Authors	Study Design	Inclusion Criteria	Pacing Mode	Number of Patients	Follow up	Outcome
Fitzpatrick et al.[42]	Cross-sectional; external pacemaker placed and tilt-table test performed	Positive tilt-table test and significant bradycardia (<60 BPM)	External DVI pacing with rate hysteresis	10 (6 male, mean age 60.2)	None	Syncope aborted by pacing in 5/6 undergoing tilt-table test
Petersen et al.[43]	Prospective; dual chamber PPM in 35 patients and VVI PPM in 2 patients	Patients with PPM for VVS. Median of 6 syncopal episodes, median frequency 2/year) with cardioinhibitory response with tilt-table test (<60 BPM)	84 % DDI with rate hysteresis	37 (21 male, mean age 62.5 years)	50.2 months	62 % syncope free 27 % symptom free
Sutton et al., 2000 (VASIS study)[47]	Multicentre, randomised; DDI PPM at 80 BPM with hysteresis of 45 bpm versus no PPM	>3 syncope episodes over prior 2 years and a positive 2A/2B cardioinhibitory (VASIS classification) response (median previous episodes was 6); asystolic response to tilt-test in 86%	DDI with rate hysteresis	42 (24 male, mean age 60 years)	Minimum 1 year and maximum 6.7 years	1 (5 %) in PPM arm had syncope versus 14 (61 %) in no-pacemaker arm (p=0.0006)
Connolly et al., 1999 (VPS Study)[37]	Randomised; DDD PPM with RDR vs. no PPM	>6 lifetime episodes of syncope, positive tilt-table test and relative bradycardia (<60 BPM if no isoproterenol, <70 BPM if up to 2 ug/ min isoproterenol used or <80 BPM if > 2 ug/min isoproterenol)	DDD with RDR	54 (16 male, mean age 43 years)	21 months	RRR 85.4 %, 95 % CI [59.7-94.7 %]; p=0.000022
Ammirati et al., 2001 (SYDIT)[48]	Multicentre, randomised, controlled trial; DDD RDR PPM versus beta-blocker	>35 years old, ≥3 syncopal episodes in preceding 2 years and positive tilt-table test occurring with relative bradycardia	DDD with RDR	93 (38 male, mean age 58.1 ± 14.3 years)	30 months	Syncope recurrence in 2 (4.3 %) after median of 390 days versus recurrence in 12 (25.5 %) with medical treatment after median 135 days OR 0.133; 95 % CI [0.028-0.632]; p=0.004)
Connolly et al., 2003 (VPS II Study)[36]	Multicentre, randomised, double-blinded DDD vs ODO	>19 years old, typical history of recurrent syncope with ≥6 total episodes of syncope or ≥3 episodes in 2 years before enrollment	DDD with RDR versus ODO	100 (40 male, mean age 49.3 years)	6 months	42 % had recurrent syncope vs. 33 % in DDD group. The RRR in time to syncope with DDD was 30 % (95 % CI [-33-63 %]; 1-sided p=0.14)
Raviele et al., 2004 (SYNPACE Study)[49]	Randomised, double-blind, placebo-controlled; DDD with RDR comparison of PPM on versus off	Severe recurrent tilt-induced vasovagal syncope (median 12 syncopal episodes in lifetime)	DDD with RDR	29 (10 male, mean age 53 ± 16 years)	715 days	8 patients (50 %) in the PPM-ON group had recurrence of syncope vs.5 patients (38 %) in the PPM-OFF group (p=ns). Median time to first syncope longer in PPM-ON vs. PPM-OFF group, although not significant (97 vs. 20 days; p=0.38)
Brignole et al., 2012 (ISSUE-3)[51]	Double-blind, randomised, placebo-controlled, multicentre; DDD with RDR on versus off	≥40 years old, with ≥3 syncopal episodes in the previous 2 years	DDD with RDR	77 (36 male, mean 63 years)	24 months or first syncope	Syncope recurred in 27 - 19 in PPM-OFF group and 8 in PPM-ON. 2-year estimated syncope recurrence rate was 57 % (95 % CI [40-74]) with PPM-OFF and 25 % (95 % CI [13-45]) with PPM-ON (p=0.039). The observed 32 % absolute and 57 % relative reduction in syncope in PPM-ON group
Brignole et al., 2015 (SUP-2)[52]	Prospective, multicentre, observational study; carotid sinus massage, tilt-table testing followed by ILR implantation. Those with asystolic response received dual chamber PPM	≥40 years with recurrent unpredictable reflex syncope	DDD with RDR versus sensing only	253 (128 male, mean 70 ± 12 years)	13 ± 7 months	Decrease of total syncopal episodes from 200 episodes before PPM to 11. Total syncope recurrence was 9 % (95 % CI [6-12]) at 1 year and 15 % (95 % CI [10-20]) at 2 years
Brignole et al., 2016 (SUP-2)[61]	Prospective, multicentre, observational study; carotid sinus massage, tilt-table testing followed by ILR implantation. Those with asystolic response received dual chamber PPM	≥40 years with recurrent unpredictable reflex syncope	DDD with RDR in 101/137 vs sensing only	137 (82 male, mean 73 ± 11 years) received a pacemaker vs 142 who did not	26 ± 11 months	Decrease in total number of syncopal episodes from 206 to 16 in year after pacemaker and 39 episodes of syncope in total follow-up
Kanjwal et al., 2010[53]	Prospective non-randomised; CLS pacing	≥2 syncopal episodes in preceding 6 months, refractory to medical therapy, evidence of asystole (>10 s) or severe bradycardia (<30 bpm) on ILR or during tilt-table test	DDD with RDR versus CLS	35 (6 male, mean age 41 ± 11 years)	9±3 months	Recurrence (59 % vs. 83 %) reduction in syncope burden and pacemaker success (84 % vs. 25 %, P=0.002) in the CLS group
Occhetta et al., 2004 (INVASY study)[55]	Prospective, randomised; DDD-CLS and DDI pacing	Severe recurrent syncope with positive tilt-table test	DDD-CLS versus DDI	55 (27 male, mean age 59 ± 18 years)	1 year	7/9 patients in DDI group had recurrence of syncope. When reprogrammed to CLS they had no syncope. Of 41 programmed to CLS, none had recurrence in 19 ± 4 months
Bortnik et al., 2012[54]	Prospective, long-term evaluation of patient before and after PPM implantation with CLS pacing	Positive type 2A or 2B (VASIS classification) cardioinhibitory response to tilt-table testing. Age >18 years. Proven refractoriness to conventional drug therapy and tilt training	CLS	35 (mean age 59 ± 15 years) (no data about gender)	3 years (61 ±3 5 months)	29/35 (83 %) were asymptomatic. 5 patients experienced syncope recurrence after CLS (1-7, with a total of 15 episodes). In each case, syncopal spells were fewer than before implantation
Palmisano et al., 2012[56]	Retrospective; CLS versus RDR	≥2 syncopal episodes in the year prior to pacemaker implantation and positive 2A or 2B (VASIS classification) cardioinhibitory response to tilt-table test	CLS versus RDR	41 (44% male, mean 53 ± 16 years)	4.4 ± 3 years	1 patient in the CLS group (4 %) and 6 in the RDR group (38 %) had syncope recurrences (p=0.016)
Palmisano et al., 2017[57]	Prospective, randomised, single-blind, multicentre; CLS versus DDD during tilt-table testing	Recurrent unpredictable VVS with significant limitation of social and working life, refractory to drug therapy, and/or tilt training treated with PPM implantation according to current guidelines. A positive 2A or 2B (VASIS classification) cardioinhibitory response to tilt-table testing performed before PPM implantation. Exclusion of other causes. Age >18 years old	CLS versus DDD	30 (18 male, age 62.2 ± 13.5 years)		CLS significantly reduced syncope induced by tilt-table test (30 % versus 76.7 %; p<0.001)
Russo et al., 2013[58]	Prospective, randomised, single-blind, crossover study; CLS on or off	≥40 years old, sinus rhythm, recurrent unpredictable syncope, no medication that could affect circulatory control, type 2B (VASIS classification) cardioinhibitory VVS, refractory to conventional drug therapy and/or tilt training	CLS	50 (33 male, mean age 53 ± 5.1 years)	36 months	The number of syncopal episodes during CLS ON was significantly lower than the CLS OFF group (2 vs. 15; P=0.007)
Barón-Esquivas et al., 2017 (SPAIN Study)[59]	Randomised, double blind, controlled study, multicentre; DDD-CLS for 12 months, followed by sham DDI for 12 months or sham DDI mode for 12 months, followed by DDD-CLS for 12 months	>40 years, >5 episodes of syncope or >2 in the last year, cardioinhibitory tilt-table test response	CLS versus DDI. 12 months cross-over	46 (22 male, mean age 56 ± 11 years)	24 months	72 % (95 % CI [47-90 %]) >50 % reduction of syncopal episodes with DDD-CLS versus 28 % (95 % CI [9.7-53.5 %]) during DDI (HR 6.7; 95 % CI [2.3-19.8])

CLS = closed loop stimulation; PPM = pacemaker; RDR = rate-drop response