CONTEMPORARY REVIEW Evidence-based treatment for vasovagal syncope Vikas Kuriachan, MD, Robert S. Sheldon, MD, PhD, Michael Platonov, MD From the Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada. Only a minority of patients with vasovagal syncope require treatment, and most can be managed conservatively. Patients should be encouraged to liberalize their fluid and salt intake, unless they have contraindications such as hypertension. All patients should be taught physical counterpressure maneuvers. Midodrine is the first-line therapy for patients having frequent presyncope or syncope or for those with brief or no prodromes. The routine use of beta-blockers, serotonin-specific reuptake inhibitors, fludrocortisone, and pacemakers is discouraged. Whether loop recorders can be used to target treatment is under investigation, as is fludrocortisone. Introduction ification through physical training, physical maneuvers, medication, and even permanent pacemaker implantation. Surprisingly, there has not been a focused review of therapies with structured recommendations, although overviews of therapy have appeared in more general reviews. Here we review current treatments followed by a suggested management strategy. Each recommendation is presented with the treatment effect and level of evidence. Treatment effect is rated as probably helpful, debatable, or probably unhelpful. The evidence is summarized as good, moderate, or poor. Good evidence is derived from multiple randomized trials or meta-analyses; moderate evidence is derived from a single randomized trial or multiple nonrandomized trials; and poor evidence is simply a consensus opinion. The recommendations are summarized in Table 1. Important trials that appeared after 2003 are summarized in Table 2. Vasovagal syncope frustrates patients and clinicians alike with its paucity of effective treatments. About 37% of people faint at least once in their lives.1,2 Usually beginning in adolescence or early adulthood, the predilection to fainting persists for decades.3 Syncope is only one of several causes of transient loss of consciousness. A useful working definition is a transient, self-limited loss of consciousness that usually leads to falling, with a relatively rapid onset and a spontaneous, complete, and relatively rapid recovery. Vasovagal syncope is by far the most common cause of syncope in the community and the dominant cause in emergency wards.4 It is due to a variable combination of reflex bradycardia and hypotension, triggered by prolonged sitting or standing; exposure to pain, blood, or medical procedures; heavy exercise; or getting up and moving abruptly.5 Even in the same patient, the triggers and presentation vary from spell to spell. The hypotension may be due to a reduction in peripheral sympathetic neural outflow, leading to venous pooling and vasodepression. The central neurophysiology is unknown. Syncope is usually recurrent. In the community, the median number of faints is about two, with a much higher symptom burden in the clinical population.1,3,4 Many patients injure themselves, and recurrent syncope is associated with significantly impaired quality of life.5 (Sheldon et al5 contains reports published before 2004, which therefore precede the articles covered in this review.) Given this reduced quality of life, effective therapies are necessary. The treatments considered to date range from dietary modSupported in part by grant no. 73–1976 from the Canadian Institutes for Health Research, Ottawa, Ontario, Canada. Address reprint requests and correspondence: Dr. R. Sheldon, Cardiovascular Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. E-mail address: [email protected]. (Received November 3, 2007; accepted August 16, 2008.) (Heart Rhythm 2008;5:1609 –1614) © 2008 Heart Rhythm Society. All rights reserved. Education and lifestyle interventions Salt and fluid Many patients with syncope are encouraged to increase their salt and fluid intake, although the evidence that this treatment is effective is weak. Most patients with a positive tilt test convert to a negative response on a subsequent test after receiving an intravenous volume load, and plasma and blood volumes and orthostatic tolerance all improve with dietary salt supplementation.5 The usual reported dose of salt tablets is 6 –9 g (100 –150 mmol) per day. Salt supplementation should be avoided in patients with hypertension, renal disease, or cardiac dysfunction. Recommendation: In the absence of contraindications, frequently symptomatic patients should liberalize their salt and fluid intake. Probably helpful, moderate evidence. Exercise training Although exercise acutely increases blood volume,5 there is limited evidence supporting the use of exercise training to prevent syncope. One study subjected 14 patients with syn- 1547-5271/$ -see front matter © 2008 Heart Rhythm Society. All rights reserved. doi:10.1016/j.hrthm.2008.08.023 1610 Heart Rhythm, Vol 5, No 11, November 2008 Table 1 Suggested levels of recommendations with their treatment effect and level of evidence Recommendation: In the absence of contraindications, patients should follow relevant national guidelines regarding physical exercise. Debatable effect, weak evidence. Treatment Treatment effect Evidence Lifestyle changes: Increase salt and fluid Probably helpful Moderate evidence Weak evidence Good evidence Physical exercise Physical counterpressure Orthostatic training: Tilt training Debatable effect Probably helpful Debatable effect Moderate evidence Home orthostatic training Probably unhelpful Good evidence Pharmacologic therapy: Beta-blockers Probably unhelpful Good evidence SSRI antidepressants Debatable effect Moderate evidence Midodrine Probably helpful Good evidence Fludrocortisone Debatable effect Weak evidence Cardiac pacemakers: Cardiac pacemakers: Probably unhelpful Good evidence routine use Debatable effect Weak evidence Cardiac pacemakers: selected use in refractory cases with asystole cope to a regimen of 12 minutes of daily progressive exercise training.5 After this, their blood volume increased 3.9%, and orthostatic tolerance to lower body negative pressure increased by 5 minutes. A recent, very underpowered randomized study did not detect a reduction in the likelihood of syncope in exercised patients.6 Table 2 Physical counterpressure maneuvers Considerable evidence supports the use of physical counterpressure pressure maneuvers (PCMs). During PCMs, the presyncopal patient does isometric contractions of either the legs (by leg crossing) or the arms and hands (by pulling apart gripped hands) or squats. These rely on a prodrome long enough to allow the technique to prevent the progression of presyncope to syncope and usually to prevent syncope during tilt tests. PCM was initially thought to work by reversing the decline in total peripheral resistance that attends vasovagal response. However, Van Dijk et al7,8 showed that leg crossing increased cardiac output 9% and arterial blood pressure 3% while reducing peripheral resistance. Adding leg tension further increased systolic blood pressure and cardiac output 10% and 8%, respectively, and peripheral resistance dropped even further. PCMs moved quickly into the clinical arena after two positive studies of PCMs during tilt testing and good outcomes in follow-up.9 The Physical Counterpressure Manoeuvres Trial (PC Trial) was a randomized controlled trial comparing conventional therapy (fluid and salt intake, counselling, avoidance) against conventional therapy augmented by one of three maneuvers in 208 patients with vasovagal syncope.9 After 18 months of follow-up, both groups experienced a similar number of presyncopal episodes, yet PCMs provided a significant relative risk reduction of 36% of patients who Summary results of major randomized clinical trials of treatment for vasovagal syncope Treatment Senior author 9 Sites, n Subjects, n Mean age Clinical outcome Effect 15 223 39 Syncope recurrence 51% 32% 60% 59% 56% 37% 47% 42% control, PCM controls vs. training control, training control, training 36% 36% 41% 51% 22% 80% 22% 36% 55% controls, metoprolol controls, propranolol, fluoxetine controls, midodrine controls, fludrocortisone 40% 31% 38% 50% controls, pacing controls, pacemakers Physical counterpressure Van Dijk Home orthostatic Foglia-Manzillo13 8 68 40 Positive tilt test Home orthostatic Duygu14 1 82 41 Syncope recurrence Home orthostatic On15 1 42 39 Metoprolol Sheldon16 14 208 42 Syncope or presyncope recurrence Syncope recurrence Fluoxetine, propranolol Theodorakis17 1 96 42 Midodrine Qingyou18 1 26 12 Fludrocortisone Salim19 1 33 14 Pacemakers Connolly21 15 100 49 Syncope or presyncope recurrence Syncope recurrence Pacemakers Raviele22 7 29 53 Syncope recurrence Only publications after 2003 are cited. NS ⫽ not stated. Syncope or presyncope recurrence Syncope recurrence P .005 NS .1 .82 .99 ⬍.05 .023 ⬍.04 .14 NS Kuriachan et al Treatment of Vasovagal Syncope fainted. Fifty-six patients on conventional treatment and 31 patients in the PCM group fainted at least once. However, 35% of patients had insufficient prodromes to perform the techniques. Finally, this was an open-label study, and the placebo effect size is unknown. PCMs can be adopted easily, without cost or side effects. Their physiologic rationale is well understood and the results of acute and long-term follow-up have been encouraging. In patients with presyncopal prodromes, these techniques should form the evidence-based core of the early, conservative care of vasovagal syncope. Recommendation: All patients should be taught physical counterpressure maneuvers. Probably helpful, good evidence. Tilt test training The imperfect reproducibility of positive tilt testing prompted speculation that this might be due to a training effect. The credit for initiating this avenue goes mainly to the group of Ector and colleagues.10 Two methods of orthostatic training are in use. Some groups have patients return daily to the clinic (or remain in the hospital) for prolonged passive tilt tests culminating in syncope and continuing until the tilt tests remain negative. They are then encouraged to stand quietly against a wall for 30 – 60 minutes daily. Other groups skip the tilt training and progress directly to prolonged quiet standing. The Ector group10 first reported success, tilting 42 patients with syncope in-hospital until they stopped having a vasovagal response. Most converted in two to three sessions, although some required up to eight sessions. Abe et al11 trained 24 patients with medically refractory syncope in home exercises, leaning against a wall with feet away from the base. After 1 month, the entire cohort stopped having vasovagal responses to tilt testing. They eventually demonstrated 100% effectiveness over 4 weeks.11 Finally, Ector et al10 tilted 202 patients until two consecutive tilts were negative and noted excellent longterm outcomes in patients who were compliant. Other acute studies are less encouraging. Kinay et al12 performed repetitive tilt training in 32 patients and found that although 20 responded by the second session, three were resistant even after eight attempts.12 Others relapsed quickly. Tilt training advocates maintain that there is a sustained response. Reybrouck et al5 reported that the 42 patients who had been trained in-hospital had an 82% freedom from syncope over 43 months, provided that home orthostatic training was performed assiduously. Those who stopped training relapsed. Similarly, 81% of the Kinay et al12 cohort was symptom-free at 12 months. The small populations studied by Abe et al11 were also asymptomatic after about 10 months. These reports were all open-label, uncontrolled, cohort studies. Open-label controlled studies of home training are not encouraging. An early study5 subjected adolescents to tilt training, with a nonrandomized control group. The tilttrained group had fewer syncopal spells during long-term 1611 follow-up, provided that they continued training at home. In contrast, Foglia-Manzillo et al13 randomized 68 patients with syncope and two positive tilt tests to a daily 30-minute self-training regimen. After 3 weeks, 60% of patients in both groups had positive tilt tests. These patients were then encouraged to continue with self-training over the subsequent year, but of the 62, only five actually did so, with 28% having recurrent syncope. Two recent randomized openlabel studies by Dugyu et al14 and On et al15 also failed to detect a benefit from orthostatic self-training at home. There is no high-level evidence of the effectiveness of orthostatic training, no obvious physiologic rationale, and three small negative randomized controlled trials. Whether these results are due to poor compliance or inefficacious therapy is unclear. Due to these factors, orthostatic training cannot be recommended yet for routine use. Recommendation: Frequently symptomatic patients with a positive tilt test might undergo tilt table training. Debatable effect, moderate evidence. Self-administered orthostatic training with prolonged standing without tilt training should not be used. Probably unhelpful, good evidence. Pharmacological therapy Beta-adrenoceptor blockers Beta-blockers were used for a variety of reasons and underwent at least 19 controlled trials of their effect on tilt test outcome. A large majority of patients on beta-blockers have negative tilt tests, particularly if the tilt tests include an isoproterenol infusion. Early nonrandomized studies provided conflicting information about whether beta-blockade prevents syncope, with some reporting marked reductions in syncope in groups that received beta-blockers and others reporting no benefit at all. There have been five randomized clinical trials of the efficacy or effectiveness of ␤-adrenergic blockers for the prevention of syncope.5 On the whole, they were negative. One small, early study of atenolol was positive, and one did report a remarkable 80%–90% reduction in all measures of presyncope and syncope in all three treatment arms (placebo, propranolol, and nadolol), with no significant difference among the three arms. We reported the results of the first Prevention of Syncope Trial in 2006.16 It was a randomized, placebo-controlled, double-blind trial that assessed the effects of metoprolol in vasovagal syncope over a 1-year treatment period. A total of 208 patients were randomized to metoprolol or placebo. Metoprolol provided no benefit, with nearly identical outcome rates in both study arms (Figure 1). Recommendation: Unselected, frequently symptomatic patients should not receive beta-adrenoceptor blockers as first-line therapy. Probably unhelpful, good evidence. Selective serotonin reuptake inhibitors (SSRIs) Serotonin plays important roles in the regulation of heart rate and blood pressure. This has led to speculation that fluctuation in central serotonin levels may contribute to vasovagal syncope. Indeed, a randomized, double blind, 1612 Figure 1 Probability of remaining free of syncope in the total population in each treatment arm of metoprolol or placebo in an intent-to-treat analysis (bottom panel) and in an on-treatment strategy analysis (top panel) in the Prevention of Syncope Trial.20 placebo-controlled study5 of 68 consecutive patients who had not responded to other treatments was reported to be positive in 1999. Disappointingly, a recent second randomized, placebo-controlled study of 96 patients found fluoxetine, propranolol, and placebo to have equal effects, although a post hoc on-treatment analysis found an improved quality of life and decreased syncope and presyncope with fluoxetine.17 Therefore, the evidence for the use of SSRIs with vasovagal syncope is mixed at best. The SSRI drugs should not be used early in the treatment of vasovagal syncope. Recommendation: Frequently symptomatic patients might be prescribed serotonin-specific reuptake inhibitors. Debatable effect, moderate evidence. Midodrine This drug is a peripherally active alpha-agonist, as is its metabolite. It is used is to ameliorate the reduction in peripheral sympathetic neural outflow that is responsible for venous pooling and vasodepression that are central to vasovagal syncope. Its inability to cross the blood-brain barrier and lack of gastrointestinal side effects are useful features. An early randomized crossover placebo-controlled study of a small number of highly symptomatic patients reported a marked reduction in symptoms, and also in the Heart Rhythm, Vol 5, No 11, November 2008 likelihood of a positive tilt test.5 Kaufmann et al5 confirmed these results when they reported that midodrine obviated the postural hypotension induced by head-up tilt in patients with vasovagal syncope.5 An early, randomized, controlled, open-label trial of midodrine, in which the investigators titrated midodrine from 5 to 15 mg three times a day over 3 weeks in an effort to render tilt tests negative, was also positive.5 Finally, Qingyou et al18 studied 26 children in a randomized, open-label trial. The children had experienced at least three vasovagal episodes per year. Midodrine was titrated from 1.25 to 2.5 mg twice a day commensurate with tilt test results in comparison with conservative diet and posture training. Clinical recurrence rates over 10 months were 20% and 80% in the midodrine and control groups, respectively. Midodrine has demonstrated short- and medium-term therapeutic success while being well tolerated in both adult and pediatric populations. The drug is reasonably well tolerated, with side effects including supine hypertension, nausea, scalp paresthesias, piloerection, and rash. These are dose-related and easily reversible. It should not be used in patients with hypertension or heart failure. It also requires careful attention to both dosing and interdose intervals and is usually best managed in specialty clinics. More robust trial designs with greater patient numbers are required to improve the strength of evidence behind its recommendation. Recommendation: In the absence of contraindications, frequently symptomatic patients should be prescribed midodrine. Probably helpful, good evidence. Fludrocortisone Fludrocortisone is a corticosteroid with mainly mineralocorticoid activity resulting in sodium and water retention and potassium excretion, which would increase blood volume. The use of fludrocortisone in vasovagal syncope has been assessed in pediatric studies. Two open-label uncontrolled studies reported that children had far less syncope and presyncope while taking fludrocortisone.5 In contrast, the randomized, double-blinded, placebo-controlled study by Salim and Di Sessa19 found more symptoms in the fludrocortisone group than in children treated with placebo. There have been no controlled studies of fludrocortisone in adults with vasovagal syncope, and the utility of fludrocortisone in the prevention of syncope remains unclear. To assess its effectiveness, we are conducting the second Prevention of Syncope Trial (POST II), a multinational, randomized, controlled clinical trial.20 Patients with recurrent vasovagal syncope are receiving either fludrocortisone or placebo for 1 year; the primary outcome is the proportion of patients with at least one syncope recurrence. Enrollment is underway in both North and South America, and the trial should conclude in 2010. Recommendation: In the absence of contraindications, frequently symptomatic patients might be prescribed fludrocortisone. Debatable effect, weak evidence. Kuriachan et al Treatment of Vasovagal Syncope Figure 2 The time to first recurrence of syncope for the patients randomized to the paced group (DDD) and to the nonpaced group (ODO) in the Second Vasovagal Syncope Pacemaker Study.21 The relative risk reduction was an insignificant (30%, P ⫽ .14). Reprinted with permission from Pacemaker Therapy for Prevention of Syncope in Patients With Recurrent Severe Vasovagal Syncope: Second Vasovagal Pacemaker Study (VPS II): A Randomized Trial, Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KE, Wilkoff BL, Morillo C, Gent M. J Am Med Assoc. 2003;289:2224 –2229. Copyright © 2003 American Medical Association. Permanent pacemakers Initial studies reported a benefit from pacing in patients with vasovagal syncope. Three observational and three openlabel randomized studies showed impressive and highly significant benefits of 80%– 87% relative risk reduction with pacing.5 However, the second Vasovagal Pacemaker Study II (VPS II), a double blind, placebo-controlled, multicenter, prospective trial randomly allocated 100 patients with a history of recurrent vasovagal syncope and a positive tilt table test to dual-chamber pacing or sensing only. Over a 6-month followup, no significant benefit was seen21 (Figure 2). The Vasovagal Syncope and Pacing trial (SYNPACE), a similar study, randomized 29 patients with recurrent syncope and a positive tilt table test to DDD or OOO mode.22 This study was terminated early because of the first interim analysis and the results of VPS II. No significant difference was seen between the two groups. Hence, the double-blind studies did not show the benefit that was seen earlier in the open-label and observational studies. A recent meta-analysis by Sud et al23 concluded that blinded trials do not show a benefit with pacing for vasovagal syncope, even when analyzed for patients with marked cardioinhibitory response on tilt table testing. In unblinded trials, there seems to be a benefit for pacing, and this might be due to an expectation effect from the patients and the medical staff.23 One unresolved question is whether the subset of patients with vasovagal syncope who have asystolic pauses during syncope might benefit from pacing. The second International Study on Syncope of Uncertain Etiology (ISSUE 2) used implantable loop recorders (ILRs) to test whether therapy targeted to the findings of the recorders could prevent syncope. ISSUE 2 implanted ILRs in 417 patients with recurrent syncope and followed them until their first syncope or for a maximum of 2 years.24 Further treatment was 1613 assigned based on the electrocardiogram findings during the episode. This resulted in 57 patients receiving a pacemaker for asystole. The patients who received pacing had a 1-year recurrence rate of 10%, compared with 41% in the 50 patients who did not receive a specific treatment and a 90% relative risk reduction for syncope. Although highly impressive, the results were very similar to those of the three earlier unblinded, studies in which patients either received a pacemaker or did not. This did not resolve the question of the efficacy of targeted therapy, and there is considerable debate about how to interpret the results. Accordingly, the investigators are now conducting ISSUE 3, a multicenter, placebo-controlled, prospective, double-blind, randomized study of 710 patients.25 This study will implant ILRs in patients with frequently recurrent, suspected vasovagal syncope. Patients with asystolic pauses will have a pacemaker implanted with double-blinded randomization to active pacing or sensing only, that is, with a VPS 2 design. This study is underway. Recommendation: Pacemakers should not be used routinely to treat vasovagal syncope. Probably unhelpful, good evidence. Drug-resistant, highly symptomatic patients with documented asystole during syncope might be prescribed dual-chamber pacing with rate-drop sensing. Debatable effect, weak evidence. The treatment cascade All patients should be encouraged to liberalize their fluid and salt intake, unless they have contraindications such as hypertension. Helpful goals include about 2 extra teaspoons of salt per day and oral fluids such that their urine is very pale. All patients with prodromal symptoms should be taught secondary prevention maneuvers such as leg crossing, isometric exercise, and squatting. For many patients, particularly those with infrequent symptoms, these will suffice. However, for patients having troublesome presyncope or syncope occurring daily to weekly or for those with brief or no prodromes it is worth trying midodrine, starting at 5 mg 3 times daily during waking hours. The first dose should be taken when the patient wakes up, with subsequent doses 4 hours apart. Usually the dose level and interval will require modification. With current knowledge, the routine use of beta-blockers, serotonin-specific reuptake inhibitors, fludrocortisone, and pacemakers is discouraged. Whether loop recorders can be used to target treatment is a matter of investigation. Two further points. Given the widespread interest in useful treatments for vasovagal syncope, and progress both within the review period and before it, we suggest that a formal consensus document in the risk stratification and treatment of vasovagal syncope is overdue. Finally, only randomized trials will provide evidence of effective treatments, and a consensus commitment to conducting these difficult studies is necessary. References 1. Serletis A, Rose S, Sheldon AG, et al. Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J 2006;27:1965–1970. 1614 2. Ganzeboom KS, Colman N, Reitsma JB, et al. Prevalence and triggers of syncope in medical students. Am J Cardiol 2003;91:1006 –1008. 3. Sheldon RS, Sheldon AG, Connolly SJ, et al and Investigators of the Syncope Symptom Study and the Prevention of Syncope Trial. Age of first faint in patients with vasovagal syncope. J Cardiovasc Electrophysiol 2006;17:49 –54. 4. Van Dijk N, Boer KR, Colman N, et al. 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The expectation effect and cardiac pacing for refractory vasovagal syncope. Am J Med 2007;120:54 – 62. 24. Brignole M, Sutton R, Menozzi C, et al for the International Study on Syncope of Uncertain Etiology 2 (ISSUE 2) Group. Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J 2006;27:1085–1092. 25. Brignole M. International study on syncope of uncertain aetiology 3 (ISSUE 3): pacemaker therapy for patients with asystolic neurally-mediated syncope: rationale and study design. Europace 2007;9:25–30.