Overview of the Contribution of Recent Clinical Trials to Advancement of Syncope Management

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Overview of the Contribution of Recent Clinical Trials to Advancement of Syncope Management Angel Moya⁎, Nuria Rivas, Jordi Perez-Rodon Unitat d'Arítmies, Cardiology Department, University Hospital Vall d'Hebron, Universitat Autónoma de Barcelona, 08035 Barcelona, Spain

A R T I C LE I N F O

AB ST R A C T

Keywords:

In this communication we review those trials that have contributed in recent years to

Syncope

improving our knowledge on the management (diagnosis and treatment) of syncope. In

Treatment

this regard, most recent trials focus on vasovagal syncope (VVS) and consequently these

Pacemaker

will be the focus of this manuscript. In essence, from a diagnostic perspective the ISSUE studies demonstrate the value of insertable loop recorders (ILR), while in terms of treatment, in the case of VVS current data strongly support use of non-pharmacologic treatment as a primary approach. There is no clear evidence supporting pharmacologic treatment with the possible exception of midodrine. Further, the most recent ISSUE trials suggest that in older very symptomatic patients with VVS in whom an asystole has been documented during spontaneous episode or possibly after ATP administration, implantation of a permanent pacemaker (PPM) can be effective. Which pacing or programming mode will be the more beneficial has not been completely clarified. Management of other forms of neurally-mediated syncope (e.g., carotid sinus syndrome) or other causes of syncope has not been addressed by clinical trials. In those cases, direction is provided by older evidence, the vast majority of which is based on observational reports or small nonrandomized patient series. © 2013 Elsevier Inc. All rights reserved.

Syncope has many possible etiologies.1 The diagnostic process, aimed at defining the specific cause(s) of syncope in an individual patient is not always easy; it includes an initial evaluation, with clinical history, physical examination and ECG, as well as risk stratification based on available clinical information.1–3 Other contributions to this issue address specific diagnostic techniques and their role in assessing the basis of syncope when the initial evaluation is non-diagnostic. Treatment of patients with syncope should be aimed at the underlying cause. When the cause and the mechanism have

been clearly identified, the selection of treatment is usually relatively straightforward (e.g., if syncope is attributed to a documented A-V block due to a disease of specific conduction system, PPM implantation is effective). However there are many situations in which the optimal treatment is not clearly established, either because the mechanism is not completely clear or because many competitive mechanisms can be playing a role. In addition the effectiveness of many of the therapeutic options has not been fully demonstrated. In this communication we analyze those recent clinical trials addressing the treatment of patients with syncope, with

Statement of Conflict of Interest: see page 400. ⁎ Address reprint requests to Angel Moya, MD, PhD, FESC, Unitat d'Arítmies, Cardiology Department, University Hospital Vall d'Hebron, Universitat Autónoma de Barcelona, P Vall d'Hebrón 119–129, 08035 Barcelona, Spain. E-mail addresses: [email protected] (A. Moya), [email protected] (N. Rivas), [email protected] (J. Perez-Rodon). 0033-0620/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2012.11.007

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Abbreviations and Acronyms

397

special emphasis in the management of BB = β-Blockers patients with reflex syncope (RS), and paCPM = Counter-pressure therapeutic maneuvers tients with syncope in the setting of bifasECG = Electrocardiogram cicular block. The ICD = Implantable cardiac treatment of patients defibrillator with syncope due to documented cardiac ILR = Insertable loop recordable arrhythmias or secPPM = Permanent pacemaker ondary to structural or cardiovascular disTT = Tilt-testing ease has not been subTTR = Tilt-training ject to clinical trials and lies beyond the RS = Reflex syncope scope of this manuVVS = Vasovagal syncope script. In most of these instances, the practitioner is directed by older clinical observations, with few prospective clinical trials available to work from.1

during a period of time followed by long asymptomatic periods. Consequently, one must be cautious before implementing aggressive treatments. According to guidelines1 there are several different therapeutic strategies that have been proposed for treating patients with RS (Table 1). Physical counter-maneuvers and cardiac pacing are the principal therapies to have been subjected to prospective clinical trial, and are emphasized here. Midodrine has also been studied, but to a lesser degree.

Reflex syncope

Water ingestion

RS, and especially VVS, is the most common cause of syncope in the general population, with a particularly high incidence in young patients; the mortality prognosis is benign, but recurrences remain a concern as they adversely affect lifestyle, work capacity and susceptibility to physical injury. The majority of RS patients do not need specific treatment (carotid sinus syndrome may be an important exception) because they have only occasional episodes triggered by often readily identified circumstances, and preceded by prodromal symptoms. However, others have frequent recurrences, without any recognizable triggers and without prodromal symptoms; in such cases symptoms may severely disrupt quality of life and put patients at risk of injury. RS has two components, a vasodepressor response that induces vasodilatation with progressive hypotension, and a cardioinhibitory component that induces bradycardia or asystole. The timing, contribution and magnitude of these two components vary from one patient to another, and sometimes from one episode to another in the same patient. Furthermore most of these patients are young without any other co-morbidity, and syncope episodes tend to occur in clusters; in the latter patients, several recurrences may occur

In the case of recurrent syncope associated with orthostatic intolerance (e.g., certain forms of VVS, orthostatic syncope) several studies5–8 have shown that acute water ingestion (500 ml) increases peripheral resistance, raising arterial blood pressure and increasing tolerance to tilt testing (TT). These studies have been confined to TT, had a sequential or crossover design and included few patients. There are no data on long-term follow-up. As this measure is not harmful and does not imply increasing costs, it can be recommended in most patients.

Table 1 – Therapeutic strategies for treating patients with reflex syncope. Explanation of the diagnosis, provision of reassurance, and explanation of risk of recurrence Increase in ingestion of salt and water Isometric physical counter pressure maneuvers Drugs Cardiac pacing Tilt training

Explanation of the diagnosis, reassurance and explanation of the risk of recurrence Education and reassurance are the first level of treatment recommended in practice guidelines to be implemented in every patient with RS.1 There are no randomized studies addressing this strategy, but explaining to patients the underlying disease, in addition to being part of medical attention in all circumstances, can help patients to identify and avoid triggers, decrease fear and reassure him/her about the nature of their symptoms. Furthermore this strategy is without side effects and does not incur additional costs.4

Physical counter pressure maneuvers In 2001, two studies focusing on VVS showed that performing certain muscle tensing maneuvers during TT, either with leg crossing or arm tensing at the beginning of the development of the reflex response in patients with a previous positive test, avoided or at least delayed induction of syncope in the majority of cases.9,10 These counter-pressure therapeutic maneuvers (CPM) were applied to 29 patients with recurrent syncope and were followed for a 14 months period. Nineteen of these patients had 260 episodes of impending syncope, and applied the CPM in 98% of episodes, aborting syncope in 99.6% of the episodes.11 Trying to add clinical evidence to CPM, a multicenter controlled study was designed, in which 223 patients with recurrent VVS and recognizable prodromal symptoms were randomized to perform CPM, either arm tensing or leg crossing, or conventional treatment consisting of explanation of the underlying mechanisms of VVS and advice with regard to lifestyle modification (i.e. avoidance of triggers, lying down in case of symptoms, and increasing fluid and salt intake).12 With a mean follow-up of 14 months, the total number of syncope episodes was 142 in patients allocated to

398

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conventional treatment and 76 in those randomized to CPM with a recurrence of 56 (50.9%) and 31 (31.6%) respectively. To the best of our knowledge, this is the only controlled study that has assessed the efficacy of physical maneuvers for therapy in patients with VVS. The limitations of this form of treatment are that it can be only implemented in patients with prodromal symptoms, those strong enough to apply the CPM, and that there are still some patients who have recurrences despite performing the CPM.

Tilt training Ector et al.13 first proposed tilt-training (TTR) as a nonpharmacological treatment for patients with recurrent neurally mediated VVS. Initially, the procedure was carried out in hospital under medical supervision. Subsequently, TTR (now also known as ‘standing training’) was proposed as a therapy to be undertaken at home. In recent years several authors have performed randomized non-blinded trials of TTR with conflicting results.14–16 Two of these trials, that included 113 patients,14,16 did not show any beneficial effect in terms of either TTR outcomes or in recurrences at follow-up. However, there was a low compliance rate at midterm follow-up that could explain, at least partially, the lack of efficacy. More recently, Tan et al.17 published a blinded pilot study in 22 patients in which the control group performed a sham maneuver. In this pilot study patients allocated to the ‘true’ TTR treatment had fewer syncopal recurrences than those in the control group. Consequently, while it cannot be concluded that this maneuver is an effective option in unselected patients, it may be that it can be helpful in well motivated patients can be effective.

Drug therapy: reflex syncope Based on the physiopathological underlying mechanism of RS, several drugs have been proposed and tested for treating those patients. The most important of them are listed in Table 2. Scopolamine,18 disopyramide19 and clonidine20 were tested in observational trials, and none proved effective in preventing RS.

Fludrocortisone Fludrocortisone was less effective than placebo in a small randomized double-blind trial in children.21 On the other

hand, POST II trial, a multicenter, randomized and placebo controlled study of fludrocortisone in the prevention of neurally mediated syncope, is completed and suggested some benefit of the drug, but is not fully published and the ultimate conclusion remains unclear.22

β-Adrenergic blockers Several studies have analyzed the role of β-blockers (BB) in patients with recurrent reflex VVS and positive TT. The drugs tested were metoprolol, propranolol, nadolol, and atenolol. In one randomized study that included 56 patients, the recurrence rate was lower in patients who were on BB treatment compared with conventional treatment.23 However, in all other double-blind, controlled studies, encompassing a total of 288 patients, BB did not show any benefit.24–27 Overall it seems that there is no evidence to support a benefit of BB therapy in patients with recurrent VVS. On the other hand, in POST,26 a randomized trial that compared metoprolol with placebo, the authors predefined two different populations according to age (≤42 year old and > 42 year old). Whereas in the younger population there was no difference in the recurrence rate of syncope, in those > 42 year there was a non-significant trend to have less syncope recurrence in those treated with metoprolol.

α-Adrenergic drugs Two studies analyzed the effectiveness of acute intravenous or oral administration of etilefrine on TT in patients with previous positive test, with conflicting results.28,29 However in one long-term study examining effectiveness of oral etilefrine administration in syncope recurrences after a 1-year followup, there were no differences in the recurrence rate between etilefrine and placebo treated patients.30 Uncontrolled studies have suggested that oral administration of midodrine decreased syncope recurrences in patients with VVS.31–33 Furthermore 2 randomized studies, showed that midodrine, used as first line therapy in 61 adult patients34 or in 26 pediatric patients35 was effective in reducing syncope recurrence when compared to placebo and conventional therapeutic regimen, respectively. However, Romme et al., have recently analyzed, in a randomized cross-over trial, the role of midodrine in patients in whom non-pharmacologic treatment failed to prevent syncope recurrence. In this trial midodrine did not have any additional benefit when compared to placebo.36 Therefore, the evidence about the usefulness of midodrine in VVS is conflicting.

Serotonin reuptake inhibitors Table 2 – Drugs that have been assessed in controlled trials. β-Blockers Dysopiramide Clonidine Serotonin reuptake inhibitors Scopolamine Fludrocortisone α-Adrenergic

Etilefrine Midrodine

Two trials analyzed the role of serotonin reuptake inhibitors in patients with VVS and positive TT. Di Girolamo et al.37 randomized 68 patients to paroxetine hydrochloride or placebo; recurrences were reported in 17% of patients with paroxetine and 52.9% of those treated with placebo. In contrast, Theodorakis et al.38 conducted a controlled trial including 96 patients with VVS that were randomized to fluoxetine, propranolol and placebo, and at follow-up there were no differences between the three groups. Overall, there is no compelling evidence favoring a treatment benefit serotonin reuptake inhibitors of in VVS.

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Cardiac pacing

Syncope and bifascicular block

As RS has two consistent components, vasodilatation and cardioinhibition, several authors have tried to analyze if those patients with recurrent syncope and a predominant cardioinhibitory form can benefit from PPM. The first controlled studies were published between 1999 and 2003. Two studies compared PPM with no specific treatment39,40 whereas a third study compared PPM with BB (the latter, at that time, was considered to be an effective treatment).41 In all these studies patients were included if they had recurrent syncope with a positive TT and some evidence of a cardioinhibitory response during TT. In each case, patients allocated to the PPM arm had a significant reduction in syncope recurrence when compared with controls. In an attempt to eliminate a possible placebo effect of simply implanting a PPM, more recent studies were designed with similar selection criteria but in which a PPM was implanted in all eligible patients. Once a PPM was implanted, patients were randomized to PPM ON or OFF.42–44 Although the INVASY study42 showed that closed-loop stimulation pacing prevented cardioinhibitory VVS, in VPS II43 and SYNPACE44 syncope recurrence rate was the same irrespective of PPM being ON or OFF. These latter observations indicate that perhaps in previous studies there was a possible placebo effect after implanting PPM.45 However, it is important to emphasize that in all these studies, the response to TT was used for identifying those patients to be eligible for implanting PPM. This selection criterion is now recognized to have been an important limitation in terms of interpreting the findings. More recently, with the use of ILR, it has been observed that TT is not a reliable tool for detecting those patients who will have asystole during spontaneous syncope.46–48 Two recent controlled blinded trials that also have compared PPM ON and OFF in patients with syncope and asystole, either triggered with intravenous administration of adenosine 5′ triphosphate49 or documented by ILR during spontaneous syncope,50 have shown that those patients with the PPM ‘ON’ had a significant reduction of syncope recurrences. Table 3 summarizes the studies which have assessed the efficacy of PPM therapy in RS.

Table 3 – Inclusion criteria and mode of pacing in studies based on tilt-testing findings. Trial

399

Inclusion criteria Number of syncopes

TT response

VPS39 VASIS40

6 in all live 3 in 2 years

SYDIT41 VPS II43 SYNPACE44

3 in 2 years 6 in all live 6 in all live

INVASY42

2 in a year

HR <60, 70, 80 bpm HR <40 bpm or asystole >3 sec. HR <60 bpm HR × AP < 6000 HR <60 bpm or asystole >3 sec. Cardioinhibitory or mixed

Mode of Pacing in active arm

DDI DDR-RDR DDR-RDR DDR-RDR DDR-RDR DDDR-CLS

TT: Tilt Test, HR: Heart rate; AP: arterial pressure.

It is known that the most common cause of syncope in patients with bifascicular block is AV block.51 However other mechanisms can be the cause of syncope in these patients; in particular tachyarrhythmias (ventricular or supraventricular) or RS may be responsible.52 Some of these patients, by virtue of severe underlying structural heart disease, are at risk of sudden death.1,51 It is well known that syncope is associated with both increased mortality and appropriate ICD discharges in patients with structural heart disease and impaired left ventricular function.53 Therefore it is essential to assess the risk of sudden death and determine whether the implantation of an implantable cardiac defibrillator (ICD) is indicated.1 In scenarios in which severe structural disease is not present, treatment is controversial. Whereas some recommendations suggest that since the most common cause of syncope is AV block, a PPM should be implanted.54 Others suggest initiating a comprehensive diagnostic approach addressed to determine the cause of syncope, and thereafter establish a treatment according to the etiology.1 Recently an observational study of 323 patients with syncope, bundle branch block and normal left ventricular function55 employed a three-phase diagnostic strategy (initial evaluation, electrophysiological study and insertion of an ILR). In this series, the etiological diagnosis could be established in 267 (82.7%) patients. Although in most cases (202 patients) the cause syncope was a bradyarrhythmia, in some cases other etiologies, such as ventricular tachycardia, or RS, were diagnosed leading to specific treatment, including implantation of an ICD in 19 (5.8%). Currently there is an ongoing randomized trial of patients with normal ventricular function that will assess the optimal management strategy for this subset of patients: an empiric permanent PPM or prolonged monitoring with an ILR.56

Conclusion Recently, several controlled trials have tried to assess the appropriate management of syncope in a variety of conditions. Most effort has been directed at VVS. Older, generally nonrandomized studies have examined other forms of RS (e.g., Carotid sinus syndrome). However, for the most part all of these studies included relatively few patients, had important methodological differences, and often offered conflicting results. In the case of VVS, current data support initial use of nonpharmacologic treatment (i.e., CPM). There is no clear evidence favoring pharmacologic treatment. However, the most recent trials suggest that in very symptomatic patients in whom marked bradycardia or an asystole has been documented during spontaneous episode or after ATP administration, implantation of PPM can be effective. Studies examining other causes of syncope are less robust. Indications for an ICD in bifascicular block with diminished left ventricular function, or in similar patients with systolic dysfunction alone (as in SCD-Heft trial), are relatively strong. In other circumstances, clinical practice tends to rely on older observational reports incorporating small numbers of patients.

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Statement of Conflict of Interest Conflict of interest: Dr. Angel Moya, received some modest fees for lectures from Medtronic. The other authors have nothing to disclosure. REFERENCES

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