Although these studies demonstrated the efficacy of pacemake
Although these studies demonstrated the efficacy of pacemaker treatment for preventing or reducing VVS, all 3 trials were retrospective and uncontrolled . Therefore, RCTs of cardiac pacing in VVS were proposed in the late 1990s.
The era of RCTs: is pacemaker efficacy due to a placebo effect? Since 1999, several RCTs of pacing therapy for refractory VVS have been conducted (Table 1). Flammang et al.  reported the efficacy of pacemaker treatment for VVS with a severe cardioinhibitory response identified by the adenosine triphosphate test. Twenty patients were randomized to 2 groups: DDD pacemaker mg to mol (10 patients) and usual medical care (10 patients). During a mean follow-up of 52 months, syncope recurred in 60% of the usual-care patients but in none of the paced patients (P<0.02). In the North American Vasovagal Pacemaker Study (VPS) , 54 patients were randomly divided into 2 groups: DDD pacemaker with RDR or no pacemaker. The results of VPS showed a marked reduction in the risk of syncope recurrence with pacemaker implantation (relative risk reduction, 85.4%). In the Vasovagal Syncope International Study (VASIS) , 42 patients were randomized to receive a DDI pacemaker with rate hysteresis or no pacemaker. Inclusion criteria were ≥3 syncope episodes over the preceding 2 years and a positive cardioinhibitory response to HUT testing. During the follow-up period of 3.7±2.2 years, there was significantly less recurrence of syncope in the pacemaker arm than in the non-pacemaker arm (5% vs. 61%, P=0.0006). In the Syncope Diagnosis and Treatment (SYDIT) Study , 93 patients were randomized to receive either a DDD pacemaker with RDR function or the beta-blocker atenolol. Inclusion criteria were age >35 years, ≥3 syncope episodes in the preceding 2 years, and positive response to HUT testing with relative bradycardia. During the mean follow-up of 17.3 months, the recurrence of syncope was significantly lower in the pacemaker group than in the pharmaceutical treatment group (4.3% vs. 25.5%, P=0.004). On the basis of the results of these 3 RCTs, pacing therapy appears to be effective for the prevention of recurrent syncope in patients with VVS. However, double-blind randomized trials showed different outcomes. In the Second Vasovagal Pacemaker Study (VPS II) , 100 patients were assigned to receive DDD pacing with RDR or to have only sensing without pacing (ODO). Inclusion criteria were history of typical VVS with ≥6 overall episodes of syncope or ≥3 episodes of syncope in the preceding 2 years and a positive HUT test. The cumulative risk of syncope at 6 months was not different between the DDD and ODO groups (31% vs. 40%). In the vasovagal SYNcope and PACing (SYNPACE)  trial, 29 patients with severe recurrent tilt-induced VVS underwent DDD-RDR pacemaker implantation and were randomized to pacemaker ON or pacemaker OFF. During the follow-up of 23.8 months, the recurrence of syncope showed no significant difference (50% in pacemaker ON and 38% in pacemaker OFF). The median time to first syncope recurrence was also not significantly different. After these 2 double-blind RCTs failed to prove the superiority of cardiac pacing over placebo in patients affected by VVS, the widely accepted opinion was that cardiac pacing therapy is not very effective and that a strong placebo effect exists . The results of VPS II and SYNPACE were disappointing. However, these 2 trials included patients with VVS of not only the cardioinhibitory type but also the vasodepressor and mixed types. Therefore, the question arises whether pacing therapy could be effective for the cardioinhibitory type of VVS, specifically that with a prolonged asystole .
Reappraisal of pacing therapy for vasovagal syncope: ISSUE 3 The implantable loop recorder (ILR) has advanced the diagnosis of syncope of uncertain etiology. ILR can record a real-time ECG at the time of syncopal episodes. Classically, the results of HUT testing were used to select patients for pacing in clinical trials [12–16]. ILR revealed that patients with a tilt-induced asystole did not always have bradycardia or asystole during the recurrent episodes of syncope [19,20]. Because the hemodynamic response during HUT testing does not predict the hemodynamic status during spontaneous syncope, it follows that the results of HUT testing cannot predict the efficacy of cardiac pacing . The Second International Study on Syncope of Uncertain Etiology (ISSUE 2)  revealed the mechanism of spontaneous neurally mediated syncope documented by ILR: approximately one-half of syncope events showed a prolonged asystole. It is reasonable that pacing therapy may be effective when asystole is documented at the time of syncope. In ISSUE 2 , patients with asystolic syncope treated with pacemakers showed more than 80% relative risk reduction of syncope recurrence in comparison with untreated groups. However, ISSUE 2 was not a formal controlled double-blind trial. Therefore, ISSUE 3, another randomized controlled clinical trial that was designed to assess the apparent pacing benefit, was conducted . The ISSUE 3  trial was a double-blind, randomized placebo-controlled study conducted in 29 centers in Europe and Canada. Subjects were limited to those aged ≥40 years and with a history of syncope suggestive of a vasovagal cause. Subjects were required to have reported >3 episodes in the preceding 2 years and at least 1 in the 6 months immediately prior to enrollment. The results of ISSUE 3 were reported in 2012 . Initially, 511 patients received an ILR; 89 of these had documentation of either syncope with an asystole of >3s or an asystole >6s without syncope within 12±10 months and met criteria for pacemaker implantation. Of these, 12 patients refused randomization. Ultimately, 77 of the 89 patients were randomly assigned to DDD pacing with RDR (pacemaker ON) or to sensing only (pacemaker OFF). The data were analyzed on the intention-to-treat principle. There was syncope recurrence during the follow-up in 27 patients, 19 of whom had been assigned to pacemaker OFF and 8 to pacemaker ON. The 2-year estimated syncope recurrence rate was significantly higher in patients with pacemaker OFF than in those with pacemaker ON (57% vs. 25%, P=0.039). The risk of syncope recurrence was reduced by 57% (95% CI, 4–81%). The ISSUE 3 study demonstrated that pacemaker therapy is effective in preventing the recurrence of syncope for selected VVS patients who had cardioinhibitory response documented by ILR. Prevention could not be ascribed to a placebo effect. Although ISSUE 3 has led to reappraisal of pacing treatment for VVS, the role of pacemaker treatment for young (age, <40 years) VVS patients remains to be established. Sra and Akhtar  pointed out that most patients with VVS are relatively young and have a benign prognosis. Therefore, apart from the efficacy and the cost of such an intervention, the implications of serious psychological sequelae and the burden of the long-term implanted device need to be justified.