Introduction. CLINICAL RESEARCH Pacing and CRT

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1 Europace (2010) 12, doi: /europace/eup346 CLINICAL RESEARCH Pacing and CRT Trend of the main clinical characteristics and pacing modality in patients treated by pacemaker: data from the Italian Pacemaker Registry for the quinquennium Alessandro Proclemer 1 *, Marco Ghidina 1, Dario Gregori 1, Domenico Facchin 1, Luca Rebellato 1, Edlira Zakja 1, Michele Gulizia 2, and Paolo Esente 1 1 Division of Cardiology, Department of Cardiopulmonary Science, Azienda Ospedaliero Universitaria S. Maria della Misericordia and I.R.C.A.B. Foundation, Udine, Italy; and 2 Cardiology Department, Ospedale Garibaldi-Nesima, Catania, Italy Received 7 August 2009; accepted after revision 9 October 2009; online publish-ahead-of-print 9 November 2009 Aims To assess the impact on clinical practice of the major published studies, we report the information collected by the Italian Pacemaker Registry (IPR) in the quinquennium Methods The IPR collected prospectively main epidemiological, clinical, and electrocardiographic data of patients treated by and results pacemaker (PM) in Italy on the basis of European PM Card. The number of reported PMs in Italy was in 2003, in 2004, in 2005, in 2006, and in 2007, respectively. The median age was 79 years in all 5 years. Among the atrio-ventricular (AV) conduction defects, third-degree AV block was the most common occurrence. Of the sick sinus syndrome (SSS), sinus node dysfunction involved the majority of cases followed by bradycardia tachycardia syndrome. Year-over-year percentages among the different indications remained stable. Syncope and dizzy spells were by far the most common symptoms. Dual-chamber pacing showed an increasing utilization in all the examined years.... Conclusion Italian PM Registry data for the study period reveal a stable pattern of PM utilization and indications. A higher use of dual-chamber pacing in comparison to single-chamber pacing was reported for all indications, despite inconclusive data of the major randomized trials Keywords Cardiac pacing Pacemaker Registry Introduction Cardiac pacing was introduced for the treatment of bradyarrhythmias more than 50 years ago, and during this time, both clinical practice and many studies have demonstrated its efficacy in terms of reduced mortality and morbidity as well as improved quality of life of patients. 1 8 Pacemaker (PM) technology has evolved dramatically since the inception of PM therapy resulting in a more physiological cardiac stimulation and much lower incidence of side effects. Decisions regarding the need for a PM have been strongly influenced by the presence of symptoms directly related to bradycardia and clinical situations at high risk for serious bradyarrhythmias. Moreover, the majority of the indications for cardiac pacing have evolved without the support of comparative randomized trials due to the absence of alternative therapeutic options. Although in the last few years several recommendations for pacing in bradyarrhythmias were published in Europe and in the USA with the purpose of defining evidence-based indications, very few studies have examined the application of these guidelines in clinical practice The National PM Registry of the Italian Society of Arrhythmology and Cardiac Pacing (AIAC, collects data of PM implantation based on a European PM Patient Identification * Corresponding author. Tel: þ , Fax: þ , ap.ircab@gmail.com Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 Clinical characteristics and pacing modality in patients treated by PM 203 Card. To evaluate the effects in the real world of major published studies and international guidelines, 9 12 we report the main clinical data and pacing features of patients enrolled prospectively in the Italian PM Registry (IPR) for the period Methods The clinical data of the enrolled patients and the technical features of implanted PMs are reported to the Registry using the European PM Patient Identification Card (see Appendix), sent by mail after implantation and explantation procedures. The European Card, first designed in July 1978, offers appropriate codes for symptoms, electrocardiographic (ECG) indications, aetiology, pacing mode, generator and lead changes, and file closure The Registry is based on voluntary activity by collaborating physicians and centres under the auspices of the National Society (AIAC). Similar to the Italian Implantable Cardioverter-Defibrillator Registry, 28,29 validation of data is performed using a two-step protocol: first, at the time of data entry, data are checked for formal consistency and then, when the annual report is generated, data are checked for internal consistency (e.g. trends in each centre are evaluated and, if out-of-trend data are observed, the outlier institution is contacted for clarification). Exploratory data analysis includes basic descriptive statistics, with categorical variables usually reported in frequencies (%) and absolute numbers, and continuous variables reported as mean (standard deviation is indicated in brackets). In the years , the IPR monitored the data concerning PM implant which included the number and volume of activity of PM implanting centres, demographics, ECG and clinical indications for PM therapy, aetiology, and type of PM [single chamber, dual chamber, and triple chamber for cardiac resynchronization therapy (CRT)]. A centre implanting PMs/year was ranked as low volume activity, PMs/year as medium volume activity, and.200 PMs/year as high volume activity. All data pertain to first-time PM implants or PM replacements. During the study period, the Registry obtained the clinical and epidemiological data of 60% of the total PM implantation activity in Italy based on sales data supplied by a trade organization (specifically 59% in 2003 and 57% in the period ). Demographic data, clinical indications, and pacing modalities for the study period were also compared with the same data for the period The IPR did not collect outcome data on survival, clinical follow-up, and complications. Univariable analysis, based on unadjusted tests of significance among groups, both for baseline characteristics and for outcomes, has been based on the Kruskal Wallis rank test for continuous variables and on a log-linear model-based test for categorical ones. Trends in implant rates have been evaluated using a generalized linear model with link log, and the corresponding P-value, reported in the text, is against a null hypothesis of zero slope. Results Demographics According to the registry, the number of PMs reported in Italy remained stable during the study period. In the year 2003, first implants and replacements were (72.8%) and 8352 (27.1%), in (73.2%) and 8566 (26.7%), in (71.1%) and 9200 (28.9%), in (71.3%) and 9123 (28.7%), and in (72.0%) and 8820 (28.3%), respectively. Also, the number of participating centres was similar year over year: 260 of 376 (69.2%) implanting centres in 2003, 260 of 378 (68.7%) in 2004, 260 of 382 (68.1%) in 2005, 268 of 387 (69.2%) in 2006, and 255 of 380 (67.1%) in During the study period, the majority of implanting centres showed a low volume of activity: 127 centres (48.8%) in 2003, 125 (48.1%) in 2004, 122 (46.9%) in 2005, 133 (49.6%) in 2006, and 123 (48.2%) in The centres with medium level of activity were 96 (36.9%) in 2003, 88 (33.8%) in 2004, 88 (33.8%) in 2005, 82 (30.6%) in 2006, and 83 (32.5%) in 2007, whereas centres with high volume of activity were 37 (14.2%) in 2003, 47 (18.1%) in 2004, 50 (19.2%) in 2005, 53 (19.8%) in 2006, and 49 (19.2%) in The median age of patients receiving the first PM implant was 79 years (73, 85; I quartile, III quartile) in 2003, 79 years (72, 83) in 2004, 79 years (73, 84) in 2005, 79 years (73, 85) in 2006, and 79 years (73, 84) in Male patients were always prevalent in the period (57.3% in 2003, 58.4% in 2004, 58.4% in 2005, 56.5% in 2006, and 57.1% in 2007). Table 1 summarizes the distribution of first-time PM implants by age brackets. Pacemaker utilization in the first four decades of life was rare and remained relatively low through the sixth decade; rising markedly in the seventh and reaching peak in the eighth. The distribution by age brackets within the study period shows a significant decreasing trend (P, 0.005) in the seventh and eighth decades, and an increasing trend (P, 0.001) in the ninth decade, whereas all other decades remained stable in the study period. Demographic data for the study period ( ) revealed in comparison to the previous 5-year period ( ) a significant increase in PM utilization in very old patients (.80 years) (Table 1). Clinical and electrocardiographic indications Table 2 shows the distribution of PM implants by ECG indication. Among the atrio-ventricular (AV) conduction disturbances, thirddegree AV block represents the most common occurrence, followed by Mobitz II AV block. Among sick sinus syndrome (SSS), sinus node dysfunction represented by sinoatrial block, sinus node arrest, and chronotropic incompetence involves the majority of cases, followed by bradycardia tachycardia syndrome. A substantial number of PMs were utilized for atrial fibrillation (AF) with slow ventricular rate. Finally, PMs were utilized for intraventricular (IV) conduction abnormalities in,6% of total cases [bundle branch blocks (BBB) and fascicular blocks]. Year-over-year percentages among the various ECG indications remained stable and differed significantly from the preceding 5-year span only for third-degree AV block and other or uncoded indications (Table 2). Table 3 summarizes the relevant subjective symptoms at the time of first PM implant, in the context of a specific ECG pattern. Syncope was by far the most common symptom in AV blocks, SSS, AF with slow ventricular response, and IV conduction defects, followed by dizzy spells, bradycardia, and heart failure. However, heart failure was the second most common symptom in IV conduction defects. Once again, the year-over-year distribution of major symptoms remained stable for the main ECG indication, with the exception of the group of patients with IV conduction defects. Considering rare aetiological indications, carotid sinus syndrome and vaso-vagal syndrome were reported in 2.4 and 0.3% of the patients in , in 2.5 and 0.4% in 2005, and in 2.1 and 0.4% in , respectively (P ¼ NS). Other rare indications

3 204 A. Proclemer et al. Table 1 Distribution of first implants by age bracket from 2003 to 2007 and in the period vs Trend P-value P-value years 0.7% 0.7% 0.6% 0.7% 0.7% NS 0.7% 0.8% NS years 0.9% 1.0% 1.0% 0.9% 1.0% NS 1.0% 1.2% NS years 3.9% 3.8% 3.5% 3.5% 3.6% NS 3.6% 4.4%, years 15.2% 15.1% 14.9% 14.3% 13.2% P ¼ % 16.8%, years 41.0% 40.2% 39.7% 39.0% 39.2% P ¼ % 41.6%, years 31.8% 33.0% 33.6% 34.8% 36.0% P, % 30.1%, years 6.5% 6.2% 6.7% 6.9% 6.4% NS 6.5% 5.1%,0.05 Mean age (years) overall Std dev Mean age (years) female Std dev Mean age (years) male Std dev Table 2 Distribution of first implants by ECG indications from 2003 to 2007 and in the period vs Trend P-value P-value... AVB (n) First-degree AVB (C01) 3.0% 3.2% 3.3% 3.2% 2.9% NS 3.1% 2.2% NS Second-degree AVB, Mobitz (C04) 10.9% 11.1% 10.8% 11.3% 11.0% NS 11.0% 10.0% NS Second-degree AVB, other (C02-3) 6.1% 7.8% 6.8% 6.7% 7.1% NS 6.9% 5.8% NS Third-degree AVB (C05-7) 23.4% 22.9% 23.1% 23.3% 23.6% NS 23.2% 24.9%,0.001 SSS (n) Sinus node dysfunction (E01 4, E07 8, E27) 17.0% 17.3% 17.4% 17.9% 17.7% NS 17.5% 14.5% NS Brady-tachy (E05) 8.8% 8.7% 8.7% 8.7% 9.1% NS 8.8% 8.2% NS AF þ Brady (E06, C08) (n) % 18.0% 17.7% 18.0% 18.1% NS 18.1% 18.9% NS Fascicular blocks (D01 11) (n) % 5.9% 5.5% 5.6% 4.9% NS 5.7% 6.2% NS Other, uncoded (n) % 5.1% 6.7% 5.4% 5.5% NS 5.6% 9.3%,0.001 AVB, atrio-ventricular blocks; SSS, sick sinus syndrome; AF þ Brady, atrial fibrillation plus bradycardia. such as surgical complications and ablate and pace were documented in 1.2 and 0.6% in and 1.3 and 0.5% in , respectively (P ¼ NS). Selection of pacemaker type Table 4 shows the utilization of each pacing modality over the period of observation along with the yearly rate change for each year-increment. Single-chamber atrial pacing (AAI AAIR) was utilized infrequently and without significant difference year over year. The dual-chamber pacing system without rate responsiveness (DDD) was the most utilized device until 2006, being surpassed by dual-chamber pacing system with rate responsiveness (DDDR) in 2007 but with a stable trend in the study period. The DDDR system showed a significant increase in the utilization year over year (P ¼ 0.009). VDD þ VDDR units comprised 10 11% of implants, stable over the period. The utilization of VVI dropped progressively with a significantly decreasing trend from 23.2% in 2003 to 17.9% in 2007 (P ¼ 0.010), whereas VVIR exhibited a non-significant variation during the study period (P ¼ NS). The share of PM with CRT (DDD-CRT) decreased insignificantly from 2.5% in 2003 to 1.7% in 2007 (P ¼ 0.09). Pacing modalities did not differ significantly from the preceding 5-year span for AAI, AAIR, DDD, VDDR, VVIR, and DDDRT modes, whereas DDDR PMs showed a significant higher utilization in the last 5-year period ( ) with respect to span (Table 4). Figures 1 3 describe the utilization of each pacing modality for SSS, AV, and IV conduction disturbances. Dual-chamber pacing modalities (DDD and DDDR) show a significantly greater utilization in the study period for patient with AV conduction defects and BBB, whereas the various pacing modalities selected for SSS did not change year over year.

4 Clinical characteristics and pacing modality in patients treated by PM 205 Table 3 Distribution of first implants by ECG indications and symptoms from 2003 to 2007 and in the period vs P-value AVB (n) Syncope 41.3% 38.7% 40.4% 40.7% 40.0% NS 40.2% Dizzy spells 21.3% 20.6% 21.4% 20.7% 21.1% NS 21.0% Bradycardia 17.5% 23.5% 20.7% 22.2% 22.1% NS 21.2% Heart failure 9.3% 7.9% 7.5% 7.1% 7.5% NS 7.9% Other 10.5% 9.3% 9.9% 9.4% 9.4% NS 9.7% SSS (n) Syncope 40.8% 39.8% 39.9% 41.4% 42.7% NS 40.9% Dizzy spells 24.3% 23.8% 23.2% 23.4% 20.8% NS 23.2% Bradycardia 21.8% 23.6% 24.6% 23.3% 24.1% NS 23.4% Heart failure 3.1% 3.1% 2.8% 2.8% 2.4% NS 2.8% Other 10.0% 9.6% 9.5% 9.1% 10.0% NS 9.7% AF þ Brady (n) Syncope 27.8% 25.6% 28.0% 27.7% 27.7% NS 27.3% Dizzy spells 23.1% 23.1% 22.9% 22.1% 22.0% NS 22.7% Bradycardia 26.6% 30.1% 29.1% 30.1% 30.2% NS 29.2% Heart failure 10.9% 10.4% 9.2% 9.5% 8.2% NS 9.7% Other 11.6% 10.8% 10.8% 10.6% 11.9% NS 11.1% BBB (n) Syncope 46.2% 46.3% 49.3% 53.3% 55.5% % Dizzy spells 9.8% 10.6% 11.6% 12.7% 14.3%, % Bradycardia 8.9% 8.8% 9.9% 9.7% 10.7% % Heart failure 25.3% 22.8% 18.1% 13.7% 10.6%, % Other 9.9% 11.5% 11.1% 10.7% 9.0% NS 10.5% AVB, atrio-ventricular blocks; SSS, sick sinus syndrome; AF þ Brady, atrial fibrillation plus bradycardia; BBB, bundle brunch blocks. Table 4 Distribution of first implants by pacing modality from 2003 to 2007 and in the period vs Trend P-value... AAI 0.2% 0.2% 0.1% 0.1% 0.1% NS 0.1% 0.3% NS AAIR 0.2% 0.2% 0.2% 0.1% 0.1% NS 0.2% 0.4% NS DDD 27.7% 26.6% 29.3% 27.5% 24.8% NS 27.2% 27.1% NS DDDR 21.9% 24.7% 25.2% 27.0% 31.3% % 21.9%,0.05 VDD 8.6% 7.2% b 6.1% 6.4% 6.1% NS 6.9% 9.4%,0.05 VDDR 3.7% 4.2% 4.4% 4.2% 4.0% NS 4.1% 3.3% NS VVI 23.2% 21.5% 21.3% 20.3% 17.9% % 25.9%,0.05 VVIR 12.1% 13.3% 11.8% 12.3% 14.1% NS 12.8% 11.1% NS DDDRT 2.5% 2.2% 1.6% 1.9% 1.7% NS 2.0% 0.5% NS Discussion Our survey indicates that during the observation period, patient s age at the time of the first implant remained constant at 77 years along with a slight prevalence of the male gender. The eighth decade was the most represented, whereas the ninth decade showed a gradual and significant increase. Compared with the most recent world surveys of cardiac pacing 30,31 our data are aligned with those of countries with sophisticated health systems. Clinical and electrocardiographic indications In reference to ECG indications for pacing, 45% of the patients had AV conduction disturbances, 25% sinus node dysfunction, and 18% chronic AF with slow ventricular response, whereas only 6% had different types of fascicular blocks. Among the SSS group, over 70% had either syncope, dizzy spells, or congestive heart failure. In our opinion, these percentages reflect a favourable

5 206 A. Proclemer et al. Figure 1 Pacing modalities trend in SSS. AAI, single-chamber atrial pacemaker; VVI, single-chamber ventricular pacemaker; DDD, dual-chamber pacemaker; R, rate responsiveness. Figure 3 Pacing modalities trend in BBB and fascicular blocks. VVI, single-chamber ventricular pacemaker; VDD, single-lead AV pacing; DDD, dual-chamber pacemaker; R, rate responsiveness; DDDRT, pacemaker with cardiac resynchronization therapy. bradycardia indication (20%) most likely falls into a Class IIa recommendation. Among the fascicular blocks, syncope and dizzyspells constituted over 60% of indication, whereas congestive heart failure decreased from 25 to 10% during the study period. This change is likely a consequence of the increasing use of implantable cardioverter-defibrillator (ICD) with resynchronization therapy which took place during the observation period. 28,29,32 Figure 2 Pacing modalities trend in AV conduction defects. VVI, single-chamber ventricular pacemaker; VDD, single-lead AV pacing; DDD, dual-chamber pacemaker; R, rate responsiveness. adherence to the European and US published guidelines, where Class I recommendations for permanent pacing include documented symptomatic bradycardia, sinus pauses, chronotropic incompetence, and sinus bradycardia secondary to drug therapy, whereas Class IIa comprise sinus bradycardia,40 bpm without a clear association to significant symptoms and syncope of unexplained origin with sinus node dysfunction discovered in electrophysiological studies Unfortunately, our data cannot identify drug-induced bradycardia due to the configuration of the reporting European card (see Appendix). We believe that 20% of the patients with bradycardia as clinical indication are possibly attributable to a Class IIa indication. Among the AV block group and AF plus bradycardia group, 60% had either syncope, dizzy-spells, or heart failure. Again the correlation with PM utilization guidelines for this group appears satisfactory, despite the impossibility to consider the single recommendation included in Class I and to identify the AV conduction disturbance location. Also for this group, the Selection of pacemaker type Among the SSS group, the dual-chamber pacing modality was by far the most utilized without a significant incrementation during the period. The atrial pacing modality was scarcely utilized, despite its validation through published data. 13,19,20 Among the AV block group, dual-chamber pacing was utilized more frequently also exhibiting an increasing trend. The balance regarded either VVI VVIR or VDD VDDR pacing modalities. The latter historically has been frequently utilized in Italy and is less common in other countries. 25,30,31 Among the fascicular blocks, DDD DDDR were used in over 50% of the cases with a trend towards higher utilization, followed by DDD-CRT. In the last world survey, the percentage of dual-chamber DDDR usage rose in all regions surveyed at the expense of single-chamber VVIR. Most developed countries showed.50 60% DDDR usage. In recent years, the principal debate with respect to pacing modality choice has been centred on the relative values of dualchamber pacing, single-chamber ventricular pacing, and singlechamber atrial pacing. There have been several randomized trials 13,14,16 19,21 comparing atrial or dual-chamber pacing with ventricular pacing and evaluating several major endpoints such as incidence of heart failure, AF, stroke or thrombo-embolic events, and mortality. The meta-analysis of the five major randomized trials showed a significant decrease in AF incidence and a decrease in borderline statistical significance in stroke with atrial or dualchamber pacing compared with ventricular pacing. The evidence

6 Clinical characteristics and pacing modality in patients treated by PM 207 also indicates a modest improvement in quality of life and functional status with dual-chamber pacing in patients with SSS. 15 On the contrary, the same meta-analysis did not show a significant difference between atrial- or dual-chamber-paced patients in comparison to ventricular-paced patients with respect to heart failure hospitalization and overall mortality. 15 The relevant percentage of patients (ranging from 4 to 37%) who crossed over from ventricular pacing to dual-chamber pacing in association to the improvement of quality-of-life indexes could justify the higher use of dual-chamber units with respect to single-chamber systems in our survey in agreement with other countries. 30,31 The share of DDD-CRT use in the study period was extremely low due to the progressive increasing utilization of ICD-CRT following the application in real world of the results of major trials and up-to-date guidelines. 29 Conclusions The IPR showed for the period a very stable pattern of pacing indications based on documented bradyarrhythmias and major symptoms. Considering the selection of pacing modality, our survey demonstrated a higher use of dual-chamber pacing in comparison to single-chamber pacing in SSS, AVB, and BBB indications, despite inconclusive data of the major randomized trials. The use of PM with CRT regarded a very limited number of patients especially in the last 3 years of the study period. In the future, electronic data transmission should be considered in order to improve information collection. Conflict of interest: none declared.

7 208 A. Proclemer et al. Appendix

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