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Prior Pacemaker Implantation and Clinical Outcomes in Patients With Heart Failure and Preserved Ejection FractionFree Access

Clinical Research

J Am Coll Cardiol HF, 7 (5) 418–427
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Graphical abstract

Abstract

Objectives:

This study examined the relationship between prior pacemaker implantation and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF).

Background:

Conventional right ventricular pacing causes electrical and mechanical left ventricular dyssynchrony and may worsen left ventricular systolic dysfunction and HF. Whether conventional pacing is also associated with worse outcomes in HFpEF is unknown.

Methods:

Patient data were pooled from the CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction), and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial) studies and were examined for the association between having a pacemaker and the risk of the primary composite of cardiovascular death or HF hospitalization, the individual components of the composite, the 2 main modes of cardiovascular death (i.e., sudden death and pump failure death), and all-cause death in unadjusted and adjusted analyses.

Results:

Of the 8,466 patients included, 682 patients (8%) had a pacemaker. Pacemaker patients were older and more often men and had lower body mass indexes, estimated glomerular filtration rates, and blood pressures but higher concentrations of N-terminal pro–B-type natriuretic peptide than those without a pacemaker. The rate of the primary composite outcome in pacemaker patients was almost twice that in patients without a pacemaker (13.6 vs. 7.6 per 100 patient-years of follow up, respectively), with a similar finding for HF hospitalizations (10.8 vs. 5.1 per 100 patient-years, respectively). This risk rate persisted after adjusting for other prognostic variables (hazard ratio [HR] for the composite outcome: 1.17; 95% confidence interval [CI]: 1.02 to 1.33; p = 0.026), driven mainly by HF hospitalization (HR: 1.37; 95% CI: 1.17 to 1.60; p < 0.001). The risk of death was not significantly higher in pacemaker patients in the adjusted analyses.

Conclusions:

These findings raise the possibility that right ventricular pacing-induced left ventricular dyssynchrony may be detrimental in HFpEF patients.

Introduction

The importance of dyssynchronous contraction of the left ventricle (LV) in patients with heart failure (HF) and reduced ejection fraction (HFrEF) is demonstrated by the poor outcomes associated with left bundle branch block (1) and the benefits of cardiac resynchronization therapy (CRT) in patients with this electrocardiographic (ECG) marker of dyssynchrony (2). Conventional right ventricular (RV) pacing also causes electrical and mechanical LV dyssynchrony and may aggravate LV systolic dysfunction and HF (3). Consistent with this clinical observation, the BLOCK-HF (Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block) trial demonstrated that CRT was superior to RV pacing, as measured by a clinical outcome of all-cause death, by the need for urgent HF care, or by a 15% or greater increase in LV end-systolic volume index in HFrEF patients with atrioventricular block and an indication for pacing (4). Because of these findings, recent guidelines recommended CRT rather than RV pacing for patients with HFrEF who require a pacemaker for atrioventricular block and to consider “up-grading” HFrEF patients to CRT for those who have a conventional pacemaker and a high frequency of RV pacing, either at the time of a scheduled generator change or if the patient has severe or progressive HF symptoms (5,6).

The potential consequences of RV pacing in patients with HF with preserved EF (HFpEF) have not been studied. Although the importance of dyssynchronous contraction of the LV in patients with HFpEF is less well understood than that in HFrEF patients, QRS prolongation and bundle branch block have recently been shown to be associated with worse clinical outcomes (compared with no QRS prolongation or bundle branch block) in HFpEF, as has been reported in HFrEF (1,7). Additionally, some cohort studies suggest that conventional RV pacing may induce HF even in patients with no history of the syndrome (8). Collectively, these observations suggest that LV dyssynchrony caused by RV pacing could be harmful in patients with HFpEF, as it is in those with HFrEF. Therefore, this study examined the relationship between baseline pacemaker implantation and clinical outcomes in patients enrolled in the 3 largest randomized trials in HFpEF, the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction), the CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), and the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial) studies.

Methods

Study population

For the present analyses, data from all patients enrolled in the CHARM-Preserved, the I-PRESERVE, and the TOPCAT studies were pooled (9–11). There were no differences between the balance of randomized therapy and placebo in those with a pacemaker and those without a pacemaker in any of the trials. The design and results of these trials have been published previously. Briefly, in the CHARM-Preserved trial, 3,023 HF patients in New York Heart Association (NYHA) functional classes II to IV with an LV ejection fraction (LVEF) >40% were randomized to receive candesartan or placebo. Patients in NYHA functional class II were eligible if they had been hospitalized for a cardiac reason within the previous 6 months (9). The I-PRESERVE study compared irbesartan therapy with placebo in 4,128 patients ≥60 years of age in NYHA functional classes II to IV and with an LVEF ≥45%. Patients in NYHA functional class II were required to have undergone HF hospitalization within the previous 6 months (10). The TOPCAT study compared spironolactone therapy with placebo in 3,445 patients ≥50 years of age in NYHA functional classes II to IV with an LVEF ≥45%; patients were required to have been hospitalized within the previous 12 months for HF or to have an elevated natriuretic peptide concentration within 60 days before randomization (i.e., B-type natriuretic peptide [BNP] concentration ≥100 pg/ml or an N-terminal pro–BNP [NT-proBNP] concentration ≥360 pg/ml) (11).

Patients with an LVEF <45% in the CHARM-Preserved study were excluded to ensure an LVEF entry threshold across trials. Patients from Russia and Georgia who were randomized in TOPCAT were also excluded because their event rates in that region of enrollment were substantially lower than those in the Americas, as well as doubts about adherence to treatment (12). Each trial was approved by the ethics committee at participating centers, and all patients provided written informed consent.

Baseline history of pacemaker implantation

Baseline history of pacemaker implantation was identified through responses to a case report form question in each trial in which investigators were asked to state whether patients had a pacemaker in situ. The specific type of pacemaker was not recorded in any of these trials.

In additional analyses, patients in the pacemaker group were divided into those found to have a paced rhythm on their baseline ECG and those with a nonpaced rhythm, and the 2 groups were compared as a measurement of pacing burden.

Outcomes

The primary outcome was a composite of cardiovascular (CV) death or HF hospitalization in CHARM-Preserved, all-cause death or CV hospitalization in I-PRESERVE, and a composite of CV death and HF hospitalization or aborted cardiac arrest in TOPCAT. In the present study, the authors investigated the association between pacemaker implantation and risk of primary composite of CV death or HF hospitalization, and the individual components of the composite, and the 2 main modes of CV death (i.e., sudden death and pump failure death), and all-cause death). Each endpoint was adjudicated by a central endpoint committee according to similar pre-specified criteria in each trial (the same committee adjudicated the events in 2 of the 3 trials, CHARM-Preserved and TOPCAT).

Statistical analyses

Baseline characteristics are presented as mean ± SD or median (interquartile range [IQR]) for continuous variables and frequencies and percentages for categorical variables. Baseline characteristics according to pacemaker usage were compared by using the Student's t-test or Mann-Whitney U test, as appropriate for continuous variables, and the chi-square test for categorical variables. Event rates for the outcomes of interest were calculated according to 100 patient-years of follow-up and illustrated by using Kaplan-Meier curves.

The hazard ratios (HRs) for each outcome were calculated using Cox proportional hazards models with adjustments for several confounding variables. These variables included age, sex, heart rate, systolic blood pressure, LVEF, NYHA functional classes III and IV, body mass index, HF hospitalization within the previous 6 months, history of diabetes, myocardial infarction or hypertension, atrial fibrillation or flutter on the baseline ECG, estimated glomerular filtration rate (eGFR), and log-transformed NT-proBNP level, with simple imputation of eGFR and NT-proBNP levels. Within-trial clustering was accounted for by use of shared frailty models. The proportional hazards assumption was examined by using the Schoenfeld residuals. To examine whether the association between pacemaker implantation and outcomes differed by LVEF, the association was examined according to the LVEF subgroups (divided by its median value). Patients with an implantable cardioverter-defibrillator (ICD) were excluded from a final sensitivity analysis.

All analyses were performed using Stata version 15 software (Stata Corp., College Station, Texas). A 2-sided p value <0.05 was considered significant.

Results

A total of 10,596 patients were enrolled in CHARM-Preserved, I-PRESERVE, and TOPCAT. Of these, 450 patients from CHARM-Preserved had an LVEF <45% and therefore were excluded. A further 1,678 patients enrolled in the Russia/Georgia region in TOPCAT and 2 with missing information as to pacemaker use were also excluded, leaving 8,466 patients for analysis. Of these, 682 patients (8%) had permanent pacemakers at baseline.

Baseline characteristics

Table 1 shows the baseline patient characteristics according to pacemaker implantation status at baseline. Patients with a pacemaker were considerably older and more often men than those without (75 vs. 70 years of age, respectively, and 53% vs. 47%, respectively). Patients with a pacemaker had a lower body mass index and lower blood pressure than those without (Table 1). The cause of their HF was less likely to be ischemia or hypertension (or a history of hypertension). Although NYHA functional class, HF symptoms, health-related quality of life, and history of recent HF hospitalization differed little between the 2 groups, mean LVEF was slightly but significantly lower (57.5% vs. 58.2%, respectively), and median plasma NT-proBNP concentrations were much higher (957 pg/ml vs. 365 pg/ml, respectively) in patients with a pacemaker than in those without. Patients with a pacemaker also had a longer duration of HF, on average, than those without a pacemaker (Table 1).

Table 1. Baseline Characteristics According to Pacemaker Implantation Status in the Combined Data Sets From the CHARM-Preserved, I-PRESERVE, and TOPCAT Studies

No Pacemaker (n = 7,784)Pacemaker (n = 682)p Value
Characteristics
Age, yrs69.7 ± 9.175.1 ± 8.7<0.0001
Age ≥75 yrs2,479 (31.8)383 (56.2)<0.0001
Males3,645 (46.8)363 (53.2)0.001
Race0.003
White6,956 (89.4)638 (93.5)
Black464 (6.0)28 (4.1)
Asian116 (1.5)2 (0.3)
Other248 (3.2)14 (2.1)
Blood pressure, mm Hg
Systolic135.0 ± 16.6129.9 ± 17.5<0.0001
Diastolic77.2 ± 10.573.4 ± 10.6<0.0001
Heart rate, beats/min70.9 ± 11.671.0 ± 9.10.87
Body mass index30.5 ± 6.429.5 ± 6.30.0001
LVEF, %58.2 ± 8.857.5 ± 9.00.036
NYHA functional classes III-IV4,482 (57.6)378 (55.4)0.27
Cause<0.0001
Ischemia2,288 (36.5)135 (30.7)
Hypertension3,079 (49.2)176 (40.0)
Other894 (14.3)129 (29.3)
HF duration<0.0001
≤1 yr2,950 (47.2)172 (39.1)
>1 to ≤5 yrs2,299 (36.7)159 (36.1)
>5 yrs1,007 (16.1)109 (24.8)
Medical history
Current smoking423 (10.8)24 (5.6)0.001
HF hospitalization within the previous 6 months3,206 (41.2)302 (44.3)0.12
Myocardial infarction2,203 (28.3)181 (26.5)0.33
Angina3,515 (45.2)269 (39.4)0.004
CABG or PCI1,750 (22.5)194 (28.4)<0.001
Hypertension6,400 (82.2)530 (77.7)0.003
Diabetes2,431 (31.2)222 (32.6)0.48
Atrial fibrillation2,307 (29.6)414 (60.7)<0.0001
Stroke698 (9.0)81 (11.9)0.012
Dyslipidemia2,756 (51.0)304 (61.5)<0.0001
Medications
Diuretics6,324 (81.3)591 (86.7)0.001
Loop4,611 (59.3)513 (75.2)<0.0001
Thiazide2,225 (28.6)134 (19.6)<0.0001
Calcium-channel blocker2,953 (38.0)203 (29.8)<0.0001
ACE inhibitors or ARBs5,057 (65.0)428 (62.8)0.25
MRA1,603 (20.6)219 (32.1)<0.0001
β-blocker4,824 (62.0)407 (59.7)0.22
Digoxin1,291 (16.6)161 (23.6)<0.0001
Antiarrhythmic agent654 (8.4)108 (15.8)<0.0001
Antiplatelet4,722 (60.7)336 (49.3)<0.0001
Oral anticoagulant1,731 (22.3)324 (47.5)<0.0001
Lipid-lowering agent3,212 (41.3)317 (46.5)0.009
ECG findings
QRS duration, ms90 (80–104)142 (106–171)<0.0001
Atrial fibrillation/flutter1,388 (17.9)180 (26.5)<0.0001
Bundle branch block1,179 (15.2)121 (17.8)0.07
Left bundle branch block304 (7.8)32 (12.7)0.006
Right bundle branch block274 (7.1)9 (3.6)0.033
Left ventricular hypertrophy1,759 (22.7)44 (6.5)<0.0001
Symptoms and signs
Dyspnea on exertion3,812 (97.5)421 (97.9)0.64
Orthopnea941 (24.2)120 (28.3)0.06
Paroxysmal nocturnal dyspnea495 (12.8)66 (15.5)0.11
Dyspnea at rest217 (9.1)27 (14.4)0.018
Jugular venous distention755 (9.8)82 (12.3)0.037
Edema3,928 (50.5)362 (53.2)0.18
Rales1,727 (22.3)136 (20.1)0.19
Third heart sound423 (6.8)28 (6.4)0.76
Hepatomegaly861 (13.8)56 (12.8)0.56
Minnesota Living with Heart Failure score42 (28–58)42 (23–58)0.32
KCCQ clinical summary score60 (42–78)59 (43–75)0.92
Laboratory measurements
eGFR, ml/min/1.73 m271.1 ± 23.362.1 ± 20.5<0.0001
eGFR <60 ml/min/1.73 m22,137 (34.6)289 (51.2)<0.0001
Hemoglobin, g/dl13.7 ± 1.613.3 ± 1.6<0.0001
NT-proBNP, pg/ml365 (139–984)957 (526–1,847)<0.0001
Without AF on ECG266 (115–635)812 (484–1,546)<0.0001
With AF on ECG1,282 (778–2,062)1345 (811–2,689)0.42

Values are mean ± SD, n (%), or median (interquartile range).

ACE = angiotensin converting enzyme; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CABG = coronary artery bypass grafting; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HF = heart failure; I-PRESERVE = Irbesartan in Heart Failure with Preserved Ejection Fraction; IQR = interquartile range; KCCQ = the Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; TOPCAT = Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist.

∗ NT-proBNP data were available in 3,838 patients (45%); and eGFR data were available in 6,736 patients (80%) patients. Minnesota Living with Heart Failure scores were available in 3,148 patients (76%) from the I-PRESERVE study, and scores ranged from 0 to 105, with lower scores indicating a better quality of life. KCCQ clinical summary scores were available in 1,727 patients (98%) from the TOPCAT study, and scores ranged from 0 to 100, with higher scores indicating better health-related quality of life.

A history of atrial fibrillation and atrial fibrillation or flutter on a baseline ECG were much more common in patients with a pacemaker than in those without (61% vs. 30% and 26% vs. 18%, respectively).

The mean eGFR was lower in patients with a pacemaker than in those without (62 vs. 71 ml/min/1.73 m2, respectively). The proportion of patients with an eGFR <60 ml/min/1.73 m2 was correspondingly larger in patients with a pacemaker than in those without a pacemaker (51% vs. 35%, respectively).

Loop diuretics were used more frequently in patients with a pacemaker than in those without (75% vs. 59%, respectively), as was the use of digoxin (24% vs. 17%, respectively) and oral anticoagulants (47.5% vs. 22.3%, respectively).

Table 2 shows a comparison among patients with a pacemaker and a paced rhythm (n = 466), patients with a pacemaker with a nonpaced rhythm (n = 214), and patients without a pacemaker (n = 7,758). Baseline characteristics of patients with a pacemaker and a paced rhythm were broadly similar to those in pacemaker patients without a paced rhythm but were dissimilar to those of patients without a pacemaker. The 2 major exceptions were QRS duration (which was much longer in pacing pacemaker patients than in nonpacing pacemaker patients) and NT-proBNP concentrations (which were higher in pacing pacemaker patients than in nonpacing pacemaker patients).

Table 2. Baseline Characteristics According to Pacemaker Implantation Status and Paced Rhythm on ECG in the Combined Data Sets of CHARM-Preserved, I-PRESERVE, and TOPCAT Studies

No Pacemaker (n = 7,758)Pacemaker Without Pacing (n = 214)Pacemaker With Pacing (n = 466)p Value
Characteristics
Age, yrs69.7 ± 9.174.4 ± 9.375.5 ± 8.30.0001
Age ≥75 yrs2,470 (31.8)112 (52.3)271 (58.2)0.0001
Males3,629 (46.8)104 (48.6)258 (55.4)0.0014
Race0.0054
White6,933 (89.4)194 (90.7)442 (94.8)
Black461 (5.9)12 (5.6)16 (3.4)
Asian116 (1.5)0 (0.0)2 (0.4)
Other248 (3.2)8 (3.7)6 (1.3)
Blood pressure
Systolic135.0 ± 16.6128.0 ± 17.4130.8 ± 17.6<0.0001
Diastolic77.2 ± 10.471.8 ± 11.074.2 ± 10.4<0.0001
Heart rate, beats/min70.9 ± 11.571.5 ± 9.670.7 ± 8.90.7211
BMI30.5 ± 6.430.1 ± 6.529.2 ± 6.20.0002
NYHA functional classes III to IV4,475 (57.7)111 (51.9)266 (57.1)0.2328
LVEF, %58.2 ± 8.857.7 ± 8.757.4 ± 9.20.0946
Cause<0.0001
Ischemia2,283 (36.5)38 (35.2)97 (29.3)
Hypertension3,075 (49.2)35 (32.4)141 (42.6)
Other892 (14.3)35 (32.4)93 (28.1)
HF duration<0.0001
≤1 yr2,946 (47.2)37 (34.3)135 (40.8)
>1 to ≤5 yrs2,294 (36.7)44 (40.7)115 (34.7)
>5 yrs1,005 (16.1)27 (25.0)81 (24.5)
Medical history
Current smoking416 (10.7)10 (6.2)14 (5.2)0.0039
Previous HF hospitalization within 6 months3,197 (41.2)88 (41.1)214 (45.9)0.133
Myocardial infarction2,195 (28.3)58 (27.1)123 (26.4)0.6363
Angina3,505 (45.2)77 (36.0)192 (41.2)0.0082
CABG or PCI1,743 (22.5)72 (33.6)121 (26.0)0.0002
Hypertension6,378 (82.2)167 (78.0)361 (77.5)0.0123
Diabetes2,424 (31.2)75 (35.0)146 (31.3)0.4969
Atrial fibrillation2,296 (29.6)117 (54.7)296 (63.5)<0.0001
Stroke698 (9.0)30 (14.0)50 (10.7)0.0222
Dyslipidemia2,747 (51.0)107 (67.3)196 (58.7)<0.0001
Medications
Diuretics6,302 (81.3)178 (83.2)411 (88.2)0.0008
Loop4,592 (59.3)153 (71.5)358 (76.8)<0.0001
Thiazide2,217 (28.6)47 (22.0)87 (18.7)<0.0001
Calcium-channel blocker2,943 (38.0)67 (31.3)136 (29.2)0.0001
ACE inhibitors or ARBs5,036 (64.9)135 (63.1)291 (62.4)0.4885
MRA1,593 (20.5)76 (35.5)142 (30.5)<0.0001
β-blocker4,809 (62.1)143 (66.8)262 (56.2)0.0134
Digoxin1,287 (16.6)51 (23.8)110 (23.6)<0.0001
Antiarrhythmic agent650 (8.4)35 (16.4)73 (15.7)<0.0001
Antiplatelet4,703 (60.7)108 (50.5)227 (48.7)<0.0001
Oral anticoagulant1,726 (22.3)98 (45.8)225 (48.3)<0.0001
Lipid-lowering agent3,197 (41.3)115 (53.7)201 (43.1)0.001
ECG findings
Atrial fibrillation/flutter1,388 (17.9)58 (27.1)122 (26.2)<0.0001
QRS duration, ms90 (80-104)103 (88-128)160 (130-178)0.0001
Bundle branch block1,179 (15.2)46 (21.5)75 (16.1)0.0384
Left bundle branch block304 (7.8)8 (15.1)24 (12.1)0.0185
Right bundle branch block274 (7.1)6 (11.3)3 (1.5)0.0044
Left ventricular hypertrophy1,759 (22.7)27 (12.6)17 (3.6)<0.0001
Symptoms and signs
Dyspnea on exertion3,788 (97.6)159 (98.8)260 (97.4)0.6104
Orthopnea932 (24.1)47 (29.4)73 (27.9)0.1364
Paroxysmal nocturnal dyspnea492 (12.8)23 (14.5)42 (15.9)0.2944
Dyspnea at rest216 (9.1)12 (21.8)15 (11.4)0.0048
Jugular venous distention749 (9.8)24 (11.5)58 (12.8)0.0852
Edema3,910 (50.4)121 (56.5)241 (51.8)0.1831
Rales1,723 (22.3)34 (16.1)102 (22.0)0.1024
Third heart sound423 (6.8)8 (7.4)20 (6.1)0.8488
Hepatomegaly861 (13.8)8 (7.4)48 (14.6)0.1442
Minnesota Living With Heart Failure score42 (28-58)43 (22-54)42 (23-59)0.5775
KCCQ clinical summary score60 (42-78)60 (44-77)58 (41-75)0.6694
Laboratory measurements
eGFR, ml/min/1.73 m271.1 ± 23.362.3 ± 20.862.1 ± 20.4<0.0001
eGFR <60 ml/min/1.73 m22,130 (34.6)94 (50.8)194 (51.3)<0.0001
Hemoglobin, g/dl13.7 ± 1.613.2 ± 1.613.3 ± 1.7<0.0001
NT-proBNP, pg/ml364 (139-982)701 (461-1,371)1,103 (564-1,931)<0.0001
Without AF on ECG266 (115-635)666 (406-948)947 (509-1,684)<0.0001
With AF on ECG1,282 (778-2,062)1,229 (529-2,273)1,356 (946-2,839)0.3619

Values are mean ± SD, n (%), or median (interquartile range).

Abbreviations as in Table 1.

∗ NT-proBNP data were available in 3,838 patients (45%); and eGFR data were available in 6,736 patients (80%) patients. Minnesota Living with Heart Failure scores were available in 3,148 patients (76%) from the I-PRESERVE study, and scores ranged from 0 to 105, with lower scores indicating a better quality of life. KCCQ clinical summary scores were available in 1,727 patients (98%) from the TOPCAT study, and scores ranged from 0 to 100, with higher scores indicating better health-related quality of life.

Clinical outcomes

Incidence rates and HRs for the risk of each outcome of interest, according to pacemaker implantation status at baseline, are presented in Table 3 and Figure 1.

Table 3. Clinical Outcomes According to Pacemaker Implantation Status in the Combined Data Sets of the CHARM-Preserved, I-PRESERVE, and TOPCAT Studies

EventAnnual Rate per 100 Person-Yrs (95% CI)Pacemaker vs. No Pacemaker HR (95% CI)
No Pacemaker (n = 7,784)Pacemaker (n = 682)No Pacemaker (n = 7,784)Pacemaker (n = 682)UnadjustedAdjustment 1Adjustment 2
CV death or HF hospitalization1,898 (24.4)258 (37.8)7.6 (7.3–7.9)13.6 (12.0–15.4)1.65 (1.44–1.88); p < 0.0011.26 (1.10–1.45); p = 0.0011.17 (1.02–1.33); p = 0.026
HF hospitalization1,285 (16.5)205 (30.1)5.1 (4.9–5.4)10.8 (9.4–12.4)1.86 (1.60–2.16); p < 0.0011.49 (1.27–1.73); p < 0.0011.37 (1.17–1.60); p < 0.001
CV death1,000 (12.8)116 (17.0)3.7 (3.4–3.9)5.1 (4.3–6.2)1.37 (1.13–1.67); p = 0.0010.92 (0.76–1.13); p = 0.4390.85 (0.70–1.04); p = 0.118
All-cause death1,493 (19.2)185 (27.1)5.5 (5.2–5.7)8.2 (7.1–9.5)1.42 (1.22–1.66); p < 0.0010.93 (0.79–1.09); p = 0.380.86 (0.74–1.01); p = 0.066
Sudden death369 (4.7)35 (5.1)1.4 (1.2–1.5)1.6 (1.1–2.2)1.18 (0.83–1.67); p = 0.3560.86 (0.60–1.23); p = 0.4080.79 (0.56–1.13); p = 0.202
Pump failure death227 (2.9)41 (6.0)0.8 (0.7–0.9)1.8 (1.3–2.5)2.08 (1.48–2.91); p < 0.0011.10 (0.78–1.57); p = 0.5791.00 (0.70–1.42); p = 0.993

Values are n (%), 100 patient-yrs (95% CI), or HR (95% CI). Adjustment model 1 included age, sex, heart rate, systolic blood pressure, LVEF, NYHA functional classes III and IV, BMI, HF hospitalization within the previous 6 months, history of diabetes, history of myocardial infarction, hypertension, and atrial fibrillation or flutter on ECG. Adjustment Model 2 included age, sex, heart rate, systolic blood pressure, LVEF, NYHA functional classes III and IV, BMI, HF hospitalization within the previous 6 months, history of diabetes, history of myocardial infarction, hypertension, atrial fibrillation or flutter on ECG, eGFR, and log NT-proBNP, with simple imputation of eGFR and NT-proBNP levels. HRs for combined data were adjusted for within-trial clustering.

BMI = body mass index; CI = confidence interval; CV = cardiovascular; HR = hazard ratio; other abbreviations as in Table 1.

Figure 1.
Figure 1.

Clinical Outcomes According to Pacemaker Implantation

Kaplan-Meier curves are shown for clinical outcomes according to pacemaker implantation in the combined data sets from the CHARM-Preserved, I-PRESERVE and TOPCAT studies. (A) Kaplan-Meier estimates of the probability of CV death or first hospitalization for HF. (B) CV death. (C) First hospitalization for HF. (D) Death from any cause. (E) Sudden death. (F) Pump failure death. CHARM-Preserved = Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity; CV = cardiovascular; HF = heart failure; I-PRESERVE = Irbesartan in Heart Failure with Preserved Ejection Fraction; TOPCAT = Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist.

In unadjusted analyses, the rate of the primary composite outcome in patients with a pacemaker was nearly twice that in patients without a pacemaker (13.6 vs. 7.6 per 100 patient-years of follow up, respectively), and this was also the case for the rate of HF hospitalization (10.8 vs. 5.1 per 100 patient-years, respectively). In analyses adjusted for other prognostic variables, prior pacemaker implantation remained associated with a higher risk of composite outcome (fully adjusted HR: 1.17; 95% confidence interval [CI]: 1.02 to 1.33; p = 0.026), which was primarily related to a higher risk of HF hospitalization (fully adjusted HR: 1.37; 95% CI: 1.12 to 1.60; p <0.001). The unadjusted rate of CV death was slightly higher in patients with a pacemaker than in those without (5.1 vs. 3.7 per 100 patient-years, respectively), but this was no longer the case after adjustment for other prognostic variables (fully adjusted HR: 0.85; 95% CI: 0.70 to 1.04; p = 0.12). A similar pattern was observed for the risk of all-cause death (Table 3).

The 2 main modes of CV death were also examined (Table 3). There were few differences in the risk of sudden death according to history of pacemaker implantation. By contrast, pump failure death was more common in patients with a pacemaker than in those without (1.8 vs. 0.8 per 100 patient-years, respectively); however, the elevated risk did not persist after adjustment for other prognostic variables (fully adjusted HR: 1.00; 95% CI: 0.70 to 1.42; p = 0.99).

Results of the same analyses within the pacemaker group that was divided into those patients with a paced rhythm at baseline and those with a nonpaced rhythm at baseline are shown in Table 4 and Online Figure 1. Although these analyses were underpowered, they suggested that the risk related to possession of a pacemaker was greatest in patients demonstrating a paced rhythm on their baseline ECG, as opposed to a nonpaced rhythm at baseline.

Table 4. Clinical Outcomes According to Pacemaker Implantation Status and Paced Rhythm on ECG in the Combined Data Sets of the CHARM-Preserved, I-PRESERVE, and TOPCAT Studies

EventAnnual Rate, per 100 Person-Yrs (95% CI)Unadjusted HR (95% CI)Adjusted 1 HR (95% CI)Adjusted 2 HR (95% CI)
No Pacemaker (n = 7,758)Pacemaker Without Pacing (n = 214)Pacemaker With Pacing (n = 466)No Pacemaker (n = 7,758)Pacemaker Without Pacing (n = 214)Pacemaker With Pacing (n = 466)Pacemaker Without Pacing Vs. No PacemakerPacemaker With Pacing Vs. No PacemakerPacemaker Without Pacing Vs. No PacemakerPacemaker With Pacing Vs. No PacemakerPacemaker Without Pacing Vs. No PacemakerPacemaker With Pacing Vs. No Pacemaker
CVD or HFH1,894 (24.4)70 (32.7)187 (40.1)7.6 (7.3-7.9)11.5 (9.1-14.5)14.6 (12.6-16.8)1.31 (1.03-1.66); p = 0.031.81 (1.56-2.11); p < 0.0011.04 (0.82-1.32); p = 0.761.38 (1.18-1.61); p < 0.0011.03 (0.81-1.31); p = 0.811.23 (1.05-1.43); p = 0.009
HFH1,283 (16.5)59 (27.6)145 (31.1)5.1 (4.9-5.4)9.7 (7.5-12.5)11.3 (9.6-13.3)1.53 (1.18-2.00); p = 0.0022.02 (1.70-2.40); p < 0.0011.27 (0.98-1.66); p = 0.071.60 (1.34-1.91); p < 0.0011.25 (0.96-1.63); p = 0.091.43 (1.19-1.70); p < 0.001
CVD998 (12.9)28 (13.1)88 (18.9)3.7 (3.4-3.9)4.1 (2.8-5.9)5.6 (4.6-6.9)1.07 (0.73-1.56); p = 0.741.52 (1.22-1.89); p < 0.0010.77 (0.53-1.13); p = 0.180.99 (0.79-1.24); p = 0.920.76 (0.52-1.12); p = 0.160.89 (0.71-1.11); p = 0.29
All-cause death1,490 (19.2)49 (22.9)135 (29.0)5.5 (5.2-5.8)7.1 (5.4-9.4)8.6 (7.3-10.2)1.18 (0.89-1.57); p = 0.261.53 (1.28-1.83); p < 0.0010.85 (0.64-1.13); p = 0.260.97 (0.81-1.16); p = 0.710.83 (0.63-1.11); p = 0.220.87 (0.73-1.05); p = 0.14
Sudden death368 (4.7)8 (3.7)27 (5.8)1.4 (1.2-1.5)1.2 (0.6-2.3)1.7 (1.2-2.5)0.90 (0.45-1.82); p = 0.771.30 (0.88-1.92); p = 0.190.71 (0.35-1.43); p = 0.330.92 (0.62-1.37); p = 0.680.72 (0.35-1.45); p = 0.360.82 (0.55-1.22); p = 0.33
Pump failure death227 (2.9)5 (2.3)36 (7.7)0.8 (0.7-0.9)0.7 (0.3-1.7)2.3 (1.7-3.2)0.78 (0.32-1.91); p = 0.5892.67 (1.87-3.8); p < 0.0010.46 (0.19-1.14); p = 0.091.37 (0.95-1.99); p = 0.090.44 (0.18-1.08); p = 0.071.22 (0.84-1.76); p = 0.30

Values are n (%), 100 patient-yrs (95% CI), or HR (95% CI). Adjustment Model 1 included age, sex, heart rate, systolic blood pressure, LVEF, NYHA functional classes III and IV, BMI, HF hospitalization within the previous 6 months, history of diabetes, history of myocardial infarction, hypertension, and atrial fibrillation or flutter on ECG. Adjustment Model 2 included age, sex, heart rate, systolic blood pressure, LVEF, NYHA functional classes III and IV, BMI, HF hospitalization within the previous 6 months, history of diabetes, history of myocardial infarction, hypertension, atrial fibrillation or flutter on ECG, eGFR, and log NT-proBNP levels with simple imputation of eGFR and NT-proBNP. HR for combined data were adjusted for within-trial clustering.

CVD = cardiovascular death; HFH = heart failure hospitalization; other abbreviations as in Tables 1 and 3.

The association between pacemaker implantation and outcomes according to subgroups divided by the median of LVEF (<58% vs. ≥58%, respectively) was examined. As shown in Online Table 1, generally, the association for each outcome in each LVEF subgroup was similar to that in the entire population. There was no interaction between LVEF and pacemaker implantation for any of the outcomes of interest. After patients who had a defibrillating function in their pacemaker (i.e., an ICD) were excluded, the results were unchanged (Online Table 2).

Discussion

The authors investigated the association between prior permanent pacemaker implantation and clinical outcomes in patients with HFpEF. It was found that pacemaker implantation was associated with a higher risk of the composite outcome of HF hospitalization or death from CV causes, that this risk persisted after adjustment for other prognostic variables, and that in adjusted analyses, the excess risk was primarily attributable to hospital admission for worsening HF.

The rate of conventional pacemaker implantation is reported to be 9% to 12% of patients with chronic HFrEF. The present study found that 8% of patients enrolled and examined in the HFpEF trials had a history of pacemaker implantation. A similar proportion, 10%, was reported in patients with HFpEF in the Swedish Heart Failure registry (13). A higher proportion (18%) was reported in U.S. patients with HFpEF in the ADHERE (Acute Decompensated Heart Failure National Registry) trial (14). That higher rate may reflect geographic variations in pacemaker implantation rates and the older average age of patients in the ADHERE study (15).

As in the few previous studies that provided data for pacemaker status in HFpEF patients, patients with a device were found to be older and more often male, and they had a high prevalence of atrial fibrillation, as well as greater use of digoxin and mineralocorticoid receptor antagonist therapy than patients without a pacemaker (14). Additional differences were found in the substantially higher levels of NT-proBNP and worse renal function among patients with a pacemaker than in those without. The large differences in NT-proBNP levels were notable given the small (if any) differences in symptoms, signs, functional classes, quality of life, and LVEF between those with and without a pacemaker. This difference in NT-proBNP levels is presumably attributable to 1 or more of concurrent atrial fibrillation, renal impairment, and greater LV systolic dysfunction not identified by using the relatively crude measure of EF or greater diastolic dysfunction (measurements of diastolic function were not collected in the baseline case report form). The ventricular dyssynchrony caused by RV pacing may result in not only a redistribution of myocardial strain and subsequently less effective contraction and decreased cardiac output but may also lead to changes in the pattern and timing of diastolic expansion and coronary perfusion and consequently a decrease in ventricular relaxation, longer Tau, slower filling, and an increase in ventricular filling pressure (16). In addition, RV apical pacing may lead to functional mitral regurgitation and left atrial remodeling (17). However, the present authors are unaware of any study of the effects of RV pacing in patients with HFpEF, and clearly a mechanistic study of that type would be valuable in understanding how this pacing mode may affect cardiac structure and function in these patients.

The more novel and important finding of the present study is that prior pacemaker implantation was associated with worse clinical outcomes in patients with HFpEF. In unadjusted analyses, the rates of the composite outcome of HF hospitalization or CV death and its components were strikingly higher in those with a pacemaker. Of additional interest was the finding that the greater risk of CV death was due to higher rates of pump failure rather than sudden death. A higher risk of sudden death rather than pump failure death might have been predicted by the presumably greater prevalence of underlying conduction system disease in the pacemaker group. However, given the likely detrimental effects of RV pacing on LV function described earlier, a greater risk of death from pump failure is also plausible. The excess risk associated with prior pacemaker implantation was attenuated when other prognostic variables, including NT-proBNP concentrations, were added to the multivariate model. However, this may reflect over-adjustment, given that some of these other variables might have been more abnormal because of the above-mentioned potentially detrimental effects of RV pacing.

Of course, a major limitation of any analysis of this type is that the pacemaker implantation was not randomized, and clearly, as indicated earlier, there were substantial differences between patients with and those without a pacemaker. Although adjustments for these differences were attempted in multivariate analyses, unmeasured “confounders” were not accounted for. However, the authors believe that supplementary analyses in patients with a pacemaker and comparisons of outcomes in pacemaker patients with and without a paced rhythm at baseline support the possibility that this observation may be biologically causative in that the worst outcomes occurred in those who showed evidence of pacing. This suggests that pacing burden, in addition to the presence or absence of pacing, may be important. In future studies, it would be useful to explore this potentially important confounder. Careful programming of the pacemaker to reduce pacing burden may be a potential method for reducing risk if the association is confirmed and if prospective randomized trials can demonstrate that outcomes are improved.

Clearly, the key question for clinical practice, raised by the current findings, is whether the use of CRT rather than RV pacing may be as preferable in HFpEF patients in need of a pacemaker as it is in those with HFrEF (5,6). The BLOCK-HF trial enrolled HF patients who had an indication for pacing due to atrioventricular block and an LVEF of 50% or less (mean: 40%). Patients were stratified, a priori, according to whether they also had an indication for an ICD. As anticipated, the stratum of patients without an ICD had a substantially higher mean LVEF (43% vs. 33%, respectively) and a higher proportion of patients with an LVEF >35% (88% vs. 26%, respectively) than patients in the ICD stratum. Despite this, the beneficial effect of CRT relative to RV pacing was similar in the 2 strata, suggesting that the benefit of CRT was not confined to patients with a particularly low LVEF (4). A more recent trial, the BIOPACE (Biventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronization) study, randomized 1,810 patients with a standard indication for pacing to undergo CRT or RV pacing, regardless of LVEF (mean: 55%; 68% had an LVEF >50%). The results of BIOPACE were not published but have been presented. There was a trend toward a reduction in the primary composite endpoint of death or HF hospitalization of borderline statistical significance (HR: 0.87; 95% CI: 0.75 to 1.01; p = 0.08). The treatment effect was consistent across subgroups as defined by an LVEF ≤50% (mean: 41%) versus an LVEF >50% (mean: 62%), respectively (18). At the time of writing, no further details were available. Collectively, the present study's finding of worst outcomes in HFpEF patients with a conventional pacemaker and the results of those 2 trials raise the possibility that CRT may be preferable to RV pacing in patients with HFpEF. Clearly, however, the hypothesis needs to be tested in a prospective randomized clinical trial.

Study limitations

First, the present study was not prospectively planned (i.e., it is a retrospective study). Second, there are no data available for the indication and mode of pacing, and having a device implanted is not equivalent to regular RV pacing. Some patients might have received only a single-chamber atrial pacemaker for sick sinus syndrome, although that would have been a small proportion of patients (19). Likewise, some patients will not use their RV pacemaker for a high proportion of time (i.e., will not have dyssynchrony induced). However, both these considerations are likely to weaken rather than strengthen any association between having an RV pacemaker and adverse clinical outcomes, and a supplementary analysis of outcomes was undertaken according to baseline rhythm in patients with a pacemaker.

Conclusions

This study found that HFpEF patients with a pacemaker were at higher risk of the composite outcome of CV death or HF hospitalization than patients without a pacemaker. This finding along with earlier reports that bundle branch block is also associated with worse outcomes in HFpEF suggests the possibility that RV pacing-induced LV dyssynchrony may be detrimental in HFpEF patients. Therefore, it is possible that CRT may be preferable to an RV pacemaker in HFpEF patients requiring pacing for atrioventricular block, although this hypothesis needs to be tested in a prospective randomized clinical trial.

Perspectives

COMPETENCY IN MEDICAL KNOWLEDGE: Among patients with HFpEF, those with a pacemaker are at higher risk for the composite outcome of CV death or HF hospitalization than those without.

TRANSLATIONAL OUTLOOK: Further studies are needed to investigate the effects of RV pacing in HFpEF patients with atrioventricular block and, potentially, to compare cardiac resynchronization therapy (biventricular pacing) to RV pacing in these patients.

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Abbreviations and Acronyms

BNP

B-type natriuretic peptide

CRT

cardiac resynchronization therapy

eGFR

estimated glomerular filtration rate

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

LVEF

left ventricular ejection fraction

NYHA

New York Heart Association

RV

right ventricular

Footnotes

Dr. Desai has received research grants from and consults for Novartis; and is a consultant for Abbott, AstraZeneca, Relypsa, Regeneron, DalCor Pharma, Boehringer Ingelheim, Boston Scientific, Signature Medical, and Corvidia. Dr. Granger has received research grants and speaker fees from and is a consultant for Abbvie, Apple, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, U.S. Food and Drug Administration, Gilead Science, GlaxoSmithKline, Janssen, Medscape, Medtronic, Medtronic Foundation, Merck Sharpe & Dohme, U.S. National Institutes of Health, Novo Nordisk, Novartis, Pfizer, Roche Diagnostics, Rho Pharmaceuticals, Sirtex, and Verseon. Dr. Komajda is a consultant for Servier and Sanofi; has received speaker fees from Servier, Novartis, Sanofi, and Merck Sharpe & Dohme; and has received speaker fees from and is a consultant for Novartis, Merck Sharpe & Dohme, Bristol-Myers Squibb, Sanofi, and Novo Nordisk. Dr. Pfeffer has received research grant support from Novartis; is a consultant for AstraZeneca, DalCor, GlaxoSmithKline, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, and Servier; and holds stock options in DalCor. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol-MyersSquibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, U.S. National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and is a consultant for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck Sharpe & Dohme, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, and Cardiac Dimensions. Dr. Swedberg is an advisory board member of AstraZeneca, Novartis, Pfizer, and Servier; and has received honoraria from Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.