a Innere Medizin III-Kardiologie und Angiologie, Universitätsklinik Freiburg, Freiburg, Germany
b Institut für medizinische Biometrie und Informatik der Universitätsklinik Freiburg, Freiburg, Germany
* Correspondence to: Dr Michael Brunner, Universitätsklinik Freiburg, Innere Medizin III-Kardiologie und Angiologie, Hugstetterstr. 55, D-79106 Freiburg, Germany. Tel: +49-761-270-3401, Fax: +49-761-270-3799
E-mail address: brunner{at}medizin.ukl.uni-freiburg.de
Received 27 June 2003; revised 1 October 2003; accepted 16 October 2003
Abstract
Permanent cardiac pacing is the treatment of choice in severe and symptomatic bradycardia. To determine factors associated with longer survival we analysed the survival times and baseline characteristics of 6505 patients after pacemaker implantation. This longitudinal study with 30 years of follow-up was performed in a single centre university hospital with all-cause mortality as the end-point.
In 6505 patients we analysed a total of 30 948 years of patient follow-up, median survival was 101.9 months (8.5 years), with 44.8% of patients alive after 10 years and 21.4% alive after 20 years. In all subgroups women had a significantly longer survival than men (118 vs 91.7 months, P<0.0001), despite a markedly higher age at implantation (73.2 years vs 71 years, P<0.0001). Survival of patients with sick-sinus-syndrome was significantly better than in patients with high degree AV-block, which in turn, was better than survival of patients with atrial fibrillation (132.9 months vs 94.2 months vs 85.1 months, P<0.0001). Multivariate analysis revealed several independent factors: age, gender, decade of implantation, type of pacemaker, index arrhythmia and initial symptoms. Interestingly, if only the patients of the last decade were analysed multivariately, neither pacing mode nor index arrhythmia wereindependently associated with survival.
In conclusion, survival of patients with pacemakers is independently influenced by several baseline characteristics which can identify patients with very long survival.
Key Words: Artificial pacemaker Long-term survival Gender
1. Introduction
Implantation of a cardiac pacemaker is the treatment of choice in severe and/or symptomatic bradycardia. Today, more than 40 years after the first pacemaker implantation, world-wide implantation rate exceeds 400 000 every year. With widespread use, pacemaker technology has greatly evolved, and highly sophisticated devices have become available providing optimal support for treating any type of bradyarrhythmia. Today, however, optimal selection of the pacemaker device needs to be based solely not on the type of arrhythmia, but in times of tight budgets also the cost effectiveness and longevity of the device needs to be considered. New devices with larger batteries and high-impedance electrodes have increased device function, despite continuing miniaturization. Despite this fact, repeated exchanges of the devices for battery depletion are an important problem in long-term survivors of cardiac pacing as the life expectancy continues to increase. Previous randomized studies, such as the CTOPP-trial,1,2the MOST-trial3and very recently the UK-PACE trial4have failed to show differences in survival in patients with dual-chamber versus single chamber pacemakers. In secondary end-pointssuch as the incidence of atrial fibrillation or stroke-differences were seen. However, most of these trials observed patients for up to 46 years, and very little is known about the very long-term survival beyond this period, despite a significant proportion of patients surviving for more than 10 years.
To analyse the factors influencing very long-term survival of pacemaker patients, we performed a study in 6505 patients treated by pacemaker implantation in a single centre over a period of 30 years. In these patients we evaluated subgroups defined by age, gender, type of bradyarrhythmia, as well as the importance of the time of implantation or the type of device were analysed for their prognostic influence.
2. Methods
2.1. Study design
The present study is based on all pacemaker implantations in a single centre university hospital between 1 January 1971 and 31 December 2000. All patients had regular 612 months follow-up intervals with standardized documentation of all relevant patient data. From January 1986 on, data acquisition was based on a prospective study which included all patients implanted until 31 December 2000, follow-up ended on 31 March 2001. Retrospective data based on paper files from 1971 until 1985 and the prospectively assessed data from 1986 to 2000 formed the basis for the following analysis.
2.1.1. Follow-up
Patient follow-up was standardized to control intervals of 6- and 12-month intervals according to the age and longevity of the pacemaker model. For patients missing the appointment, a telephone follow-up was performed, andif appropriatedate and cause of death was obtained from the patient's physician. If telephone follow-up did not yield sufficient information, patients were censored as alive but lost-for-follow-up' at the day of their last visit.
Data acquisition considered the following parameters: age, gender, baseline ECG-characteristics (rhythm, AV-conduction [normal, 1st degree AV-block, 2nd degree AV-block Mobitz or Wenkebach, 3rd degree AV-block], QRS-width, type of bundle branch block, type of arrhythmia) and symptoms leading to pacemaker-implantation, date of implantation. Symptoms were classified as: (i) syncope (MorgagniAdamStokes) with brief loss of consciousness, (ii) near-syncope with dizziness or vertigo associated with bradycardia, but without documentation of significant pauses; and (iii) non-syncopal bradycardia, i.e. significant, documented bradycardia/pauses without associated symptoms (usually Holter-monitoring documented bradycardia and/or pauses). All data was entered into a custom built computerized database. The type of pacemaker and the programming were left to the discretion of the treating physician, but were based on the current recommendation by the AHA, the ESC and the German Cardiac Society. Patients were categorized into three decades according to the date of the implantation of their first pacemaker: 19711980 (the seventies); 19811990 (the eighties) and 19912000 (the nineties). End-point of the study was all-cause mortality.
2.2. Statistical analysis
Data are presented as mean values±SD or medians for continuous variables and as absolute and relative frequencies for categorical variables. Comparisons between groups were performed using Student's t-tests, MannWhitney tests and chi-square tests, where appropriate. Survival probabilities were estimated by the method of KaplanMeier. For survival rates times from implantation of pacemaker to date of death of any cause or date of last contact were used. Patients lost to follow-up were censored at the time of their last visit. The prognostic relevance of clinical patient characteristics on survival was assessed univariately and multivariately by Cox's proportional hazards regression models. In these models all available baseline characteristics of our database (see above) were entered using no formal model building process. The assumption of proportionality of the Cox models was verified by visual inspection of the log(-log) survival plots. Results of the Cox models are presented as relative risk ratios with 95% confidence intervals together with the P values from Wald's tests. All tests of significance were two-sided and a P-value of <0.05 was considered statistically significant. For comparisons of more than two groups a closed test procedure was applied testing overall effects first followed by pairwise tests if the overall test was significant. Therefore, no further adjustment was made for multiple testing. Data extraction and analysis software was written in Perl (Version 5, http://www.perl.org). Statistical analysis was performed using SAS (SAS Institute, Gary, NJ, USA) and Graphpad Prism (Version 3.03; Graphpad Inc, San Diego, CA, USA).
3. Results
We analysed a total of 30 948 patient-years of follow-up in 6505 patients, 2585 patients (39.7%) died during the follow-up. At the end of the study 21.7% (n=1407) were alive. Mean age of deceased patients was 78.3 years (±10.2) vs 76.0 years (±11.7) in patients lost for follow-up (P<0.0001). Baseline patient characteristics are summarized in Table 1: The median patient survival after pacemaker implantation was 101.9 months (approx. 8.5 years), at 5, 10, 15 and 20 years after implantation 65.6%, 44.8%, 30.8% and 21.4%, respectively, of patients were still alive.
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Significant differences were seen in the survival of patients during the decades: As seen in Fig. 1, the survival of patients increased with the decades (P<0.0001). Median survival was 76.7 months for patients implanted in the seventies, and 109.1 months for those implanted in the eighties; a median survival time is not available for patients implanted in the nineties, as more than 50% of these were still alive at the end of the study. At 5 years after first pacemaker-implantation, 57.0% of patients implanted in the first decade were still alive, as opposed to 67.9% of those implanted in the second and 74.5% of those implanted in the third decade. Similarly, survival at 10-years post implant was 36.8%, 47.0% and 52.4% respectively. At 15 years after implantation, nearly a quarter (24.2%) of patients implanted in the first decade and a third (33.6%) of patients implanted in the second decade were still alive, no data is yet available on 15 year follow-up of patients from the third decade. This increase in survival times of patients was observed despite a significant increase in age at implantation, with a mean age at implantation of 71.2 years, 72.1 years and 72.9 years in the first, second and third decade, respectively (P<0.0001, Table 1).
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3.3. Gender differences in survival
During the study period, a total of 3087 women received pacemakers. Overall the mean age of women at pacemaker implantation was significantly higher than the age of men (73.2 years±11.3 vs 71.0 years±12.4, P<0.0001). This difference increased throughout the three decades: In the first decade, mean ages of women vs men were 71.6 years±10.0 vs 70.8 years±11.1 (P=ns), in the second 73.6 years±11.5 vs 70.9 years±12.6 (P<0.0001) and in the third 75.0 years±12.4 vs 71.2 years±13.6; (P<0.0001).
Despite the higher age of women at pacemaker-implantation, their median survival time during the 30-year study period was 118.0 months vs 91.7 months in men (P<0.0001). Similarly, survival proportions at 5, 10, 15 and 20 years differed significantly (Table 2, Fig. 3). Regarding the gender differences and the index arrhythmia, women (n=1176) with sick sinus syndrome lived significantly longer than men (n=942): median survival time in women was 145.2 months vs 115.2 months in men (P<0.02). Similarly, women with atrial fibrillation (n=741) survived significantly longer than men (n=886): The median survival time was 93.6 vs 70.8 months (P<0.01). The difference was also seen in patients with AV-block, where the median survival of women (n=1057) was 106.6 months vs men (n=1496) with 83.9 months (P<0.0001).
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Patients receiving a VVI-pacemaker had a significantly shorter median survival of 84.3 months compared to those receiving an AAI pacemaker (175.0 months) or a dual-chamber (DDD/VDD) pacemaker (199.3 months, P<0.0001). No difference in survival was seen between AAI and VDD/DDD pacemakers. There were, however, significant age differences between the groups: Patients receiving VVI-pacemakers (n=4298) were significantly older (72.8 years±11.1) than those receiving AAI (69.7 years±12.9; n=432) or DDD/VDD devices (71.0±13.2; n=1775).
Using subgroup analysis, baseline ECG-parameters were tested for an influence on survival: analysis was performed on the ECG at presentation, with measurement of the QRS-width of the predominant spontaneous rhythm. Comparing the overall survival of patients with isolated left bundle-branch block (LBB, n=287) to those with normal QRS-width (<120ms, n=4104) a trend towards a worse survival of patients with LBB was seen: Median survival was 95.0 vs 115.9 months (P=0.052). However, when comparing all patients with either LBB or partial left bundle branch block (left anterior or left posterior blocks) to those with normal QRS-width revealed a significant difference in survival: median survival was 84.0 vs 115.9 months (P<0.0001). No difference was seen between patients with right bundle-branch block and those with a normal QRS.
Regarding differences within the high degree AV-block groups, no differences were seen in survival between 2nd degree AV-block and 3rd degree AV-block. Also the age between the two groups of AV-block did not differ significantly.
Included in the study population was a small proportion (0.5%) of 34 children (21 boys [62%] and 13 girls [28%]) aged up to 16 years (mean age 8.6 years±5.6) with cardiac pacemakers. The median follow up period after implantation for these was 49.4 (range: 1.2313.3) months, 10 (29.4%, nine male) of these young patients died during the follow up after a median follow up duration of 31.3 (range 1.2131.1) months. KaplanMeier survival is depicted in Fig. 4, the median survival time remains undefined as more than 50% are still alive.
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The decade of implantation, with patients implanted during the last decade having a significantly longer survival compared to those implanted in the two earlier decades (risk-ratio (RR) 0.762 and 0.594, respectively; P<0.0001). As expected the age at implantation influenced survival inversely with younger patients having a significantly longer survival (RR for each 1-year age increase 1.050; P<0.0001). The gender was an independent factor, as women had a significantly longer survival after pacemaker implantation (RR=0.734; P<0.0001). The mode of pacing was an independent factor, as patients with a DDD or AAI pacemaker survived longer compared to those receiving a VVI pacemaker (RR=0.649 and 0.618, respectively; P<0.0001). Sick sinus syndrome was independently associated with better survival compared to patients with atrial fibrillation (RR 0.889, P<0.05). Thus the index-arrhythmia remained an independent prognostic parameter after correction for differences in age and gender. Interestingly, symptoms leading to pacemaker implantation were independently associated with survival: Near-syncope was associated with a significantly longer survival than syncope or non-syncopal bradycardias (RR 0.705 and 0.715; P<0.0001). The independent risk factors are summarized in Fig. 5.
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4. Discussion
Since the implantation of the first artificial pacemaker in 1958 these devices have become the treatment of choice in bradycardias. Despite its widespread use, overall long-term survival of pacemaker patients has been addressed by only few studies during the last three decades.510Most studies focused on differences between AAI, VVI and DDD pacing in sick-sinus syndrome or AV-block,1117and few studies evaluated differences in survival in a general pacemaker population2,3,69,12,14,1820or in elderly patients.2123In this study, we evaluated the survival of 6505 patients after pacemaker implantation from 1971 until 2000 with the aim of identifying prognostic factors. With more than 30 000 patient years of follow up and an observation period of 30 years the present study isto the best of our knowledgeby far the largest analysis of very long-term survival in pacemaker patients. To avoid a bias due to the learning curve of the very first pacemakers, the study period was started in 1971, whereas the first pacemaker in our hospital was implanted in 1962. Thus before the beginning of the study, we had already gathered experience in more than 400 pacemaker-patients treated by the same team ofphysicians.
One of the main results of this study is the longevity of pacemaker patients: approximately one-third of the patients survived for 15 years, with one-fifth of patients surviving up to 20 years. Given the fact, that due to medical advances the life expectancy continues to rise (as seen during the last decade) this has clear implications on device selection for the subgroup of very long-term survivors: To avoid the risk and the cost of repeated exchanges of pacemaker-devices due to battery depletion, the implantation of devices with a longer battery life and the use of electrodes with high impedance to preserve energy needs to be considered in these groups.
We found several highly significant factors, which influence survival: First of all, gender is an independent prognostic factor for survival in our study: It is well known that the life expectancy of women is higher, and that cardiovascular diseases are delayed in the female gender.24In the present study, 10-year survival of women was nearly 50%, and 20 year survival was 25.5% (opposed to 40.4% and 16.8%, respectively, in men) regardless of the index arrhythmia. Despite women being more than 2 years older at the time of implantation, their overall median survival is still more than 2 years longer compared to men, and the gender difference in survival even increased during the last decade. Even though gender differences in survival have been reported, neither a differential influence depending on the type of arrhythmia nor this magnitude have been previously reported.
Secondly, the symptoms leading to pacemaker implantation are independently associated with survival: Patients experiencing classical AdamStokes type syncope and those with asymptomatic bradycardia (i.e. ECG-documented bradycardia) have identical, but worse survival compared to patients with near-syncope as the initial symptom. This data concurs to a previously published study by Müller et al., who reported a better survival in patients with near-syncope compared to patients with syncope in a smaller number of patients.5The reason for this markedly better survival remains elusive: We assume however, that in this subgroup which was treated despite the lack of syncope and documented ECG proven pauses (i.e. those patients with suggestive symptoms and ECG proven bradycardia but without significant pauses) relatively healthier' patients were selected. Clearly it would be interesting to compare the survival of these patients with and without pacemaker therapy, to analyse if pacemaker implantation affects survival at all in this subgroup, however, to the best of our knowledge, no study has yet addressed this question.
Thirdly, the choice of VVI pacing influenced survival adversely, a difference which was more evident during the first two analysed decades. Interestingly, there was no significant difference between AAI and dual-chamber pacemakers, which were both associated with a markedly longer survival than VVI. In a retrospective study of short-term survival with a follow-up of 2 years, Lamas et al.23reported a similar association of VVI- vs dual-chamber pacemaker therapy; after adjusting for other factors, an independent association of pacing mode and survival was confirmed. Previous studies showed no significant differences in survival but in symptoms or secondary end-points, especially in patients with sick-sinus syndrome.3,25Interestingly, in a recently published sub-study of the MOST-study, Greenspon and co-workers found an increase in the incidence of clinical heart failure in patients with sick sinus syndrome when they were treated VVI-mode vs patients treated with DDD mode of pacing.26This might be an explanation for the differences in survival during our very long-term follow-up. Interestingly, if only the 1855 patients of the last decade are analysed multivariately, differences between AFIB and SSS or DDD vs VVI are no longer significant, perhaps reflecting improved survival in patients with VVIpacemakers. The other influencing factors remained significant.
One of the main limitations of this study is that we could not control for other factors influencing survival (such as left ventricular ejection fraction, medication or other concomitant diseases), as data collection was started in the seventies. This might have lead to a selection bias by choosing AAI/DDD/VDD devices in the healthier' group of patients and VVI pacemakers, which are easier and faster to implant in the sicker' subgroup of patients. The possible selection-bias to use VVI in older patients (>80 years) was confirmed in a study by Jahangir and co-workers.18This is a limitation of this study: as an observational, yet prospective study we cannot exclude a certain selection-bias, which would be avoided in a randomized trial. However, no randomized trial has been conducted to date with a similar number and duration of follow-up in pacemaker patients. This clearly shows, that a large, randomized study on the very long-term effects (beyond the usual 46 years of follow up in previously published trials) of pacing mode on survival are warranted. Another limitation of this study is the number of patients with loss of follow-up: We have used a conservative approach and classified patients who were lost for follow-up as being alive on the day of their last visit and being lost for follow-up thereafter. Given the mean age of these patients (76 years) it is likely, however, that a substantial proportion of these patients died thereafter, but our telephone follow up (which was performed the day after their missed appointment, i.e. after 612 months) did not yield sufficient information on the vital status of the patients. As these patients were censored at their last visit, this should not affect the estimated survival probabilities according to the KaplanMeier method.
Finally, as expected, age is an independent prognostic factor in the multivariate analysis, with every year of age increasing the mean risk of death by 5%. In the subset of older patients, Jahangir et al. reported a (univariate) increase in mortality of 9%.18We have also analysed a small subgroup of children with implanted pacemakers, but similar to studies by Balmer27and Sachweh28the absolute numbers are small compared to the adult population. Due to the size and the heterogeneity of this subgroup, a multivariate analysis was not attempted. However, this subgroup exhibits both a high mortality rate (10 of 34 children died during follow-up) but also potentially a very long duration of pacemaker therapy. Clearly, a larger study on the characteristics of long-term survivors after pacemaker implantation in children would be very interesting.
Interestingly, the presence of left bundle-branch blockwhich has been shown to be associated with worse survival in patients with tachyarrhythmias or coronary artery diseaseis not an independent factor for survival: Overall patients with complete LBBB showed only a trend towards a shorter survival, but it was not an independent risk factor in multivariate analysis. A delay in left ventricular conduction (LBBB and LAHB) influenced survival in univariate analysis, but also was not independently associated with survival in multivariate analysis.
Regarding the last decadewhich is probably the most important to influence clinical practice in the futuremultivariate independent prognostic factors at baseline were: gender, age at implantation and symptoms; however, neither index arrhythmia nor mode of pacing were significant after correction for other factors. This mayat least in partalso be due to the markedly shorter observation period of patients implanted during the nineties, and due to the fact that overall survival has markedly increased compared to the previous two decades.
Acknowledgments
The authors wish to thank Klaus A. Brunner, MSc (University of Technology, Vienna, Austria) for his continuing support in developing the data analysis software and Christoph Büchner, MD, for his effort and foresight in building and maintaining the database.
References