Clin Auton Res (2014) 24:127–134 DOI 10.1007/s10286-014-0238-x

RESEARCH ARTICLE

The role of cardiac pacing in carotid sinus syndrome: a meta-analysis Bing-Wei Chen • Zhi-Guang Wang • Na-Qiang Lv • Yan-Mei Cheng • Ai-Min Dang

Received: 30 July 2013 / Accepted: 5 March 2014 / Published online: 29 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose Cardiac pacing can be used to treat carotid sinus syndrome (CSS), but clinical studies have shown conflicting results. We conducted a systematic review and metaanalysis to evaluate the role of pacing for CSS. Methods A systematic search of publications in PubMed, Embase, and the Cochrane Library without language restriction was performed. Prospective randomized studies that compared cardiac pacing with standard therapy or pacing with different algorithms were included if the recurrence of syncope or the number of falls was observed. Results Eight studies enrolling 540 patients were identified. In open-label studies, the recurrence of syncope was reduced significantly by cardiac pacing compared with standard therapy. The recurrence of syncope was not different between single- and dual-chamber pacing, but a lower rate of patients with pre-syncope was observed in the group with dual-chamber pacing. Double-blind clinical studies failed to observe the role of cardiac pacing for preventing falls in patients with CSS. Conclusion The results of meta-analysis supported the use of cardiac pacing for patients with dominant cardioinhibitory CSS. Keywords Carotid sinus syndrome  Pacemaker  Syncope  Meta-analysis

B.-W. Chen  Z.-G. Wang  N.-Q. Lv  Y.-M. Cheng  A.-M. Dang (&) Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing 100037, People’s Republic of China e-mail: [email protected]; [email protected]

Introduction Patients with carotid sinus syndrome (CSS) are characterized by exaggerated response to carotid sinus stimulation with bradycardia and/or hypotension. In the elderly, the prevalence of CSS is relatively high [1]. CSS is present in up to 22 % of patients over the age of 60 years with unexplained syncope [2]. Cardiac pacing can be used to counteract the cardioinhibitory component of CSS. In the guideline for the diagnosis and management of syncope from European Society of Cardiology, cardiac pacing is considered for the patients with dominant cardioinhibitory CSS, and dual-chamber pacing is preferred over single-chamber ventricular pacing [1]. However, clinical trials got conflicting results. Although a previous systemic review which evaluated the cardiac pacing for CSS identified five studies, the effectiveness of pacing is still uncertain without synthetic analysis of the conflicting results from these studies [3]. Of note, one included study reported the proportion of patients with hypotension during carotid sinus massage other than during follow-up [4]. Recently, several prospective randomized studies supplied additional evidence about the effectiveness of cardiac pacing and the comparison between dual- and single-chamber pacing for CSS [5, 6]. The aim of this study was to evaluate the role of cardiac pacing in CSS by conducting a metaanalysis of randomized prospective studies.

Methods Literature search and selection We systematically searched the electronic databases PubMed, Embase, and the Cochrane Library without language

123

128

restriction up to Jan 2014. The following search terms were used: carotid sinus hypersensitivity, carotid sinus syndrome, artificial pacemaker, cardiac pacemaker, cardiac pacing. The detailed search strategies were presented in ‘‘Appendix 1’’. The reference lists of original and review articles were reviewed to identify any additional relevant studies. Studies were included in the meta-analysis if they met the following criteria: (1) prospective randomized design; (2) patients over 18 years of age with CSS were enrolled; (3) pacemaker therapy was compared with medical or no specific therapy, or different type of pacing algorithms were compared; (4) the recurrence of syncope or number of falls was reported in each group. If multiple published articles from the same study were available, only the study with the most detailed information was included. Data extraction and study quality CSS was defined as syncope or pre-syncope in combination with 3 s or more asystole (cardioinhibitory response) and/or 50 mmHg or more drop in systolic blood pressure (vasodepressor response) in response to carotid sinus stimulation. Cardiac pacing was considered when cardioinhibitory response was observed. The major outcome we concerned Fig. 1 Flow chart of study selection

123

Clin Auton Res (2014) 24:127–134

was the recurrence of syncope or number of falls. We also assessed the rates of patients with pre-syncope, which were defined as symptoms caused due to bradycardia and/or hypotension, usually with presentation such as nausea, clouding of vision, weakness, sweating, and dizziness. All literature search results were screened independently by two authors (B-WC and A-MD) for potentially relevant articles. Extracted data included the first author’s name, year of publication, number of participants, participants’ age and gender, duration of follow-up, the therapy for each group, and carotid sinus massage test criteria for CSS. Data-extraction was also performed independently by the above two authors. The form for data extraction was presented in ‘‘Appendix 2’’. Uncertainty or disagreement was resolved by discussion and consensus. Studies were assessed for quality by randomization, blinding, reporting of withdrawals, generation of random numbers, and concealment of allocation. Trials scored one point for each area addressed, with a possible score between 0 and 5 [7]. Statistical analysis The relative risk (RR) was used as the measure of effect and the results were expressed as a RR with 95 %

Clin Auton Res (2014) 24:127–134

129

Fig. 2 Forest plot shows recurrence of syncope with cardiac pacing versus standard treatment

confidence intervals (CIs). The heterogeneity among studies was tested by Q-statistic (significance level at p \ 0.10) and I-statistic [8]. The combined RRs were computed using either fixed-effects or random-effects models, depending on the absence or presence of heterogeneity, respectively. A p value\0.05 was considered to be statistically significant. All statistical analyses were performed using REVMAN software (version 5.0; Cochrane Collaboration, Oxford, UK).

Results Main features of included studies Eight studies enrolling 540 patients were identified based our criteria (Figs. 1). The characteristics of these studies are presented in Table 1. The primary outcome of five studies was the recurrence of syncope [5, 9–12]. Another 3 studies took the number of falls during follow-up as their primary outcome [6, 13, 14], and in one of them [14] the recurrence of syncope was also reported. Three open-label studies compared cardiac pacing with medical therapy or no specific therapy [11, 12, 14], and 3 studies compared singleand dual-chamber pacing using cross-over design [5, 9, 10]. Two studies used double-blind design to assess the number of falls. One of them used implanted loop recorder in the control [6], and another one used cross-over design by programming the pacemakers to DDD or ODO mode [13]. The results of the study by McLeod et al. [5] were published as an earlier abstract [15]. A preliminary study [16] was published in 1988 before the publication of the study by Brignole et al. in 1992 [11]. The result of a comparison between dual- and single-chamber pacing in 23 patients with a cross-over design were found in 3 articles [9, 17, 18], and the article with most detailed information was included [9]. In the study by Brignole et al. published in 1991 [10], 60 patients with CSS were treated with dualchamber pacemaker (n = 26) or single-chamber pacemaker (n = 34) according to the clinicians’ preference other than randomization, while a randomized, cross-over

study was performed in the 26 patients with dual-chamber pacemaker to compare dual- and single-chamber pacing. The results of the cross-over study were included. The same results could be found in another article by Brignole et al. [19]. Cardiac pacing and recurrence of syncope Compared with standard therapy, the recurrence of syncope was reduced significantly with cardiac pacing therapy (RR 0.31; 95 % CI 0.18–0.53; p \ 0.001; Fig. 2). The recurrence of syncope was not different between single- and dual-chamber pacing (RR 0.20; 95 % CI 0.04–1.12; p = 0.07; Fig. 3a), but the recurrence of pre-syncope was lower with dual-chamber pacing (RR 0.53; 95 % CI 0.33–0.85; p = 0.008; Fig. 3b). No evidence of significant heterogeneity between studies was presented according to the results of Q statistic (p = 0.26, 0.93 and 0.13, respectively). Cardiac pacing and number of falls The SAFEPACE study showed that comparing with standard treatment, cardiac pacing reduced the number of falls significantly (OR [odds ratio] 0.42; 95 % CI 0.23–0.75) [14]. While the SAFEPACE 2 [6] and the study by Parry et al. [13] failed to observed the role of cardiac pacing in preventing falls, and the combined RR were also not statistically significant (RR 0.82; 95 % CI 0.63–1.06; p = 0.126).

Discussion Compared with standard treatment, cardiac pacing showed advantage in reducing the recurrence of syncope. Dualchamber pacing showed no advantage over single-chamber ventricular pacing in terms of recurrent syncope, but it could help to prevent pre-syncope. Double-blind trials failed to observe the benefit of cardiac pacing in reducing the number of falls.

123

130

Clin Auton Res (2014) 24:127–134

Table 1 Characteristics of included studies Study

Pulication year

Age (mean)

Male (%)

Brignole

1988

69

91

Sample size 23

Intervention

Control

DVI/DDD

VVIa a

Brignole

1991

68.6

73

26

DVI/DDD

VVI

Brignole

1992

69.7

80

60

DDD/VVI

Kenny

2001

73

41

175

DDD-RDR

Standard therapy Standard therapy

Claesson

2007

75.1

70

60

Ryan

2009

78

38

Parry

2009

77

21

Mcleod

2012

74.2

81

Follow-up (months) 4

Outcome assessed

Quality score

Recurrence of syncope

2

4

Recurrence of syncope

2

34

Recurrence of syncope

3

12

Recurrence of syncope; number of falls

4

DDDR/VVIR/ AAIR

Standard therapy

12

Recurrence of syncope

4

141

DDD-RDR

ILR

24

Number of falls

4

34

DDD-RDR

ODOa

12

Number of falls

4

21

DDDR-SBR

VVIa

18

Recurrence of syncope

5

ILR implantable loop recorder, RDR rate-drop response, SBP sudden brandy response a

Cross-over design was used

Fig. 3 Forest plots show the comparison between single- and dual- chamber pacing a the recurrence of syncope b the rate of patients with presyncope

Compared with the study by Romme et al. [3], the present study confirmed the effectiveness of cardiac pacing to prevent recurrent syncope by synthesizing the conflicting results. However, it should be noted that all included studies lacked double-blind design and did not use a placebo control arm. Pacing for CSS became a Class IIa recommendation in the European Society of Cardiology Syncope Guideline [1] and a Class I recommendation in the North American equivalent [20] with these limited evidence. According to these guidelines, it seems to be unethical to design a placebo arm in future study to

123

evaluate the cardiac pacing for CSS. Placebo effect can really affect the efficacy of pacing for other neutrally mediated syncope, such as vasovagal syncope [21]. Careful evaluation of placebo effect of pacing for CSS seems to be necessary in the future. The double-blind trials evaluating cardiac pacing for preventing falls in patients with CSS got negative results. In the included studies, systematic evaluation was conducted to exclude other possible causes of falls, but it is known that unexplained falls are multifactorial in etiology in the elderly rather than solely related to CSS. Thus it is not surprising that

Clin Auton Res (2014) 24:127–134

pacing failed to be effective in patients with fall. Placebo effect may also play a role in these trials. In the study by Parry et al. [13], the significantly reduced number of falls was still observed after the pacemakers were programmed to off mode. The advantage of pacemaker compared with standard treatment presented in the SAFE PACE study [14] may also be partly contributed to placebo effect. The single-chamber pacing itself can induce some symptoms, including palpitations and dizziness, which can be avoided by consequent atrial-ventricular pacing. In addition, dual-chamber pacing can restore the synchrony between atrium and ventricle, and avoid the damage to heart function and risk of atrial fibrillation that are associated with singlechamber pacing [22]. In studies with single-chamber pacing, higher rates of pre-syncope were observed in pacing group with significantly decreased rates of syncope, and authors interpreted pre-syncope as aborted syncope that was prevented by pacing [12]. Although with similar recurrence of syncope, dual-chamber cardiac pacing is obviously useful for preventing these syndromes induced by aborted syncope. There are several limitations to our analyses. First, the quality of the data cannot go beyond the quality of the individual studies included. Second, although no significant heterogeneity was found between included studies, the power of Q and I2 statistics to detect heterogeneity was limited in case that total number of studies and patients was relatively small. Residual confounding and bias remain a possibility. Third, potential information may be omitted due to the exclusion of the article without available fulltext. Fourth, the recurrence of syncope cannot give more detailed information about the total syncopal ‘‘burden’’, which can be represented as the number of syncope per unit time and may be better for evaluating the efficacy of treatment. However, our results are important in guiding the assessment of current evidence and the definition of future research strategies.

Conclusions Although conflicting results were presented in studies, the results of meta-analysis supported the recommendations in

131

guidelines that cardiac pacing should be considered for patients with dominant cardioinhibitory CSS and dualchamber pacemaker should be the preferred selection. However, as evidence available to date is still limited, more trials are required.

Conflict of interest

None declared.

Appendix 1: Search strategies PubMed #1 ‘‘carotid sinus hypersensitivity’’ #2 ‘‘carotid sinus syndrome’’ #3 #1 OR #2 #4 ‘‘Cardiac Pacing, Artificial’’[Mesh] OR ‘‘Pacemaker, Artificial’’[Mesh] #5 pacemaker* #6 pacing* #7 #4 OR #5 OR #6 #8 #3 AND #7 EMBASE #1 ‘‘carotid sinus hypersensitivity’’ #2 ‘‘carotid sinus syndrome’’ /exp #3 #1 OR #2 #4 pacemaker* #5 pacing* #6 ‘‘artificial pacemaker’’ /exp #7 ‘‘cardiac pacing’’/exp #8 ‘‘heart pacing’’/exp #9 #4 OR #5 OR #6 OR #7 OR #8 #9 #3 AND #9 Cochrane Library #1 ‘‘carotid sinus hypersensitivity’’ #2 ‘‘carotid sinus syndrome’’ #3 #1 or #2 #4 pacemaker* #5 pacing* #6 #4 or #5 #7 #3 and #6

123

132

Clin Auton Res (2014) 24:127–134

Appendix 2: Data extraction form—cardiac pacing and carotid sinus syndrome

Data extraction form – Cardiac pacing and Carotid sinus syndrome Study details: Study ID: First author: Year of publication: Article title: Cohort: Country of publication: Publication type: journal / abstract Study eligibility Study inclusion criteria Type of study design Patients characteristics

Type of interventions

Type of outcomes

Include exclude Reason for exclusion:

Study characteristics Patients Sex(number): Male Female Age: mean Ethnicity: Sample size: Study interventions: Study control: Duration of follow-up: Carotid sinus massage test criteria:Notes:

123

Clin Auton Res (2014) 24:127–134

133

Results Comparison: Outcomes: Subcategory 1: Treatment group:

Control group:

Treatment group:

Control group:

Number Num of pts with outcome Lost to follow up Reason for loss:

Subcategory 2: Number Num of pts with outcome Lost to follow up Reason for loss:

Quality score Score Randomization Blinding Generation of random numbers Concealment of allocation Reporting of withdrawals Sum

References 1. Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, Deharo JC, Gajek J, Gjesdal K, Krahn A, Massin M, Pepi M, Pezawas T, Ruiz Granell R, Sarasin F, Ungar A, van Dijk JG, Walma EP, Wieling W (2009) Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 30(21): 2631–2671 2. Kumar NP, Thomas A, Mudd P, Morris RO, Masud T (2003) The usefulness of carotid sinus massage in different patient groups. Age Ageing 32(6):666–669 3. Romme JJ, Reitsma JB, Black CN, Colman N, Scholten RJ, Wieling W, Van Dijk N (2011) Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev (10):CD004194 4. McIntosh SJ, Lawson J, Bexton RS, Gold RG, Tynan MM, Kenny RA (1997) A study comparing VVI and DDI pacing in elderly patients with carotid sinus syndrome. Heart (British Cardiac Society) 77(6):553–557 5. McLeod CJ, Trusty JM, Jenkins SM, Rea RF, Cha YM, Espinosa RA, Friedman PA, Hayes DL, Shen WK (2012) Method of pacing does not affect the recurrence of syncope in carotid sinus syndrome. Pacing Clin Electrophysiol 35(7):827–833 6. Ryan DJ, Nick S, Colette SM, Roseanne K (2010) Carotid sinus syndrome, should we pace? A multicentre, randomised control trial (Safepace 2). Heart (British Cardiac Society) 96(5):347–351

7. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, Tugwell P, Klassen TP (1998) Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 352(9128):609–613 8. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414): 557–560 9. Brignole M, Sartore B, Barra M, Menozzi C, Lolli G (1988) Is DDD superior to VVI pacing in mixed carotid sinus syndrome? An acute and medium-term study. Pacing Clin Electrophysiol 11(11 Pt 2):1902–1910 10. Brignole M, Menozzi C, Lolli G, Oddone D, Gianfranchi L, Bertulla A (1991) Validation of a method for choice of pacing mode in carotid sinus syndrome with or without sinus bradycardia. Pacing Clin Electrophysiol 14(2 Pt 1):196–203 11. Brignole M, Menozzi C, Lolli G, Bottoni N, Gaggioli G (1992) Long-term outcome of paced and nonpaced patients with severe carotid sinus syndrome. Am J Cardiol 69(12):1039–1043 12. Claesson JE, Kristensson BE, Edvardsson N, Wahrborg P (2007) Less syncope and milder symptoms in patients treated with pacing for induced cardioinhibitory carotid sinus syndrome: a randomized study. Europace 9(10):932–936 13. Parry SW, Steen N, Bexton RS, Tynan M, Kenny RA (2009) Pacing in elderly recurrent fallers with carotid sinus hypersensitivity: a randomised, double-blind, placebo controlled crossover trial. Heart (British Cardiac Society) 95(5):405–409

123

134 14. Kenny RA, Richardson DA, Steen N, Bexton RS, Shaw FE, Bond J (2001) Carotid sinus syndrome: a modifiable risk factor for nonaccidental falls in older adults (SAFE PACE). J Am Coll Cardiol 38(5):1491–1496 15. McLeod CJ, Trusty JM, Jenkins SM, Rea RF, Cha YM, Espinosa RA, Friedman PA, Shen WKA (2009) Method of pacing does not affect the recurrence of syncope in carotid sinus syndrome. Heart Rhythm 6(5):S309 16. Brignole M, Menozzi C, Lolli G, Sartore B, Barra M (1988) Natural and unnatural history of patients with severe carotid sinus hypersensitivity: a preliminary study. Pacing Clin Electrophysiol 11(11 Pt 2):1628–1635 17. Brignole M, Barra M, Sartore B, Menozzi C, Lolli G (1988) Comparison of permanent cardiac pacing and cardiac pacing on demand in mixed carotid sinus syndrome. Acute- and mediumterm follow-up study. G Ital Cardiol 18(1):32–38 18. Brignole M, Sartore B, Barra M, Menozzi C, Lolli G (1989) Ventricular and dual chamber pacing for treatment of carotid sinus syndrome. Pacing Clin Electrophysiol 12(4 Pt 1):582–590 19. Brignole M, Menozzi C, Lolli G, Sartore B, Bertulla A (1989) The choice of stimulation mode in patients with cardioinhibitory

123

Clin Auton Res (2014) 24:127–134 or mixed carotid sinus hypersensitivity, with or without associated sinus dysfunction. G Ital Cardiol 19(1):28–34 20. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Tracy CM, Darbar D, Dunbar SB, Ferguson TB Jr, Karasik PE, Link MS, Marine JE, Shanker AJ, Stevenson WG, Varosy PD (2013) 2012 ACCF/ AHA/HRS focused update incorporated into the ACCF/AHA/ HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 61(3):e6–e75 21. Sud S, Massel D, Klein GJ, Leong-Sit P, Yee R, Skanes AC, Gula LJ, Krahn AD (2007) The expectation effect and cardiac pacing for refractory vasovagal syncope. Am J Med 120(1):54–62 22. Dretzke J, Toff WD, Lip GY, Raftery J, Fry-Smith A, Taylor R (2004) Dual chamber versus single chamber ventricular pacemakers for sick sinus syndrome and atrioventricular block. Cochrane Database Syst Rev (2):CD003710

The role of cardiac pacing in carotid sinus syndrome: a meta-analysis.

Cardiac pacing can be used to treat carotid sinus syndrome (CSS), but clinical studies have shown conflicting results. We conducted a systematic revie...
302KB Sizes 1 Downloads 3 Views