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European Heart Journal - Cardiovascular Pharmacotherapy Advance Access published March 31, 2015
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Optimization of heart failure medication after cardiac
resynchronization therapy and the impact on long-term survival
Christoffer Tobias Witt1, Mads Brix Kronborg1, Ellen A. Nohr2, Peter Thomas Mortensen1,
Christian Gerdes1, and Jens Cosedis Nielsen1
1
Department of Cardiology, Aarhus University Hospital, Skejby, Denmark
2
Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
Address for Correspondence: Christoffer Tobias Witt, Department of Cardiology, Aarhus
University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark, Tel: 0045
78452115; Fax: 0045 78452118; Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For
permissions please email: [email protected]
2
Abstract
Aims: Treatment with evidence-based heart failure (HF) medication reduces morbidity and
mortality, yet they remain underused and underdosed. Cardiac resynchronization therapy (CRT)
improves hemodynamics, and might allow for optimization of HF medication. We analyzed
treatment with HF medication after CRT implantation, long-term adherence to this treatment and its
association to patient survival.
Methods and results: This observational study included 826 consecutive patients who received a
CRT device at a tertiary centre. Data were obtained from patient files and prescription data from the
Danish National Prescription Registry. Doses are expressed as percentages of target doses. We used
Cox proportional hazard model to compute hazard ratios (aHR) for survival with 95% confidence
intervals (CI), adjusted for potential confounders. During median (quartiles) follow-up of 4.4 (3.06.7) years, 324 patients died. Daily doses of beta-blocker (BB) (53 (27-90)% vs. 43 (22-75)%;
p<0.001) and angiotensin-converting enzyme inhibitor (ACEi) / angiotensin receptor blocker
(ARB) (78 (45-100)% vs. 74 (44-97)%; p=0.02) had increased after 6 months of follow-up
compared with pre-implantation doses. After 4 years, adherence was 95% to BB and 94% to
ACEi/ARB. Treatment with low (≤50%) and high (>50%) doses were associated with prolonged
survival for BB (low: aHR 0.65 (0.47-0.90); p=0.009, and high: aHR 0.50 (0.35-0.70); p<0.001)
and for ACEi/ARB (low: aHR 0.68 (0.46-1.00); p=0.05, and high: aHR 0.55 (0.38-0.80); p=0.002).
Conclusion: After CRT implantation, optimization of HF treatment is possible, and long-term
adherence to HF medication remains high. Higher doses of BB and ACEi/ARB were associated
with prolonged survival.
Keywords: Chronic heart failure; Optimal medical therapy; Compliance/adherence; Cardiac
resynchronization therapy
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Introduction
Cardiac resynchronization therapy (CRT) is an established treatment for patients with heart failure
(HF) due to left ventricular systolic dysfunction and intraventricular conduction delay.1-3 Prior to
CRT implantation, patients are required to receive recommended, or highest tolerated dose of HF
medication,4 which includes neurohormonal therapy with beta-blockers (BB), angiotensinconverting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), and aldosterone
antagonist. In daily clinical practice, achieving target doses is often challenging due to side-effects
or co-morbidity.5-9 Likewise, the long-term adherence is important to ensure optimal benefit of
these therapies.10
Studies have reported that patients with CRT are treated with suboptimal doses of HF
medication.5,11 Thus after CRT implantation, re-evaluation of HF medication is important, as
increase in blood pressure, improved renal function, and avoidance of bradycardia might facilitate
initiation or further optimization of medical therapy in patients who previously did not tolerate this
treatment.4 Accordingly, recent studies indicated that higher doses of HF medication are achieved
after CRT implantation,11,12 as well as in patients with CRT when compared to patients without
such device.5
The purpose of this study was to describe the changes in HF medication during the first 6 months
after CRT implantation and the adherence to medical therapy during long-term follow-up.
Furthermore, we aimed to examine patient survival according to doses of HF medication after CRT
implantation.
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Methods
Study Population
We screened a cohort of 1101 consecutive patients who received their first CRT device at Aarhus
University Hospital, Denmark between 2000 and 2010. Of those, 936 patients had reduced left
ventricular ejection fraction (LVEF) (≤ 35%) and a wide QRS complex (≥120 ms). We excluded
patients who died, underwent heart transplantation or system downgrade to implantable
cardioverter-defibrillator (ICD) or cardiac pacemaker within 225 days of implantation to ensure a
90 days period for calculation of daily drug doses around the point in time of 6 months after
implantation, resulting in a study cohort of 826 patients. Patients were followed until September
2013. The study was approved by the Danish Health and Medicines Authority and the Danish Data
Protection Agency.
Clinical data
We collected clinical, electrocardiographic and echocardiographic data retrospectively by review of
all patient medical charts at baseline and during follow-up. One investigator (CTW) performed this
review. All patients underwent follow-up at 1 and 6 months at the implanting center, and afterwards
every 6 months at their local hospital. Patients who had an improvement in New York Heart
Association (NYHA) functional class from baseline to the 6 months follow-up visit were defined as
responders.
The primary outcome was all-cause mortality, and patients were censored at time of heart
transplantation, or system downgrade to ICD or cardiac pacemaker. Information on vital status and
date of death was obtained from the Danish Civil Registration System.13 All data sources were
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linked by use of the personal identification number, a unique identifier assigned to all Danish
residents.
Medical Treatment
In Denmark, information of all prescriptions dispensed from Danish pharmacies since 1995 are
recorded in the Danish National Prescription Registry.14 The prescriptions are coded according to
the Anatomic Therapeutical Chemical system. The registry includes information about the
dispensing date of the prescription, the strength of the drug, and the total number of tablets
dispensed, but no information about the prescribed dose of the individual drug.
Initiation of medical therapy was defined as the date of claiming a prescription. The daily dose of
BB, ACEi/ARB, aldosterone antagonist and loop diuretics was calculated from the average daily
dose given during a 90 days period which could include more than one prescription. If a dose was
administered for less than 40 consecutive days during the 90 days period, it was counted as no
treatment. Doses were assessed in a 90 days period prior to implantation, and subsequently at 6
months, 1, 2, 3 and 4 years after implantation in a period from 45 days before until 45 days after
each time point. Doses are presented as the percentage of target dose according to guidelines,15
except for loop diuretics, which was presented as mg equal to treatment with furosemid. The
presented mean daily doses represent doses prescribed among patients who received medication.
The following daily target doses were used for the most frequently prescribed drugs: carvedilol 50
mg; metoprolol 200 mg; bisoprolol 10 mg; ramipril 10 mg; trandolapril 4 mg; losartan 50; enalapril
20 mg; spironolactone 50 mg. During the study period, the daily target dose of losartan increased
from 50 mg to 150 mg. We set the target dose at 50 mg per day until end 2009 and 150 mg per day
afterwards. Doses of BB and ACEi/ARB prescribed was divided into 3 groups according to
percentage of target dose 6 months after implantation; 0 (no), 1-50% (low) and >50% (high). We
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defined adherence to medical therapy as continued treatment during follow-up in patients receiving
a HF medication 6 months after implantation, and report proportion of those adherent each year
after implantation.
Statistical Analysis
Distributions were tested for normality using Q-Q plots and histograms. Continuous data are
reported as mean and standard deviation (SD) if normally distributed and as median with 25th–75th
interquartile range (IQR) if non-normally distributed. Categorical data were presented as number
and percentage. When differences were assessed between implantation and 6 months after, data
were analyzed as paired data based on paired Student´s t-test or McNemar's test. If non-paired,
differences between groups were assessed by χ² test, student’s t-test or a non-parametric test as
appropriate.
Patients were followed from 225 days after implantation, which was defined as the index date, and
until the date of death, heart transplantation, system downgrade to ICD or cardiac pacemaker, or the
end of follow-up, whichever came first. Hazard ratios (HR) and adjusted HR (aHR) of survival with
95% confidence intervals (CI) were estimated using Cox proportional hazard models. We adjusted
for a-priori selected confounders; gender, age, estimated Glomerular Filtration Rate (eGFR) in 2
groups (≤60 vs. >60 ml/min/1.73m2), QRS width, LVEF, heart rate, systolic blood pressure, NYHA
functional class, presence of coronary artery disease, ICD-backup, left bundle branch block
(LBBB), chronic obstructive lung disease, diabetes mellitus and history of atrial fibrillation at time
of implantation, and diuretic treatment at 6 months. The survival curves represent the hazard
estimates based on the adjusted Cox model. Due to the long inclusion period, we choose to adjust
for early or late implantation (implantation before or after January 2005). The proportional hazard
assumption was evaluated for all variables by comparing estimated log − log survivor curves, and
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tests for interactions were performed by inclusion of an interaction term in the analysis. A P-value
of less than 0.05 was considered significant. All statistical analyses were performed using STATA
software (STATA IC for Windows, version 12).
Results
A total of 826 patients were included in the study cohort. Reasons for exclusion were QRS width <
120 ms (99 patients), LVEF > 35% (66 patients), or follow-up for less than 225 days due to death,
heart transplantation or system downgrade (110 patients). No patients were lost to follow-up.
Patient characteristics at CRT implantation are presented in Table 1. The median follow-up after
implantation was 4.4 years (3.0-6.7), during which 324 patients (39%) died, 19 patients underwent
heart transplantation and 10 patients had their system downgraded to an ICD or cardiac pacemaker
without CRT.
Change in heart failure medication after CRT implantation
Six months after implantation, the proportion of patients who received BB had increased (88% vs.
75%; P < 0.001) with an increase in daily dose (median 53% vs. 43%; P < 0.001) (Table 2), and a
higher proportion of patients received high dose of BB (48% vs. 32%; P < 0.001) as compared to
baseline. The proportion of patients treated with ACEi/ARB was unchanged at 6 months (91% vs.
90%; P = 0.75) as well as the proportion of patients who received high dose of ACEi/ARB (63% vs.
63%; P = 0.96). An increase in daily dose was however observed (median 78% vs. 74%; P = 0.02).
Overall, the proportion of patients who reached doses equal to target doses of BB or ACEi/ARB at
6 months was 21% and 37%, respectively. The most commonly prescribed BBs were metoprolol
(33%) and carvedilol (63%), while ramipril (35%), trandolapril (19%) and losartan (14%) were the
most commonly used ACEi/ARB's. There was no difference in the proportion of patients treated
with aldosterone antagonists (59% vs. 58%; P = 0.28) or daily doses (median 49% vs. 51%; P =
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0.46) at 6 months of follow-up compared to pre-implantation doses. More patients seemed to
receive loop diuretics (82% vs. 79%; P = 0.05), but daily dose was unchanged (median 80 mg vs.
80 mg; P = 0.22) 6 months after implantation.
At baseline, patients who were uptitrated with BB within the first 6 months after CRT implantation
were more likely to receive diuretics and an ICD, and those uptitrated with ACEi/ARB were
younger and had better renal function. Otherwise, the patients’ baseline characteristics were similar.
In general, patients treated with high dose of BB and ACEi/ARB after 6 months had less comorbidity than those who either received no or lower doses. Thus patients who received high dose
of BB were younger (67 (60-73) vs. 70 (63-76) years; P < 0.001), had higher systolic blood pressure
(119 ± 17 vs. 116 ± 18 mm Hg; P = 0.004), better renal function (eGFR: 66 ± 25 vs. 58 ± 27
ml/min/1.73m2; P < 0.001), less symptomatic (NYHA class; 2.68 ± 0.54 vs. 2.81 ± 0.57; P = 0.001),
higher body mass index (26 (24-30) kg/m2 vs. 25 (23-29) kg/m2; P < 0.001) and were less likely to
have coronary artery disease (47% vs. 56%; P = 0.008) and a diagnosis of chronic obstructive lung
disease (14% vs. 21%; P = 0.013). Similarly, patients treated with high dose of ACEi/ARB were
younger (67 (59-73) vs. 71 (63-76) years; P < 0.001), had higher systolic blood pressure (119 ± 17
vs. 116 ± 17 mm Hg; P = 0.004), better renal function (eGFR: 66 ± 25 vs. 57 ± 25 ml/min/1.73m2; P
< 0.001), and higher body mass index (26 (24-30) kg/m2 vs. 25 (23-29) kg/m2; P < 0.001). No
difference was found in regard to LVEF, heart rate, history of atrial fibrillation or diabetes mellitus
between patients who received low versus high dose of either ACEi/ARB or BB.
Adherence to heart failure medication during follow-up
During long-term follow-up, both the proportion of patients who received HF medication and the
proportion of patients who received higher dose remained high after 4 years of follow-up (Figure 1).
The adherence was 95% for BB and 94% for ACEi/ARB at 4 years. Mean daily dose for BB and
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ACEi/ARB remained stable at 1, 2, 3 and 4 years (BB: 58 (29-95) %; 56 (34-95) %; 63 (35-96) % ;
and 59 (36-96) %; ACEi/ARB: 78 (45-100) %; 77 (41-100) %; 76 (43-99) %; and 82 (44-100) %,
respectively). Adherence to aldosterone antagonist decreased within the first 2 years, and was 77%
at 4 years.
Long-term survival and heart failure medication
As compared with no medication, the intake of BB and ACEi/ARB in low or high dose after 6
months was associated with significantly better survival (Figure 2). After adjustment for a priori
selected variables, both low and high doses of BB and ACEI/ARB were associated with prolonged
survival (Table 3). The higher dose of both BB and ACEi/ARB was associated with prolonged
survival as compared with the low dose (BB: aHR, 0.76; 95% CI 0.59 to 0.99; P = 0.04.
ACEi/ARB: aHR, 0.82; 95% CI, 0.63 to 1.06; P = 0.13), although the association was statistically
significant only for BB. Patients not treated with diuretics had better survival than those who
received diuretics, both in unadjusted and adjusted analysis. No association was observed between
treatment with aldosterone antagonists and all-cause mortality in unadjusted or adjusted analysis.
Heart failure medication in responders to CRT
In 791 of the patients (96%) NYHA functional class was available at 6 months follow-up and of
those, 410 patients (52%) were classified as responders. The proportion of responders was higher in
patients with LBBB or right ventricular pacing than in those who had right bundle branch block or
non-specific intraventricular conduction delay at baseline (56% vs. 41%; P < 0.001). More
responders received treatment with ACEi/ARB at 6 months (94% vs. 84%; P = 0.01), and there was
a trend towards a higher mean daily dose in responders compared to non-responders (85 (46-100) %
vs. 76 (44-99) %; P = 0.09). Responders received a lower dose of diuretics than non-responders (60
(40-120) mg vs. 90 (40-160) mg; P < 0.001). There was no difference in the proportion of patients
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treated or the mean daily doses prescribed between responders and non-responders for BB and
aldosterone antagonist.
Discussion
This study indicates that optimization of treatment with BB and ACEi/ARB is possible after CRT
implantation in an unselected cohort of patients with HF, and that adherence to HF medication
remains high with sustained mean doses during 4 years of follow-up. Treatment with higher doses
of BB and ACEi/ARB at 6 months is associated with prolonged long-term survival after CRT
implantation.
Medical therapy with BB and ACEi/ARB reduces mortality and morbidity in patients with left
ventricular systolic dysfunction,16-18 and studies have indicated an increased benefit with higher
doses.19,20 Current guidelines therefore recommend doses comparable to those used in the clinical
trials or maximum tolerable doses.15 The addition of a CRT device to medical therapy improves
survival in a subgroup of these patients;1-3 however patients with CRT are often treated with doses
of HF medication below those recommended in guidelines.5 Treatment with CRT improves
hemodynamics and clinical symptoms, and prevents bradycardia,1,6 which might allow further
optimization of treatment with BB and ACEi/ARB. The present large-cohort study demonstrates
that up-titration and initiation of HF medication is indeed possible after CRT implantation,
supporting and strengthening the findings from prior studies.11,12,21 We have no detailed
information regarding the reasons for not initiating or achieving target doses of BB and ACEi/ARB
treatment in our patients before CRT implantation, but the proportions of patients treated with BB
and ACEi/ARB at baseline in our cohort was comparable to pivotal CRT trials 1,2 and previous
observational studies.22,23 The mean doses achieved at 6 months were lower than recommended in
guidelines,15 and only 21% and 37% of the patients received target doses of BB and ACEi/ARB,
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respectively. Consecutive real-world patients are older, more symptomatic and with more comorbidity than patients included in randomized trials,16,18,19 which may partly explain that target
doses of HF medication were reached in only a minority of our patients. However, the achieved
doses in our study are similar to or higher than reported in previous observational studies in CRTpatients as well as in general heart failure populations.5,11,24
The findings of high adherence to medical therapy and sustained doses with BB and ACEi/ARB
during our follow-up period of 4 years are reassuring, since adherence to high-dose neurohormonel
blockage with BB and ACEi/ARB is correlated to prolong survival in HF patients.10 Adherence to
aldosterone antagonists was high but declined significantly during follow-up, most likely explained
by side effects like worsening of renal function and hyperkalemia.25 Prior studies have reported
lower long-term adherence to medical therapy in the general HF population.24,26 This difference
from our findings may have several explanations. In addition to the improved hemodynamic after
CRT, the regular follow-up in dedicated CRT-HF clinics probably facilitated a better long-term
compliance.
The present study demonstrated that BB and ACEi/ARB therapy was associated with prolonged
survival, and better survival was related to higher doses. Previous studies have reported a similar
additional benefit of higher doses of HF medication in patients with CRT when assessed either at
baseline or during follow-up.11,12,27,28 These results highlight the importance of re-evaluation of HF
medication after CRT implantation. Although these results suggest a dose-related association
between HF medication and prolonged survival in patients with CRT, no causality can be concluded
from this observational study. Prior studies have pointed out that patients who received no or low
doses of BB and ACEi/ARB have more co-morbidity compared to patients treated with high
doses.5,11 This was also the case in our study. In the multivariate models, we adjusted for the most
12
important of these factors and still found a similar association between doses of medical therapy
and survival.
Among our CRT-responders, a higher proportion of patients were treated with ACEi/ARB and they
seemed to receive a higher daily dose. This is accordant with prior findings.11,29 These results could
support a relationship between medical therapy and response to CRT, however, whether medical
therapy causes a higher CRT-responder rate, CRT-responders better tolerate medical therapy, or a
combination of the two is currently unknown.
We did not find any difference in BB therapy between responders and non-responders, probably
because our patients received higher mean percentages of target doses throughout the follow-up
period as compared with previous reports (59% vs. 48% of target doses respectively).11 The effect
of loop diuretics on mortality is largely unknown, and thus diuretics are mainly prescribed to relieve
symptoms of congestion. Treatment with diuretics should be adjusted to maintain lowest effective
doses. Our findings that responders to CRT received lower doses of loop diuretics compared to nonresponders, as well as shorter survival among patients treated with diuretics are similar to other
studies,11,30 and likely reflect that diuretics are needed for the sickest patients with the worst
prognosis.
This study has important implications for the clinical strategy of follow-up after CRT implantation.
We found that higher doses of HF medication were associated with prolonged survival in patients
with CRT. Therefore, optimization of medical therapy should be attempted after CRT implantation.
Furthermore this study indicates that patient’s compliance to these medications can be maintained at
a high level during long-term follow-up.
13
Limitations
The major limitations of the current study are those inherent for observational studies. Given the
Danish health care system's partially reimbursement of expenses for medication, all Danish
pharmacies are required to register all dispensed drug prescriptions, which ensures complete
registration of the HF medication data. The study was restricted to include only patients with more
than 8 months of follow-up, and the findings regarding survival therefore are valid only beyond that
period. The association observed between higher doses of medical therapy and survival might in
part be caused by confounding-by-indication, as a number of poor prognostic patient factors were
statistically associated with low doses of BB and ACEi/ARB. Furthermore, the use of only one
target dose for each drug might have led to a simplification when comparing drug doses, since
individual patient characteristics could have made the phycisians choose different target doses. We
defined responders according to improvement in NYHA class, as an echocardiogram was available
in only 57% of the patients within the first 12 months after implantation. Although our responder
rate is lower than previously reported by observational studies, our percentage of responders are
consistent with the numbers from the clinical trials.31 However, this study included a large cohort of
consecutive CRT patients with a complete and long-term follow-up, and the point-estimates
indicating beneficial effect of higher doses of ACEi/ARB and BB were quite robust and consistent
in unadjusted and adjusted analyses.
Conclusion
This study indicates that optimization of treatment with BB and ACEi/ARB is possible after CRT
implantation in a large unselected cohort of patients, and that the adherence to HF medication
remains high with sustained daily doses during 4 years of follow-up. Treatment with higher doses
14
of BB and ACEi/ARB at 6 months is associated with prolonged long-term survival after CRT
implantation.
Funding
This work was supported by the Danish Council for Independent Research [grant number 12127221]; the Central Denmark Region Research Foundation; and Fabrikant Karl G. Andersens
Foundation.
Conflict of interest
JCN has received speakers’ honoraria from Biotronik and Biosense Webster, consultants’ honoraria
from Boston Scientific and a research grant from Biosense Webster. MBK, CG and PTM have
received speakers’ honoraria from Biotronik. CTW and EAN have no conflicts of interest to
disclose.
15
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Ahmed A, Husain A, Love TE, Gambassi G, Dell'Italia LJ, Francis GS, et al. Heart failure, chronic
diuretic use, and increase in mortality and hospitalization: an observational study using propensity score
methods. Eur Heart J. 2006;27:1431-1439.
31.
Sohaib SM, Chen Z, Whinnett ZI, Bouri S, Dickstein K, Linde C, et al. Meta-analysis of
symptomatic response attributable to the pacing component of cardiac resynchronization therapy. Eur J
Heart Fail. 2013;15:1419-1428.
17
Figure legends
Figure 1. Proportion of patients treated with heart failure medication (green), proportion who
received more than 50% of target dose (red), and proportion adherent to treatment (continuing
treatment after 6 months) (blue). ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin
receptor blocker; BB, beta-blockers.
Figure 2. The survival estimates of all-cause mortality according to doses of heart failure
medication 6 months after CRT implantation. The curves represent the hazard estimate obtained
from the adjusted Cox model described under the statistical analysis. Doses of beta-blocker (BB)
and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) are
divided into three groups; 0%, 1-50% and >50% of target doses, and aldosterone antagonists and
loop diuretics into two groups; patients with or without treatment. Follow-up started 225 days after
implantation.
18
Table 1. Patient characteristics.
All (n = 826)
Age, years
68 (60-74)
Male (%)
656 (79)
Previous RV pacing (%)
159 (19)
CRT-D (%)
396 (48)
Systolic blood pressure, mmHg
118 ± 18
Diastolic blood pressure, mmHg
71 ± 11
Body mass index, kg/m2
26 (23-29)
Heart rate at implantation, beats/min
70 ± 15
QRS, ms
165 ± 27
LBBB (%)
444 (54)
Ejection fraction, %
24 (6)
NYHA functional class (%)
I
20 (2)
II
197 (24)
III
567 (69)
IV
32 (4)
Missing
10 (1)
Risk factors
Atrial fibrillation (%)
328 (40)
COPD (%)
144 (17)
Coronary artery disease (%)
397 (48)
19
Diabetes mellitus (%)
216 (26)
Hypertension (%)
287 (35)
eGFR, mL/min/1.73 m2
Implantation
62 ± 26
6 months
61 ± 24
Continuous variables are reported as mean ± standard deviation if normally distributed otherwise as median
with 25th and 75th interquartile ranges (IQR). Categorical variables are reported as numbers and
percentages. COPD, Chronic obstructive pulmonary disease; eGFR, estimated Glomerular Filtration Rate;
ICD, implantable cardioverter-defibrillator; LBBB, left bundle branch block; LVEF, left ventricular ejection
fraction; NYHA, New York Heart Association.
20
Table 2. Number and proportion of patients on beta-blocker (BB), angiotensin-converting enzyme
inhibitors (ACEi)/angiotensin receptor blockers (ARB), aldosterone antagonists and loop diuretic,
and the mean daily doses at CRT implantation and after 6 months. Daily doses are presented as
percentage of target dose, except for loop diuretics which are presented in mg equal to treatment
with furosemid. Continuous variables are reported as medians with 25th–75th interquartile range,
and categorical data are presented as numbers and percentages. Data were analyzed as paired
samples based on Wilcoxon signed rank test or McNemars test.
Patients, n (%)
Daily dose (% of target)
Implantation
6 months
P-value
Implantation
6 months
P-value
BB
620 (75)
724 (88)
<0.001
43 (22-75)
53 (27-90)
<0.001
ACEi/ARB
747 (90)
753 (91)
0.51
74 (44-97)
78 (45-
0.02
100)
Aldosterone
antagonists
Loop diuretic
475 (58)
490 (59)
0.28
51 (38-65)
49 (36-58)
0.46
654 (79)
676 (82)
0.05
80 (40-120)
80 (40-
0.22
140)
21
Table 3. Long-term risk of all-cause mortality according to heart failure medication and doses of
HF medication assessed at 6 months. Beta-blocker (BB) and angiotensin-converting enzyme
inhibitors (ACEi)/angiotensin receptor blockers (ARB) were divided into three groups according to
percentage of target dose; no treatment, low (1-50%) and high (>50%) doses. Aldosterone
antagonists and loop diuretics were divided in two groups, according to the presence or absence of
treatment.
Unadjusted
HR
95% CI
Adjusted
P-value
HR
95% CI
P-value
BB
No treatment
Reference
Low
0.71
0.52-0.96
0.027
0.65
0.47-0.90
0.009
High
0.43
0.31-0.59
<0.001
0.50
0.35-0.70
<0.001
ACEi/ARB
No treatment
Reference
Low
0.54
0.38-0.78
0.001
0.68
0.46-1.00
0.05
High
0.39
0.28-0.55
<0.001
0.55
0.38-0.80
0.002
Aldosterone antagonist
0.88
0.71-1.10
0.27
1.05
0.82-1.34
0.70
Loop diuretics
2.60
1.76-3.83
<0.001
1.56
1.04-2.34
0.03
22
Figure 1.
Survival
Survival
1
.8
.6
.4
.2
0
1
.8
.6
.4
.2
0
0
0
2
No
Yes
2
4
6
Analysis time/year
Aldosterone
4
6
Analysis time/year
No
1-50%
>50%
BB
8
8
.2
0
1
.8
.6
.4
.2
0
Survival
Survival
.4
.6
.8
1
0
0
2
No
Yes
2
4
6
Analysis time/year
Diuretic
4
6
Analysis time/year
No
1-50%
>50%
ACEi/ARB
Covariate-adjusted survivor estimate
8
8
23
Figure 2.