Introduction

Vasovagal syncope (VVS) is the most common cause of syncope in all decades of life. The lifetime cumulative incidence of VVS up to age 60 years is estimated to be about 42% [1, 2], with additional cases presenting first in older subjects. VVS usually begins in adolescence and young adulthood [3], has a lifelong predilection, and is more common in females than males [4].

Although VVS is not associated with an increased risk of mortality, it can be alarming and worrisome [5], and it remains a significant cause of emergency department visits, cost, morbidities, and reduced quality of life [5]. Depending on the country, the admission rate through emergency departments to inpatient hospital beds ranges from 10% to 80%, despite the lack of evidence that hospital admissions reduce mortality [6, 7]. In fact, two propensity analyses have reported that hospital admission is associated with increased mortality [6, 7], when accounting for baseline factors. Even the use of syncope risk scores does not seem to reduce admissions significantly.

The likelihood of syncope recurrence is best estimated from numerous observational and randomized studies of patients with moderately frequent syncope [8]. In a large multicenter prospective study, Toarta et al. [9] followed about 5000 patients for 1 month after emergency room discharge. The discharge diagnosis was presumed to be VVS in 53.3% of patients and cardiac syncope in 5.4%. No deaths were reported in the VVS group. In observational and randomized studies of VVS [8] the median number of historical syncope spells is in the range of 10–20 faints, and the likelihood of fainting again in the next 1–2 years is 30–60%. The strongest predictor of syncope recurrence is the number of faints in the year before specialist assessment [10]. The high number of lifetime spells and high likelihood of recurrence is not generally appreciated, and they are associated with injury, poor quality of life, anxiety, and depression.

Quality of life and injuries in vasovagal syncope

Syncope and injuries

Although VVS is usually considered a benign disorder, the potential for injury is worrisome (Table 1). A recent systematic review of 23 studies and 3593 VVS patients reported the proportion of patients injured due to syncope [11]. At least 82% had had at least 3 syncopal spells. The mean proportion of injured patients was high, at 34%. The likelihood of injury was higher in older subjects and had no relationship with sex, positive tilt test, or hypertension. The proportions of patients ever injured with syncope were 26% in younger patients (mean age < 50 years) and 43% in older patients (p = 0.002). Major injuries occurred in 14% of patients. This systematic review based on retrospective studies concluded that injuries due to syncope are frequent, and the risk of major injuries is substantial [11].

Table 1 Impact of vasovagal syncope on patients
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This review of retrospective studies was complemented by an analysis of injury data prospectively collected in 3 Prevention of Syncope Trials (POST) [12]. POST 2 and 4 were randomized trials of fludrocortisone and midodrine in younger adults, and POST 3 was a pragmatic trial of two interventions in much older syncope patients with bifascicular heart block. Injury was defined as minor (bruising, abrasions), moderate (lacerations), and severe (fractures, burns, joint pain), and recorded up to 1 year after enrolment. In a total of 459 patients (median age 39 years) 186 fainted, sustaining a total of 710 faints. Fully 30% of patients with syncope were injured (12% of the overall group). Injuries occurred with 14% of faints, and of these injuries 19% were deemed to be moderate or severe. Neither patient age, sex, nor the presence of prodromal symptoms were associated with injury-free survival. In VVS patients, pharmacological therapy significantly reduced the likelihood of an injury due to a syncopal spell (relative risk 0.64, 95% CI 0.43–0.96, p = 0.015).

Both retrospective [11] and prospective studies [12] consistently report that about 30% of syncope patients are injured at some time due to a faint, about 15% of faints are associated with physical trauma, and about 20% of injuries are moderate to severe. Counterintuitively we failed to confirm that a syncope-related injury negatively impacts HRQoL [13].

Syncope and quality of life

The poor quality of life in syncope patients (Table 1) has been documented repeatedly since first noted by Linzer et al. [14]. Several factors including associated presyncopal episodes, recurrent faints, new onset syncope, and comorbidities were associated with significantly worse social and emotional functioning, general health and vitality compared to a Dutch general population [15]. Similar findings were reported in a VVS population [5]. VVS patients had significantly poorer physical functioning and general health perception, greater role limitations, poorer emotional well-being and social functioning compared to a healthy matched control population [5]. Health-related quality of life measures were found to improve in as little as 6 months, with sustained improvement at one year. These improvements occurred regardless of allocation to placebo or active therapy or type of therapy. It is worth noting that recurrent faints during follow up were associated with less improvement in quality of life.

Conservative treatment for vasovagal syncope

The mainstay of management remains conservative non-pharmacologic interventions with its three pillars (Table 2) being (1) reassurance of the benign nature of the disease, (2) education on triggers and strategies to avoid them and (3) lifestyle interventions [16].

Table 2 Conservative treatment approach
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Natural history and placebo

There are large decreases in recurrences following specialist evaluation even without specific medical therapy. A recent meta-analysis evaluated prospective cohorts and placebo arms of randomized controlled trials (RCTs) [8]. The analysis included 1912 subjects from 11 RCTs and 6 observational cohorts with a median pre-enrolment observation period of 1 year and a median follow-up of 2 years. The patients reported improvement with no specific intervention aside from being evaluated and enrolled in trials. Compared to the pre-enrollment year during which 97% of the patients fainted with an average 2.6 faints, in the follow up period only 36% of those patients fainted, with a risk ratio of 0.44. These improvements occurred regardless of the type of intervention in the active comparator arm of RCTs. This might be due to the placebo effect, due to education about acting on prodromal symptoms, or due to regression to the mean. In addition, syncope events tend to cluster before the index event, which is usually around the time of evaluation [17]. Placebo intervention has great potential but studies of placebo effect are difficult [18]. This very large risk reduction in control arms does emphasize the need for strictly controlled studies.

Education

A small nonrandomized study with up to 30 month follow-up reported that education significantly reduced recurrences by 70% in VVS patients with a positive head-up tilt (HUT) test [19]. Aydin et al. followed VVS patients for 2 years after a standardized educational approach [20] including instructions on upper and lower extremities counter pressure maneuvers using their Hamburg syncope prevention protocol (adapted in Table 2). Recurrence rates were comparable to the preceding study with 72.5% of patients being free from recurrence at 2 years regardless of the tilt test result. The frequency of traumatic injuries was also reduced by 40%.

Salt and fluid

Increased fluid and salt intake may improve orthostatic tolerance [21], but hydration alone is not sufficient to prevent symptoms [22]. In the absence of contraindications patients should be encouraged to increase their hydration with close monitoring of blood pressure in patients at risk of hypertension. In addition, reducing anti-hypertensive polypharmacy may help. In a small cohort of elderly hypertensive patients with confirmed VVS, withdrawing or reducing hypotensive therapy resulted in significant reduction in presyncope and syncope [23]. These patients were tightly controlled and adjusting therapy meant having to allow the systolic blood pressure to rise up to 140–150 mmHg. Finally, an easy lifestyle modification that might increase orthostatic tolerance and increase the prodromal time allowing for further action is head-up sleeping with the head of the bed elevated to 10° [24].

Physical manouevres

Physical counterpressure maneuvers are valuable techniques to abort VVS in patients with prodromes. The first open-label, randomized controlled trial of these maneuvers showed a 36% relative risk reduction in recurrence with counterpressure maneuvers [25]. However, there was no sham intervention in the control arm. Somewhat later the effectiveness of counterpressure maneuvers was questioned in elderly patients and patients with no or minimal prodromes [26]. In a recent meta-analysis of 688 patients enrolled in 11 studies out of which 2 were randomized trials, Dockx et al. [27] concluded that counterpressure maneuvers might be effective for prevention of VVS, but with a low level of evidence. There is no evidence for effectiveness in patients above age 40 years. The most effective maneuver, and the most appropriate ages, remain to be determined.

Orthostatic training

Tilt training consists of maintaining upright posture either through repeated tilt testing or home training against a wall with feet 15–30 cm away from the wall for up to 30 min [28]. Tilt training and less well‐monitored stand training appeared to have benefits in open‐label observational studies, but not in properly randomized, controlled studies [29, 30]. Perhaps this is due to true inefficacy, or perhaps it is because it is difficult to persuade people to stand quietly doing nothing else for 30–60 min every day. Long term compliance is poor. More aggressive tilt training up to 6 times a week was associated with a higher non-compliance rate and no effectiveness in other randomized trials [29,30,31,32]. Thus, overall home orthostatic training is of little value in managing VVS.

Physical exercise

Takahagi et al. [33] reported a randomized, open‐label study that supervised physical exercise reduced syncope outcomes compared to a control group without any supervised exercise [33]. More recently Aghajani et al [34] reported a prospective, parallel arm, open label randomized clinical trial of closely monitored and encouraged exercise and stand training in patients with recurrent, moderate risk VVS. The results highly favored the intervention arm. The intervention arm subjects received the same instructions, and supervised, periodic, ongoing personal training in tilt training, and personal, supervised, periodic, ongoing moderate‐intensity physical exercise under the supervision of a physical medicine and rehabilitation specialist at a Cardiac Rehabilitation Center. Therefore, the intervention arm patients received four interventions in total: personalized instruction, ongoing tilt test training advice and encouragement, ongoing, moderate‐intensity physical therapy, and personalized training in an expert environment. At least two of these—those involving personalized interactions—are powerful factors in placebo [18] and other incremental interventions are lesser but still significant placebo factors.

Yoga

Two recent randomized open‐label studies hint that yoga programmes may be effective in preventing VVS [35, 36]. Both yoga studies were longitudinal, both included several poses, and one of them featured meditation, focused breathing, and Shavasana, the corpse pose. These suggest a powerful effect above the level of the brainstem, possibly as ways to trigger a beneficial placebo effect.

Pharmacological therapies

Up to 30% of VVS patients continue to suffer recurrent symptoms despite education, lifestyle modifications, and counterpressure maneuvers [8], particularly those with shorter prodromes. Several drugs targeting different aspects of the vasovagal reflex cascade show promising results in randomized studies (Table 3). There are no data regarding the effectiveness or safety of pharmacologic therapies in pregnant women [37]. The physiologic cascade leading to syncope is usually failure of venoconstriction and reduced preload, hypotension, and terminal bradycardia and, in some patients, arteriolar vasodilation. VVS is due to inappropriate sympathetic withdrawal causing vasodepression, reflex cardioinhibitory bradycardia, or a combination of both, leading to marked hypotension.

Table 3 Medical treatments for troublesome vasovagal syncope
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Fludrocortisone

The rationale for the use of the mineralocorticoid fludrocortisone was that it would cause fluid retention and maintain cardiac preload. The Prevention of Syncope Trial II (POST2) [38] was a randomized, placebo-controlled, double-blind trial that assessed the effects of fludrocortisone in VVS over a 1-year treatment period. It enrolled 210 patients with VVS who otherwise had normal blood pressure and randomized them to 0.1–0.2 mg of fludrocortisone. In a multivariable model, fludrocortisone significantly reduced the likelihood of syncope (Hazard Ratio 0.63; 95% CI 0.42–0.94; p = 0.024). When the analysis was restricted to outcomes after 2 weeks of dose stabilization, there was a significant benefit due to fludrocortisone (Hazard Ratio 0.62; 95% CI 0.40–0.95; p = 0.019). In patients who received the target dose of 0.2 mg daily there was a highly significant 49% relative risk reduction. Therefore, fludrocortisone 0.2 mg daily is a reasonable first line medical therapy, and should be avoided in patients with hypertension, heart failure, or fluid overload.

Midodrine

The rationale for the use of midodrine is that it is a prodrug whose active metabolite is a peripherally acting alpha agonist. This should reduce venous pooling and peripheral vasodilation, with the intent of maintaining preload and blood pressure. The Prevention of Syncope Trial IV [39] was a randomized, placebo-controlled, double-blind trial that assessed the effects of midodrine in VVS over a 1-year treatment period. It enrolled 133 patients who had had a median of 6 syncope episodes in the prior year (median age, 32 years; 73% female). They were randomized to placebo or midodrine 5 mg orally every 4 h, three times daily, with forced dose-adjustment in the first 2 weeks. Midodrine was associated with a significantly reduced relative risk of 0.69 (95% CI 0.49–0.97; p = 0.035). The number needed to prevent a person fainting over 1 year was 5.3. After allowing for dose adjustment in the first 2 weeks, the hazard ratio for syncope recurrence in the midodrine arm fell to 0.60 (95% CI 0.41–0.90; p = 0.013). A subsequent meta-analysis found a reduced relative risk with midodrine of 0.71 (95% CI 0.53–0.95), p = 0.02 [40]. The effect sizes were much larger in unblinded randomized studies and in studies with tilt test outcomes, emphasizing the importance of rigorous trial design and conduct.

Therefore, midodrine 2.5–10 mg three times daily is a reasonable first line medical therapy, and should be avoided in patients with hypertension, heart failure, or liver disease.

Beta blockers

Nonrandomized trials of beta blockers showed conflicting data for efficacy; several randomized controlled trials later confirmed lack of benefit [41,42,43]. A small study on atenolol showed positive results [44]. Beta blockers have a limited role, if any, in the prevention of VVS.

Serotonin-specific reuptake inhibitors

The rationale for the study of serotonin-specific reuptake inhibitors is the known role of at least 2 serotonin receptors in regulating blood pressure, considerable early, small, uncontrolled acute studies that were positive. The potential effects of serotonin are confounded by the ability of the SSRI clomipramine to acutely induce VVS [45], and possible remodeling over time of the neurophysiologic pathways. Nonetheless 3 small randomized controlled studies were positive [46,47,48], and SSRI agents could be considered. The difficulty clinicians face is the high numbers of seemingly depressed patients who are taking these medications, and not knowing if they are pro-syncopal or anti-syncopal.

Norepinephrine transport inhibitors

Norepinephrine transporter (NET) inhibition shows promise as a treatment option. Norepinephrine that is released at synapses is either cleared by diffusion or reuptake through active transport into terminals by the presynaptic NET, which recaptures as much as 90% of released norepinephrine [49]. This decreases intrasynaptic norepinephrine, effectively decreasing sympathetic nervous system tone. VVS patients might benefit from pharmacological NET inhibitors, which would restore sympathetic tone. Both reboxetine, a clinical antidepressant in Europe, and sibutramine, an anorexigenic, are highly specific NET inhibitors, and both prevent syncope induced by tilt table testing [50]. Sibutramine appeared to suppress VVS in an open-label case series of severely symptomatic patients [51].

We reported a randomized, placebo-controlled trial of the efficacy of atomoxetine in preventing VVS on tilt tests [52]. Significantly fewer VVS patients fainted with atomoxetine than with placebo. Atomoxetine, a selective NET inhibitor available in North America, was found to inhibit tilt test-induced syncope, terminal bradycardia, and hypotension in VVS patients [52]. A recent meta-analysis of NET inhibitors for syncope showed a consistent and highly significant decrease in syncope with NET inhibition during tilt tests [50].

There is currently no strong evidence that NET inhibition prevents clinical VVS in the community. However, NET inhibition is promising, in particular because it seems to be safe in patients with hypertension, which occurs in many older patients with VVS.

Invasive therapies

Permanent pacemakers

This has been an active field of investigation for 25 years, generally featuring industry-funded studies. Early observational and open label randomized studies were uniformly positive, but the negative results of the more tightly controlled and conducted VPS II [53] and SYNPACE [54] trials cast doubt on the treatment. Most of the early positive results appeared to be due to a placebo effect [55].

More recently the ISSUE-3 trial [56] was the first double blind RCT to show a significant 57% relative risk reduction in syncope recurrence with pacing for VVS. The understanding of this study has been complicated by an ISSUE-3 substudy that found that found that preimplant positive tilt tests, including those with asystole, predicted a complete lack of benefit from pacing [57]. These results were replicated by the Syncope Unit Project 2 investigators registry [58]. After 3 year follow up, patients receiving PPM and a negative tilt test had a 5% recurrence versus 23% recurrence in patients with a positive tilt test response.

Two recent clinical trials of closed loop stimulation (CLS) have produced fascinating results (Table 3). CLS is a pacing algorithm utilizing a contractility sensor aiming to deliver early pacing therapy in the reflex cascade, ahead of vasodilation and cardio inhibition. Both the double-blind SPAIN trial [59] and the double-blind BIOSYNC [60] trial reported highly significant benefit from CLS pacing. In the SPAIN study CLS pacing significantly reduced the syncope burden by more than 50% with 8.7% of patients fainting while in CLS pacing mode compared to 46% while in sham pacing [59]. The BIOSYNC trial [60] was terminated early due to superiority of CLS pacing over no pacing with a hazard ratio of 0.23 (95% CI 0.11–0.47), p = 0.00005, and a number needed to treat of 2.2. A meta-analysis of CLS trials [61] (excluding the recent BIOSYNC trial) confirmed the benefit of this pacing mode in patients with positive tilt test. In patients with confirmed cardioinhibitory response on tilt testing, a DDD–CLS device appears useful (Table 3).

Cardioneuroablation

The rationale for the study of endocardial ablation to cure VVS is involvement of epicardial autonomic ganglia in the vasovagal reflex. In the past decade, catheter-based modulation of the intrinsic cardiac autonomic nervous system, or cardioneuroablation (CNA), has emerged as an innovative therapy for VVS [62]. Most of the autonomic neurons involved with the cardiac autonomic nervous system are in epicardial ganglionated plexi. CNA is an invasive procedure during which the locations of these ganglionated plexi are mapped and subsequently ablated with radiofrequency ablation or cryoablation [62]. Well-designed randomized clinical trials are lacking. Previous studies have used varied methodologies, anatomic targets, acute procedural success criteria, and clinical outcomes [62]. Although all studies report high success rates, none has been adequately controlled or blinded (Table 3).

It is very important when considering both these invasive treatments to remember that VVS is not associated with mortality, is associated with moderate to severe injuries in only 4% of faints and about 1% of patients, and that VVS usually enters remission. The enthusiasm for cardioneuroablation generally arises in cardiologists who perform atrial fibrillation ablations [63], and not in physicians with experience, expertise, and engagement in providing care to patients with syncope. Physicians might use these therapies in many patients, but should they?

Future directions for VVS management

The phenotypic variability of VVS dictates careful evaluation and in the era of precision medicine-warrants targeted management. It seems likely that VVS has a strong genetic predisposition. Humans are the only animals known to faint [64]. Furthermore, gender and age susceptibility, reproducibility of triggering factors, reproducibility of both inducibility and non-inducibility all point to genetic origin to VVS. This is further supported by pedigree analysis showing strong evidence to familial clustering of VVS [2]. In a kindred candidate gene analysis catecholamine methyltransferase, the serotonin transporter, and a serotonin receptor gene 5HT1A were significantly associated with the vasovagal phenotype [65]. Genome-wide association studies have reported several other linkage variants of uncertain physiologic mechanisms [66,67,68]. Perhaps further genetic studies will provide more precise therapeutic targets.

Final words

Most patients with VVS have a reasonably normal disease-related quality of life with education, reassurance, and minor lifestyle interventions. Medical and drug history should include comorbidities requiring vasoactive drug therapy; reasonably adjusting such medications may reduce the burden of VVS. Counter pressure maneuvers in physically capable patients are a valuable tool in delaying and preventing spells.

For the few patients who require more than this, fludrocortisone and midodrine have good evidence for effectiveness, but should be avoided in patients with hypertension or heart failure. SSRIs might have a limited role in these patients, and NET inhibitors are under investigation. Pacing therapy should be reserved for patients older than 40 years with documentation of > 3 s pauses either on tilt tests or implantable loop recorders, preferably with a CLS-capable pacemaker. Ablation should be avoided except in clinical studies.