Author + information
- Received June 20, 2003
- Revision received September 29, 2003
- Accepted October 15, 2003
- Published online June 2, 2004.
- Mark S Link, MD*,* (, )
- Anne S Hellkamp, MS†,
- N.A.Mark Estes III, MD*,
- E.John Orav, PhD‡,
- Kenneth A Ellenbogen, MD§,
- Bassiema Ibrahim, MD∥,
- Arnold Greenspon, MD¶,
- Carlos Rizo-Patron, MD#,
- Lee Goldman, MD**,
- Kerry L Lee, PhD†,
- Gervasio A Lamas, MD††,
- MOST Study Investigators
- ↵*Reprint requests and correspondence:
Dr. Mark S. Link, Tufts-New England Medical Center, Box #197, 750 Washington Street, Boston, Massachusetts 02111, USA.
Objectives We evaluated the incidence, predictors, and treatment of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based (VVIR) pacing in the Mode Selection Trial (MOST).
Background Pacemaker syndrome, or intolerance to VVIR pacing, consists of cardiovascular signs and symptoms induced by VVIR pacing.
Methods The definition of pacemaker syndrome required that a patient with single-chamber VVIR pacing develop either congestive signs and symptoms associated with retrograde conduction during VVIR pacing or a ≥20 mm Hg reduction of systolic blood pressure during VVIR pacing, associated with reproducible symptoms of weakness, lightheadedness, or syncope.
Results Of 996 patients randomized to VVIR pacing, 182 (18.3%) met criteria for pacemaker syndrome in follow-up. Pacemaker syndrome occurred early in most patients (13.8% at 6 months, 16.0% at 1 year, increasing to 19.7% at 4 years). Baseline univariate predictors of pacemaker syndrome included a lower sinus rate and higher programmed pacemaker rate. Previous heart failure, ejection fraction, and drop in systolic blood pressure with VVIR pacing at implantation did not predict the development of pacemaker syndrome. Post-implantation predictors of pacemaker syndrome were a higher percentage of paced beats, higher programmed low rate, and slower underlying spontaneous sinus rate. Quality of life decreased at the time of diagnosis of pacemaker syndrome and improved with reprogramming to atrial-based pacing.
Conclusions Severe pacemaker syndrome developed in nearly 20% of VVIR-paced patients and improved with reprogramming to the dual-chamber pacing mode. Because prediction of pacemaker syndrome is difficult, the only way to prevent pacemaker syndrome is to implant atrial-based pacemakers in all patients.
Pacemaker syndrome is defined as intolerance to ventricular-based (VVIR) pacing due to loss of atrioventricular (AV) synchrony. Although there is no universal agreement on the definition or diagnostic criteria of pacemaker syndrome, symptoms include dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, orthostatic hypotension, and even syncope (1–3). The incidence of pacemaker syndrome in various studies ranges from 2% (4)to 83% (5), depending to a large degree on the diagnostic criteria. The Mode Selection Trial (MOST) (6,7)randomly assigned patients with sick sinus syndrome to atrial-based (physiologic) or VVIR pacing. Pacemaker syndrome was prospectively defined and evaluated, thereby offering the opportunity to determine the incidence and predictors of pacemaker syndrome in a large clinical cohort.
The principal eligibility criteria for the MOST study included a clinical diagnosis of sick sinus syndrome requiring implantation of a permanent pacemaker. A clinical diagnosis of sick sinus syndrome was defined as one of the following: 1) a documented symptomatic sinus pause ≥3 s; 2) an asymptomatic sinus pause ≥5 s; 3) chronic sinus bradycardia with a heart rate <50 beats/min, accompanied by symptoms of fatigue and dyspnea caused by chronotropic incompetence; or 4) sinus bradycardia with a heart rate <50 beats/min that restricted the use of long-term medical therapy that was deemed necessary for other medical conditions. Patients were eligible if they were age 21 years or older. The patient had to be eligible for a dual-chamber pacemaker utilizing a transvenous approach and to provide written, informed consent. Exclusion criteria included clinically overt congestive heart failure, chronic atrial fibrillation without documented sinus mechanism within the previous six months, malignancy expected to limit the patient's life-span during the course of the trial, severe psychiatric illness that would limit compliance, or inadequate atrial or ventricular capture or sensing thresholds at the time of pacemaker implantation.
All patients received dual-chamber pacemakers. After adequate atrial and ventricular sensing and threshold parameters were achieved, patients were randomized to either rate-modulated VVIR or dual-chamber (DDDR) pacing. At the time of pacemaker implantation, the implanting physician recorded the presence or absence of retrograde atrial activation during VVIR pacing at both 70 and 100 beats/min, as well as blood pressure during native sinus rhythm and during VVIR pacing at heart rates <15 beats/min greater than the native sinus rhythm. Baseline quality-of-life measures, including the 36-item Medical Outcome Study Short-Form (SF-36) (8), the specific activity scale (9), health utilities using the time tradeoff method (10), and self-reported quality of life on a scale of 0 to 100 (11)were collected before pacemaker implantation. Initial recommended programming of the pacemaker included a lower rate of 60 beats/min, with rate modulation adjusted to a heart rate of 90 to 110 beats/min after a 1-min brisk walk.
Follow-up was performed at one, three, and six months after pacemaker implantation and then every six months. Follow-up data included the interim clinical history, physical examination, pacemaker interrogation, and quality-of-life status. The primary end point of the MOST study was the first occurrence of stroke or death.
A secondary end point and the focus of the current analysis was the incidence of pacemaker syndrome. In the MOST study, pacemaker syndrome was defined by: 1) new or worsened dyspnea, orthopnea, elevated jugular venous pressure, rales, and edema with ventriculoatrial (VA) conduction during ventricular pacing; or 2) symptoms of dizziness, weakness, presyncope or syncope, and a >20 mm Hg reduction of systolic blood pressure when the patient had VVIR pacing compared with atrial pacing or sinus rhythm (performed during follow-up evaluation).
When pacemaker syndrome was diagnosed at the clinical site, investigators were required to discuss the case with the Clinical Coordinating Center. Before crossover from VVIR to DDDR, investigators were encouraged to pace the ventricle at a lower rate and/or to decrease the aggressiveness of the sensor-driven rate. If symptoms did not resolve, they were required to call the principal investigator of the study, who reviewed the indications for crossover. Before and after crossover, patients were evaluated using the SF-36, the specific activity scale, the time tradeoff approach, and the self-reported 0 to 100 scale.
The association of baseline and implant variables and discharge medications with the risk of pacemaker syndrome was assessed using a single-predictor Cox proportional hazards model for each variable. The model for heart rate contained a linear spline, which allowed a different risk relationship below and above 55 beats/min. For baseline and implant variables, all 996 VVIR patients were included. For discharge medications, all patients who did not meet the criteria for pacemaker syndrome in the hospital were included (n = 961). The Kaplan-Meier methods were used to estimate six-month event rates for subgroups defined by baseline and implant variables.
Because analysis of variables that are measured repeatedly over time is inherently complex, descriptive statistics and formal hypothesis tests for the association of follow-up variables with pacemaker syndrome risk employed two different approaches. For descriptive statistics, follow-up data from before the onset of pacemaker syndrome were used for patients who developed it; for patients who did not develop pacemaker syndrome, follow-up data from the first 196 days were used, as this was the third quartile of time to pacemaker syndrome and represented the time span during which patients were at greatest risk of developing pacemaker syndrome. Variables were defined for each patient as follows: mean value of reported intrinsic heart rates, total percentage of beats that were VVIR paced, total percentage of beats paced at 90 beats/min or higher, programmed low rate at which the patient spent the most time, and presence of VA conduction reported at any time. The association of these variables with risk of pacemaker syndrome was formally assessed in patients who did not develop pacemaker syndrome in the hospital and whose follow-up included at least one visit while in VVIR pacing, using separate Cox proportional hazards models with the variable of interest entered as a time-dependent co-variate. These models allow patients' values for these co-variates to change over the course of the follow-up period. All follow-up data were used in these models. Approximately 800 patients were included in this analysis, but the number differed by variable, depending on the extent of missing data. Assessments for VA conduction after randomization were performed only in patients who were suspected of having pacemaker syndrome; because of the bias in this sample, summary statistics, but no significance tests, are presented for VA conduction during follow-up.
Baseline and follow-up variables that were significant in univariate tests were entered into a multivariable Cox proportional hazards model. A backward selection procedure was used to identify independent predictors.
Changes in quality of life before and after crossover were tested utilizing the paired nonparametric Wilcoxon signed-rank test. These analyses were restricted to patients who crossed over during the first year of follow-up and who had questionnaires obtained at baseline, before crossover, and after crossover.
There were 2,010 patients with sinus node dysfunction randomized, of whom 996 were assigned to single-chamber, rate-modulated VVIR pacing. Of those randomized to VVIR pacing, 477 (48%) were female, and the median age was 74 years. New York Heart Association functional class III or IV heart failure was present at baseline in 145 patients (15%). Of the 996 patients, 209 (21%) had concurrent AV block and 52 (5%) had a history of complete heart block.
Among VVIR patients, 182 (18.3%) met criteria for pacemaker syndrome, as defined by the study protocol. Forty-one patients met definition 1 only, 64 met definition 2 only, and 77 met definitions 1 and 2, as discussed earlier. By life-table analysis, the incidence of pacemaker syndrome was 13.8% at six months, 16.0% at one year, 17.7% at two years, 19.0% at three years, and 19.7% at four years (Fig. 1).
Baseline and implant data
The incidence of pacemaker syndrome was similar regardless of the criterion by which a patient was defined as having sick sinus syndrome. However, a slower sinus rate at the time of implantation was associated with the development of pacemaker syndrome. The hazard ratio (HR) for developing pacemaker syndrome was 1.11 (95% confidence interval [CI] 1.04 to 1.19, p < 0.01) for each 5-beat/min decrease in patients with baseline heart rates above 55 beats/min. For heart rates below 55 beats/min, further reductions in sinus rates were not predictive of the development of the pacemaker syndrome (p = 0.9). A higher programmed ventricular rate was associated with the development of pacemaker syndrome, with a HR of 1.15 (95% CI 1.04 to 1.26) for each 5-beat/min increase in the programmed rate (p = 0.005). No other patient characteristic before or at implantation, including age, gender, left ventricular ejection fraction, presence or absence of VA conduction, systolic blood pressure drop with VVIR pacing at implantation, and duration of QRS or PR intervals, was associated with the development of pacemaker syndrome (Table 1).
There was no association between use of beta-blockers, calcium antagonists, or amiodarone at hospital discharge and the risk of subsequent pacemaker syndrome.
The risk of pacemaker syndrome was significantly higher in patients with a higher percentage of ventricular paced beats (p = 0.0001; HR 1.22 [95% CI 1.16 to 1.28] for each 10% increase), a higher programmed, lower pacemaker rate (p = 0.0001; HR 1.27 [95% CI 1.16 to 1.38] for 5-beat/min increase), and a slower underlying sinus heart rate (p = 0.0005; HR 1.09 [95% CI 1.04 to 1.15] for 5-beat/min decrease) (Table 2). The presence of chronotropic incompetence, as documented by having fewer native beats at a rate >90 beats/min, showed a trend toward increased risk of pacemaker syndrome (p = 0.060, HR 1.07 [95% CI 0.99 to 1.14] for a 5% decrease).
Of the univariate predictors of pacemaker syndrome (baseline and follow-up sinus rate, programmed low rate, percentage of beats paced, and percentage of beats paced at >90 beats/min were entered into the multivariate model), only a higher percentage beats paced was an independent predictor (p = 0.0001; HR 1.22 [95% CI 1.16 to 1.28] for each 10% increase). A programmed lower rate, the second most important factor, made a marginal and nonsignificant contribution to the predictive model (p = 0.073; HR 1.11 [95% CI 0.99 to 1.23] for a 5-beat/min increase).
Quality of life
At the time of diagnosis of pacemaker syndrome, quality of life was lower than that at the time of implantation for nine of the 10 SF-36 scales and was significantly worse for six of these scales (data based on 80 patients) (Table 3). In addition, specific activity scale class (p < 0.001) and self-reported health on a scale of 0 to 100 (p = 0.03) worsened significantly, compared with their values at the time of implantation. After crossover to physiologic pacing, 9 of the 10 SF-36 scales improved, and 6 improved significantly, as did scores on the specific activity scale (p = 0.02), the time tradeoff score (p = 0.01), and the self-reported 0 to 100 scale (p < 0.001; data based on 153 patients). The most striking improvements were in energy and physical role, both of which improved to become substantially better than they were even before pacemaker implantation.
In the MOST study, a large, prospective study of individuals with sick sinus syndrome randomized to VVIR versus DDDR pacing, the life-table incidence of pacemaker syndrome was 13.8% at one year and 19.7% at four years. The only pre-implant clinical data and implant data that predicted pacemaker syndrome were a lower sinus rate at implantation and a higher programmed pacemaker rate. In follow-up, a greater percentage of beats paced predicted the development of pacemaker syndrome, but this information is of little use at the time of implantation in determining whether a patient should receive a physiologic pacemaker. Most notably, quality of life, as assessed by a variety of metrics, decreased at the time of diagnosis of pacemaker syndrome and improved after the pacemaker was reprogrammed to a physiologic mode. (However, a placebo effect cannot be truly ruled out, because neither patients nor physicians were blinded to the crossover status.)
In other studies, the incidence of pacemaker syndrome has varied from <2% to as high as 83%, depending on the criteria by which pacemaker syndrome was diagnosed and the therapy used to resolve that diagnosis (i.e., surgical revision or reprogramming only) (1). In previous studies in which patients received VVIR pacemakers and thus required surgical revision to upgrade to physiologic pacing, the incidence of pacemaker syndrome has been reported to be quite low. In a Danish study published in 1994, 225 patients were randomized to VVIR versus atrial-based pacemakers; the incidence of pacemaker syndrome was reported to be 2% (4). In the Canadian Trial of Physiologic Pacing (CTOPP) published in 2000, in which surgical revision was required to upgrade a patient from VVIR pacing to physiologic pacing, the incidence of pacemaker syndrome was reported to be 2.7% at three years (12).
By contrast, in studies in which all patients received a dual-chamber pacemaker and could have it reprogrammed, the reported incidence of pacemaker syndrome has been much higher. For example, in the Pacemaker Selection in the Elderly (PASE) study, the incidence of pacemaker syndrome was 20% at six months (13). In the current study, all patients received a DDDR system, so crossover from VVIR to DDDR could be achieved relatively easily by reprogramming without the need for a repeat surgical procedure. However, because pacemaker syndrome was rigorously defined prospectively and documented by changes in quality of life, the current study may more accurately reflect the incidence of pacemaker syndrome in this population.
It is quite likely that differences in the incidence of pacemaker syndrome may largely be due to potential barriers to diagnosis when surgical revision is necessary to resolve the diagnosis. It is possible that subclinical pacemaker syndrome may be present and undiagnosed in studies that require surgical revision to upgrade patients to a physiologic-based system (14,15). In one study, 16 patients with VVIR pacemakers were given atrial leads and randomized to ventricular demand pacing or physiologic pacing; perceived well-being and exercise capacity were improved during physiologic pacing (14). This finding was confirmed in 2001 in a similar study of 20 patients who had an atrial lead placed at the time of generator replacement; stroke volume and exercise capacity were increased in all individuals, and those with sick sinus syndrome had an improvement in quality of life (15).
Finally, it is also possible that the greater percentage of beats paced (which was predictive of the development of pacemaker syndrome in the current study) was lower in those studies that reported low frequencies of pacemaker syndrome. In the CTOPP (12)and Danish (4)studies, the percentage of beats paced was not reported.
In our current investigation, patients with more severe bradycardia (lower resting sinus rates at implantation and a higher percentage of paced beats at follow-up) were more likely to develop pacemaker syndrome. Similarly, in the CTOPP study, patients with a lower resting heart rate were more likely to benefit from physiologic pacing (16). In a recent publication from the MOST cohort, the percentage of ventricular beats that were paced in patients randomized to DDDR correlated with the risk of congestive heart failure (17). The finding that a higher percentage of VVIR beats increases the risk of pacemaker syndrome and congestive heart failure may be evidence that ventricular dyssynchrony induced by pacing one ventricle may cause pacemaker syndrome, even in the presence of AV synchrony.
In elderly patients who receive pacemakers, physical function and quality of life generally improve quickly, while bradycardia is prevented, but then often decline because of the progression of cardiac disease, the development or progression of co-morbid conditions, or even aging itself (7,11,13). In some patients who receive VVIR pacing, however, a more precipitous decline may represent pacemaker syndrome. When this syndrome is suspected, careful evaluation is mandatory because atrial-based, physiologic pacing may markedly improve physical function and quality of life. Because prediction of pacemaker syndrome is difficult, the only way to prevent the syndrome is to implant an atrial lead in all patients. Whether such an approach is cost-effective will likely depend on the relative cost of the alternative pacing modalities and the tradeoff between the benefits of physiologic pacing and its association with a shorter battery life.
☆ This study was supported by grants U01 HL 49804 (Dr. Lamas), U01 HL 53973 (Dr. Lee), and U01 HL 55981 (Dr. Goldman) from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland. Medtronic Inc., Guidant Corp., and St. Jude Medical donated additional support for study meetings and ancillary studies.
- Canadian Trial of Physiologic Pacing
- confidence interval
- dual-chamber pacing
- hazard ratio
- Mode Selection Trial
- 36-item Short Form
- ventricular-based (pacing)
- Received June 20, 2003.
- Revision received September 29, 2003.
- Accepted October 15, 2003.
- American College of Cardiology Foundation
- Ware J.E,
- Kosinski M,
- Keller S.D
- Goldman L,
- Hashimoto B,
- Cook F,
- Loscalzo A
- Sulke N,
- Dritsas A,
- Bostock J,
- Wells A,
- Morris R,
- Sowton E
- Tang S.L.A,
- Roberts R.S,
- Kerr C,
- et al.
- Sweeney M.O,
- Hellkamp A.S,
- Ellenbogen K.A,
- et al.