart failure. The Task
Force for the diagnosis and treatment of acute and chronic heart
failure of the European Society of Cardiology (ESC) Developed with the
special contribution of the Heart Failure Association (HFA) of the
ESC. European Heart J 2016; 37: 2129-2200.
- Ouwerkerk W, Voors AA, Anker SD, et al. Determinants and clinical
outcome of up titration of ACE-inhibitors and beta blockers in
patients with heart failure: a prospective European study. European
Heart J 2017; 38: 1883-1890.
- Stiles MK, Fauchier L, Morillo CA, and Wilkoff BL. 2019
HRS/EHRA/APHRS/LAHRS focused update to 2015 expert consensus statement
on optimal implantable cardioverter-defibrillator programming and
testing. Europace 2019; 21: 1442-1443
- Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable
cardioverter-defibrillator for congestive heart failure (SCD-HefT). N
Engl J Med 2005; 352:225-237.
- Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator
implantation in patients with nonischemic dilated cardiomyopathy
(DEFINITE). N Engl J Med 2004; 350: 2151-2158.
- Moss AJ, Schuger C, Beck CA, Brown MW, et al. Reduction in
inappropriate therapy and mortality through ICD programming. New Engl
J Med 2012; 367: 2275-2283.
- Callans DJ, Marchlinski FE. Characterization of spontaneous
termination of sustained ventricular tachycardia associated with
coronary artery disease. Am J Cardiol 1991; 67: 50-54.
- Schmitt H, Waldecker B. Mechanisms for spontaneous termination of
monomorphic sustained ventricular tachycardia: Results of activation
mapping of reentrant circuits in the epicardial border zone of
subacute canine infarcts. JACC 1998; 31: 460-472.
- Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the
prevention of sudden death in patients with coronary artery disease
(MUSTT trial). N Engl J Med 1999; 341: 1882-1890.
- Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a
defibrillator in patients with myocardial infarction and reduced
ejection fraction (MADIT-II). N Engl J Med 2002; 346: 877-883.
- Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus
implantable defibrillator: randomized trial in patients with
nonischemic dilated cardiomyopathy and asymptomatic nonsustained
ventricular tachycardia. (AMIOVIRT). J Am Coll Cardiol 2003; 41:
1707-1712.
- Bänsch D, Antz M, Boczor S, e al. Primary prevention of sudden cardiac
death in idiopathic dilated cardiomyopathy: The cardiomyopathy Trial
(CAT). Circ 2005; 105: 1453-1458.
- Dorian P. Antiarrhythmic action of beta-blockers: potential
mechanisms. J Cardiovasc Pharmacol Ther. 2005 Jun;10
- Grandi E and Ripplinger CM. Anti arrhythmic mechanism of BB therapy.
Phramacol Res 2019; 146.
- Fiuzat M, Wojdyla D, Pina I, et al. Heart rate or beta blocker dose?
Association with outcomes in ambulatory heart failure patients with
systolic dysfunction. JAVV Heart Fail 2016; 4: 109-115.
- Bristow MR. Treatment of chronic heart failure with beta-adrenergic
receptor antagonists: a convergence of receptor pharmacology and
clinical cardiology. Circ Res 2011; 109: 1176-1194.
- Kotecha D, Flather MD, Altman DG, et al. Heart rate and rhythm and the
benefit of beta-blockers in patients with heart failure. JACC 2017;
69: 2885-2896.
Table 1 - Patient characteristics and comparison of patients with and
without VA