A systematic review of the risk of motor vehicle collision in patients with syncope

Journal Pre-proof A systematic review of the risk of motor vehicle collision in patients with syncope Justin N. Chee, PhD(c) MSc, Chris Simpson, MD FHRS FCCS, Robert S. Sheldon, MD PhD FHRS FCCS, Paul Dorian, MD FHRS, Jamie Dow, MD MBA, Juan Guzman, MD MSc, Satish R. Raj, MD MSCI FHRS, Roopinder K. Sandhu, MD MPH FHRS, Venkatesh Thiruganasambandamoorthy, MBBS MSc, Martin S. Green, MD, Andrew D. Krahn, MD FHRS FCCS, Sarah Plonka, BSc, Mark J. Rapoport, MD FRCPC

PII:

S0828-282X(20)30173-2

DOI:

https://doi.org/10.1016/j.cjca.2020.02.070

Reference:

CJCA 3623

To appear in:

Canadian Journal of Cardiology

Received Date: 23 February 2019 Revised Date:

28 January 2020

Accepted Date: 10 February 2020

Please cite this article as: Chee JN, Simpson C, Sheldon RS, Dorian P, Dow J, Guzman J, Raj SR, Sandhu RK, Thiruganasambandamoorthy V, Green MS, Krahn AD, Plonka S, Rapoport MJ, A systematic review of the risk of motor vehicle collision in patients with syncope Canadian Journal of Cardiology (2020), doi: https://doi.org/10.1016/j.cjca.2020.02.070. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.

A systematic review of the risk of motor vehicle collision in patients with syncope Short Title: Syncope and Motor Vehicle Collision Risk Justin N. Chee1,2,3 PhD(c) MSc, Chris Simpson4, MD FHRS FCCS, Robert S. Sheldon5, MD PhD FHRS FCCS, Paul Dorian2,6, MD FHRS, Jamie Dow7, MD MBA, Juan Guzman8, MD MSc, Satish R. Raj5, MD MSCI FHRS, Roopinder K. Sandhu9, MD MPH FHRS, Venkatesh Thiruganasambandamoorthy10, MBBS MSc, Martin S. Green11, MD, Andrew D. Krahn12, MD FHRS FCCS, Sarah Plonka3, BSc, Mark J. Rapoport1,2, MD FRCPC 1. Sunnybrook Health Sciences Centre, Department of Psychiatry, 2075 Bayview Avenue, Toronto, ON M4N 3M5; 2. University of Toronto, Faculty of Medicine, 1 King’s College Circle, Toronto, ON M5S 1A8; 3. Ministry of Transportation of Ontario, Safety Policy and Education Branch, 87 William Hearst Avenue, Toronto, ON M3M 0B4 4. Queen’s University and Kingston Health Sciences Centre, 76 Stuart St, Kingston, ON K7L 2V7; 5. Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, Health Research Innovation Centre (HRIC) 3280 Hospital Drive NW, Calgary, AB T2N 4Z6; 6. St. Michael's Hospital, 30 Bond St. Room 709F, Toronto, ON M5B 1W8; 7. Société de l’assurance automobile du Québec, 333 boulevard Jean-Lesage, C-4-12, case postale 19600, Québec, QC G1K 8J6; 8. McMaster University, Department of Medicine, Hamilton General Hospital, 237 Barton St. East Hamilton, ON L8L2X2; 9. University of Alberta, Division of Cardiology, 2C2 Walter C MacKenzie Health Sciences Centre, 8440 112 St. NW, Edmonton, AB T6G 2R7; 10. Department of Emergency Medicine, University of Ottawa; The Ottawa Hospital Research Institute, F6, 1053 Carling Avenue, Ottawa, ON K1Y 4E9; 11. University of Ottawa, Division of Cardiology, H-1285, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7; 12. Heart Rhythm Vancouver, Division of Cardiology, Department of Medicine, University of British Columbia, Gordon & Leslie Diamond Health Care Ctr., 2775 Laurel Street, 9th Floor, Vancouver, BC V5Z 1M9; Corresponding Author (with Address for Reprints): Justin Chee, MSc, HonBSc Sunnybrook Research Institute, Clinical Evaluative Sciences Room F111, 2075 Bayview Avenue, Toronto, ON, M4N 3M5 T: 1-416-480-6100, Ext. 3095; F: 416-480-5318; E: [email protected]

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6,984 words

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A systematic review of the risk of motor vehicle collision in patients with syncope

ABSTRACT (Maximum word limit: 250 words; Current abstract word count: 236 words)

BACKGROUND Drivers at risk of sudden incapacitation from syncope pose a potential threat to themselves and to society. The purpose of this systematic review is to synthesize the risk of motor vehicle collisions (MVC) for patients with a history of syncope. METHODS We systematically searched MEDLINE (1946 – 2019) as well as CINAHL, Embase, Psychinfo and the Transportation Research Information Documentation (1806 – 2017) for articles on MVC and drivers with vasovagal syncope (VVS), arrhythmic syncope, or syncope not yet diagnosed (NYD). Quality ratings were assigned by team consensus. RESULTS Eleven studies of moderate quality were included (n = 42,972). Compared to the general populations of Canada, the USA, and the UK (0.49-2.29% per driver-year), the prospective MVC risk was lower for VVS (0.0-0.31% per driver-year; 3 studies; n = 782) and higher for arrhythmic syncope (1.9-3.4% per driver-year; 2 studies; n = 730). The results were more variable for syncope NYD (0.0-6.9% per driveryear prospectively; 6 studies; n = 41,460). Patients with syncope NYD had an almost two-fold increased MVC risk in the largest study, although the smaller studies showed contradictory findings.

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CONCLUSIONS VVS patients appear to be at very low risk for MVCs, supporting current guidelines which do not recommend driving suspension for these patients in most cases. While the data for other forms of syncope is too limited for definitive conclusions and must be improved, arrhythmic syncope does appear to be associated with non-trivial risk.

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BRIEF SUMMARY (Maximum word limit: 75 words; Current brief summary word count: 72 words)

This systematic review examines the motor vehicle collision (MVC) risk of 42,972 patients with a history of syncope in eleven relevant studies. VVS patients have a very low MVC risk (<1% per year), supporting current guidelines which do not recommend driving suspension for these patients in most cases. While the data for other forms of syncope is limited and must be improved, arrhythmic syncope does appear to be associated with non-trivial risk.

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INTRODUCTION Motor vehicle driving is a privilege, not a right. However, for many the ability to drive is central to their lives.1-3 It is important for employment, social interactions, and day-to-day activities. Drivers at risk of sudden incapacitation from syncope, however, present a potential risk to themselves as well as to society. The issue of syncope and driving is of clinical, pathophysiological, and social interest for several reasons and, when determining fitness to drive, physicians and regulatory bodies must balance the potential threat that their patients pose on the road against the negative consequences that driving cessation would have on their lives. For some syncope patients, driving is a necessary component of their employment; thus, revoking their driving privileges could result in job loss and adversely affect their quality of life. In other cases, it is common for family members of elderly syncope patients to notify physicians about their concerns regarding the patient’s driving abilities with the goal of having them taken off the road. In the absence of robust evidence, legislation and societal expectations of “erring on the side of caution” – i.e., suspending licenses in those perceived to be at higher risk – may well be collectively doing more harm than the good that is intended if we are including substantial numbers of low-risk individuals in a larger group that is collectively felt to be at higher risk. Fitness-to-drive with medical conditions has received considerable attention by regulators in many jurisdictions.4-11 In Canadian provinces,4, 5 as in many other jurisdictions around the world, syncope, or transient severe impairment due to loss of consciousness (LOC), is a common disqualifying condition. The restriction of privileges varies depending on several factors, including the cause and expected recurrence of syncope, license class, and corrective measures taken.4, 5 For example, vasovagal syncope (VVS) is a common cause of syncope1, 2 and some patients have high recurrence rates3. Drivers with recurrent VVS within 12 months are prohibited from driving private vehicles in Canada for one

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week following the episode, while those with recurrent unexplained syncope must wait 3 months.4 Requirements for drivers of commercial motor vehicles (e.g., passenger-carrying vehicles, trucks and emergency vehicles) are traditionally much more stringent, given that these drivers frequently spend a larger proportion of their day at the wheel, even when less ideal driving conditions prevail. Accordingly, the waiting period is much longer for commercial drivers with these types of syncope (i.e., 12 months).4, 8

Patients who have suffered from an episode of sustained ventricular tachycardia (VT) or ventricular

fibrillation (VF) have a Guideline Class I indication for an implantable cardioverter defibrillator (ICD).12 While ICDs are designed to reduce the risk of sudden cardiac death, they may not prevent LOC. Shocks for ventricular arrhythmias occur in such ICD patients at a rate of 7-8% per patient-year in the secondary prevention population.13 Based on these data, the American Heart Association13 and the Canadian Cardiovascular Society2 recommend that patients not be allowed to drive a private vehicle for 6 months after an episode of sustained VT/VF causing impairment of consciousness. These drivers are disqualified from operating commercial motor vehicles in Canada altogether.4 Although such national and international guidelines on medical fitness to drive for people with syncope exist, they have consistently struggled with limited data.14 On the contrary, there is ample evidence that senior drivers have an even higher motor vehicle collision (MVC) risk (e.g., in Ontario, 2.4% of individuals ≥65 years old experienced collisions in 201415), but retain their driving privileges nonetheless. This raises questions of consistency and relativity in regulatory guidelines. What is the “acceptable” risk to society, and why do we apply different risk thresholds to different groups? Is there a systemic bias against those with medical illness in general when there is a paucity of data to prove they are at low risk? We conducted a systematic review of the risk of MVC for patients with prior syncope. Syncope is generally categorized by etiology (e.g., VVS, syncope secondary to tachy- or brady-arrhythmias [arrhythmic syncope], etc.). However, at first presentation, the specific diagnosis may not be apparent in

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many cases (syncope not yet diagnosed [NYD]). Accordingly, we sought to determine the risk of MVC associated with VVS, arrhythmic syncope, and syncope NYD by systematically reviewing observational studies and comparing the MVC risk to that of the general driving population.

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METHODS This systematic review was performed in accordance with PRISMA guidelines.16, 17 Our search included all studies that were relevant to determining the risk of MVC associated with VVS, arrhythmic syncope, and syncope NYD. Literature Search Published literature from 1806 to 2019 was searched on: VVS, arrhythmic syncope, or syncope NYD; and MVC or automobile driving. The search was applied to MEDLINE (1946 – 2019 April 15), CINAHL (1981 – 2017 January 09), EMBASE (1947 – 2017 January 06), and PsychINFO (1806 – January Week 1 2017). The Transport Research Information Documentation database (2011 – 2017 January 08) was also searched given that it is the largest bibliographic resource on transportation research.18 The MEDLINE search was initially applied to a coverage period ending on 2017 January 08, but was subsequently updated to identify any relevant literature published between 2017 and 2019. We used a combination of free-text keywords and controlled vocabulary terms, such as Medical Subject Headings (MeSH) and other validated terms, to maximize the retrieval of search results. The complete MEDLINE search strategy is provided in the Supplemental Methods S1. Similar strategies were used for the other databases. In the master list of syncope records that were being screened at the abstract level, we sought VVS with common terms (i.e. “vasovagal", “faint", “unconscious", "neurally-mediated", and “collapse”) (Supplemental Methods S2). Selection Criteria Observational studies containing primary data were the focus of this study. The participants were comprised of persons with VVS, arrhythmic syncope, and syncope NYD. These subgroups were chosen because of the high prevalence and the presumed availability of a body of literature. There were no age,

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gender, or other demographic restrictions. The primary outcome was the likelihood of MVC in individuals with a history of syncope and its specifically identified subsets. Editorials, conference proceedings, dissertations, abstracts without full reports, reports in a language other than English, and studies pertaining to other causes of syncope were excluded (i.e., not VVS, not arrhythmic syncope, not syncope NYD, such as structural cardiac or cardiopulmonary disease (e.g., aortic stenosis, pulmonary embolism), metabolic causes (e.g., hypoxia, hypoglycemia), psychiatric causes (e.g., hysteria, somatization disorders), and neurological causes (e.g., seizure disorders, transient ischemic attacks) etc.). Studies were also excluded if insufficient information was provided to confirm eligibility or if numerator-denominator malposition was evident. Additionally, we searched the bibliographies of included studies and published review articles from 1949 to January 2019 to identify any other potential articles. Information on the roles and responsibilities of the research team who performed this study are provided in the Supplemental Methods S3. Titles, abstracts, and full-texts of studies were independently dual-screened by pairs of reviewers to confirm eligibility and relevance to the research question. Disagreements were resolved by consensus (Supplemental Methods S4). Data Extraction and Risk of Bias Assessment A data extraction template was piloted with a member of the research team. Subsequently, one author (JNC) extracted the data from each identified article onto the standardized forms (Supplemental Methods S5), and formatted them into summary tables. Data extracted from each study was verified by another member of the research team to confirm its accuracy and comprehensiveness. Subsequently, the quality of evidence in each of the studies was assigned a rating (Class I, II, or III), which constituted our risk of bias evaluation. This classification approach was developed by Dubinsky et al.19 to stratify and divide the evidence, by quality, on whether automobile driving by persons with syncope poses a significant traffic safety problem (Supplemental Methods S6). Quality ratings were initially assigned by

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one author during the data extraction process. The research team then met face-to-face to vote on the quality of the studies and debate data interpretation. A narrative synthesis of aggregate data was conducted and final quality ratings were derived by consensus. Team members with conflicts of interest as defined by the TCPS2 policy statement20 did not participate in associated discussions of quality and interpretation.

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RESULTS Study Selection The results of the study selection and data extraction processes are summarized in Figure 1. The database searches identified 887 citations. These were narrowed down to 11 relevant studies, which were entered into a narrative synthesis. Inter-rater agreement was excellent to substantial (see the Supplemental Results S1 for a detailed explanation and the Supplemental Results S2 for a list of final included studies).21-31

Characteristics and Results of Individual Studies The included studies were published between 1994 and 2016, with none more recent despite searching for literature as recently as April 2019. The methodological characteristics of these studies are presented in Table 1. Collectively, they examined the driving risk of 42,972 patients with syncope from 9 countries (i.e., Canada, the United States, Australia, Columbia, Denmark, Finland, Germany, Italy, and Portugal). Of these patients, 41,039 (95.5%) came from a single 2016 study26 based in Denmark and the other studies were much smaller. Differences in age and sex proportion between the studies are summarized in the Supplemental Table S1. Most studies (n = 9) used prospective self-reported data.21-25, 28-31

One used prospective administrative data26 and another used retrospective data from both

administrative and self-reported sources.27 A summary of the MVC risk for VVS, arrhythmic syncope, and syncope NYD relative to the general population is presented in Table 2. Three of the studies reported on VVS patients, revealing a low MVC risk (<1% per driver-year).21-23 Two others reported on arrhythmic syncope and found a higher MVC risk (1.9% and 3.4% per driver-year).24, 25 Six studies reported on syncope NYD, with conflicting results. The largest, most influential study revealed an MVC risk of 1.6% per year for drivers

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with a first-time primary diagnosis of syncope investigated in a hospital.26 Four other studies showed that the annualized MVC risk of patients with syncope NYD was quite variable during prospective, follow-up periods (0.0% to 6.9% per patient-year),28-31 and the remaining one provided insufficient information to compute an annualized risk.27 Furthermore, conflicting results for MVC risk were similarly reported for the different syncope diagnoses in the 3 studies that compared them to the general population or a comparison group. Patients with VVS were reported as having a lower risk of MVC relative to the general population of the UK, USA, and Canada.21 Older drivers with syncope in the USA had a relative risk of MVC injury that was no worse than that of older drivers with other neurological diseases.27 In contrast, patients who received a first-time primary diagnosis of syncope NYD investigated in a hospital exhibited a nearly two-fold increase in the risk of MVC relative to the general population in Denmark (Rate Ratio of 1.83 (95% CI: 1.74-1.91), p <0.001).26 Among the other 8 studies without comparison groups, MVCs were uncommon. Further information on individual study results is provided in the Supplemental Results S3. Overall, the mean level of evidence across the included studies was Class II (“moderate quality”) (Supplemental Table S2).

DISCUSSION We performed a systematic review evaluating the risk of MVC among persons with VVS, arrhythmic syncope, and syncope NYD and identified 11 relevant out of a potential 887 studies since 1806 in our comprehensive search of seven databases (moderate quality). As a whole, the results suggest that, relative to the general driving population, the MVC rates of patients with syncope were generally

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lower among those with VVS, higher among those with arrhythmic syncope, and more variable for those with syncope NYD, with the largest study pointing to an elevated risk for a first-time diagnosis. Three previous reviews were conducted on this topic, but none were systematic and each had different goals than the present work (Supplemental Discussion S1).32-34 The present knowledge synthesis provides a more rigorous and extensive overview of the state of the literature on collision risk and syncope. As expected, we found that MVC risk differed considerably depending on the syncope diagnosis. However, several factors can influence the risk observed and potentially confound the results, including the extent to which the syncope groups are well-defined, the median age of the patients, the presence of prodrome or the lack thereof, the success of treatment approaches, and patient education, among many others. These factors should be taken into consideration when interpreting the results (Supplemental Discussion S2

Vasovagal Syncope and Driving According to the literature, there is moderate quality evidence to suggest that the risk of an MVC due to vasovagal syncope is low,21-23 in spite of the high recurrence rates typically reported.3 The three studies had annualized point estimates of MVC risk below 0.5% per driver-year, which is lower than the general driving population21 and even some higher risk groups, such as elderly drivers.15 VVS patients who experience a typical prodrome of diaphoresis, warmth, nausea, or pallor might be expected to pilot their vehicle to the roadside prior to syncope, unless the syncope is found to occur in a sitting position or the prodromal features are determined to be insufficient.4 Further prospective data using robust methodology is needed to determine the risk of serious harm in patients with VVS while driving, to better inform patients, healthcare professionals, and policymakers. Sustained Ventricular Tachycardia or Ventricular Fibrillation and Driving with ICDs

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The arrhythmia group was mainly composed of patients with ICDs, which makes them a more defined group with a history of ventricular arrhythmias and commonly a reduction in left ventricular function.24, 25 The issue in terms of driving risk is the risk of incapacitation due to VT, VF, or ICD discharge leading to MVC. However, not all incapacitation in patients with cardiac arrhythmias is caused by those arrhythmias, especially in ICD patients (e.g., who may have syncope from hypotension). Another limitation of this literature is that data on the cause of the observed MVCs are scarce. Therefore, the MVCs may be a result of factors that are common in ICD patients (e.g., age, frailty, sleep deprivation, cognitive dysfunction, etc.), but not necessarily related to ICD therapies. Data on an ICD discharge at the time of an MVC would be of interest, if available, but it is not commonly reported. The two included studies on this topic24, 25 presented evidence of moderate quality on ICD patients revealing a relatively low risk of MVCs, but a risk that is slightly higher than the risk for the general driving population (e.g., in Canada, the USA, and the UK21). Therefore, there are insufficient data to recommend a shorter duration of driving restriction than stipulated by current guidelines. Syncope NYD and Driving The third classification of drivers with syncope is the most concerning because it includes patients with no diagnosis to-date. The reality is that these patients are the most common in the emergency room and primary care, but proceeding with fitness-to-drive recommendations for this group is problematic. There is moderate-quality evidence that the risk of an MVC among patients with syncope NYD varies from “quite low” to “somewhat higher than that of the general population”,26-31 although this estimate is likely closer to the upper limit given the outcome and relative size of the largest study.26 It should be considered that the null MVC risk reported in two of the studies29, 31 could be a result of instruction from physicians on driving restriction or self-motivated driving cessation. Moreover, the wide range of results likely reflects the broad array of diagnoses embedded in this undifferentiated

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cohort, and the overall low event rates in the studies. The heterogeneity of the patients makes the NYD group difficult to define and may well explain the impossibility of an appropriate comparison with a reference control group. A concern with using older data to extrapolate the risks in this cohort is that, today, there is widespread use and acceptance of structured clinical pathways, ambulatory external ECG monitors, as well as implantable loops that allow for appropriate and better risk stratification. There has also been a marked reduction in the overall number of crashes occurring in many provincial jurisdictions in recent years (e.g., Quebec35 and Ontario15), which further complicates the determination of the risk posed by patients with syncope. Furthermore, only two of the studies29, 31 reported on syncope leading to MVC in the NYD group, whereas the others did not specify whether or not the syncope occurred while driving. Regardless, this is an important population to consider because front-line physicians frequently are required to provide advice on driving to syncope patients who lack a causal diagnosis. Current clinical guidelines indicate that physicians should be instructing patients with a single episode of unexplained syncope to wait one week before driving a private vehicle, or three months for patients with a recurrent episode of unexplained syncope. It is uncertain if the etiology of syncopal episodes was better specified after the initial evaluation. Nevertheless, further testing is necessary to determine the cause and treat it accordingly, which may also help to reduce the waiting period. These results suggest the importance of trying to properly diagnose the cause of syncope and not leaving these patients with a diagnosis of syncope NYD. The risk of MVC is influenced by factors that can be assessed by the physician in addition to the risk of arrhythmia, such as: the likelihood that arrhythmia will cause syncope (i.e., VT vs. VF); other comorbidities (i.e., risk of hypotension, congestive heart failure, cognition, etc.); and the amount and type of driving. Therefore, future research should focus both on the risk of an MVC in this population: a) based on the diagnostic impression of primary care and emergency physicians; and b) after review by a consultant with expertise in syncope.

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Such research should also report the nature of crashes (i.e., at-fault or otherwise). MVC caused by the driver (i.e., at-fault) must be distinguished from other types of collisions. There are logistical challenges associated with retrieving all pertinent information from the charts on these patients, but this would be necessary in order to better establish a cause-effect relationship. For patients who have had restrictions placed on their driving permits, a timely follow-up with a consultant to review these driving restrictions might minimize its deleterious effect on the quality of life. However, there is substantial variation in accident rates among different demographic groups that should be considered. Overall, patients need to be better classified in order to understand the relationship between syncope and MVC taking into account age, gender, and type of collision (at-fault vs. otherwise). Limitations There are important limitations to this literature that warrant discussion. These limitations include predominantly self-reported or administrative data, and the details of at-fault or other MVC are missing pertinent information. Few of the studies were prospectively conducted or controlled, and few included comparisons to national MVC data. We could not obtain estimates of the levels of risk that are acceptable to the community at large, and therefore we resorted to publicly available MVC reports. We were also unable to control for self-motivated risk adjustment (e.g., the patient who drives in a different way when they know their risk is higher, drives fewer hours, or chooses to stay off the highway or other high-risk areas). Some of the studies were performed with administrative data, which carry their own limitations of accuracy and completeness. Similarly, some prospectively conducted studies were actually secondary analyses of unrelated parent studies, and therefore adapted data for unrelated purposes. It is unclear whether the MVC in patients who faint are caused by the faint or other confounding variables. The MVC risk almost certainly varies depending on the cause of syncope. Many studies included subjects who had been seen by specialists, or subjects concentrated in specific ages or diagnoses, and

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whether these are relevant to the population at large is unknown. Little was reported about the regulatory framework where the studies were conducted, and about any instructions given to the patients. Even the definitions of collisions and attributable mortality and morbidity vary, and often are not stated. Future Directions Despite the breadth and depth of the work summarized in this review, clearly more data and better data are needed. Ideally a very large, prospective, longitudinal study is needed to provide confident estimates of outcomes in various categories, and to permit secondary analyses on specific demographic and diagnostic subgroups. This may be precluded by funding realities and limitations associated with robust monitoring and the ability to acquire data on control populations. It might be possible to acquire information from prospectively defined sub-studies of prospective multi-centre clinical trials and epidemiologic studies, although they too may not be sufficiently large. One attractive alternative is to optimize the use of combined big data from motor vehicle departments, health ministries, vital statistics, and physician billings. Lastly, research that quantifies the relative effectiveness of current interventions for drivers with syncope (e.g., the effects of different driving restriction programs) or that explores the efficacy of new interventions for this clinical population applicable to driving (e.g., continuous monitoring of physiological signals for the onset of prodrome) would also prove useful.

CONCLUSIONS Overall, the findings of this study call into question the role and effectiveness of guidelines for fitness to drive in those who have had syncope, considering that some sub-groups of patients with syncope may pose a lower MVC risk than the general population (e.g., patients with VVS and some with

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syncope NYD). Accordingly, do we actually have sufficient evidence to support restricting individuals with syncope from driving private vehicles or for having even more restrictive policies for commercial drivers? If not, why are we restricting them? Do we have evidence that placing restrictions on them is cost-effective? The current Canadian Cardiovascular Society guidelines differentiate VVS from syncope NYD and arrhythmic syncope, with typically no restrictions for the VVS group2 as supported by the findings of this review. Given that the number of people with syncope far exceeds those reported for syncope (likely by orders of magnitude), it raises questions of efficacy. We also know that many, if not most, medical events behind the wheel are sentinel events—in other words, even if we suspended all the “high risk” people, there would still be many MVCs secondary to medical events because “low risk” people with sentinel events comprise a much larger group. It is our hope that more studies with better data in the future will foster the development of fitness-to-drive guidelines that improve road safety on the whole. Such guidelines will need to find ways of avoiding the tendency of being unfairly punitive to those with medical illnesses, in alignment with society’s unscientific views on the topic, but for whom driving may indeed be safe and enriching to their quality of life.

Registry Details This work was registered on Prospero on Dec 16, 2017. http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016053667

Acknowledgements We would like to thank the authors who responded to our inquiries for information about their research studies: Dr. Toshio Akiyama, Dr. Kirsti Martikainen, Dr. Mariana Silva, and Dr. John Windle.

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We would also like to recognize Dr. Yoassry Elzohairy at the Ministry of Transportation of Ontario and Janice Cooney from Joule Inc. for their support.

Funding Sources This work was financially supported by the Ministry of Transportation of Ontario, under the Road Safety Research Partnership Program (MTO RSRPP 16-17); and partially funded by Joule Inc., a Canadian Medical Association Company (CMA-DS-001). The funders played no role in the study methodology, interpretation of results, preparation of the manuscript, or the process of disseminating this work. They accept no responsibility for the contents.

Disclosures Several coauthors disclosed research grants/funding for their work (MJR, JD, JG AK, SRR, RSa, RSS, VT). RSS, PD, JG, SRR, RKS, VT, and AK are Cardiac Arrhythmia Network of Canada (CANet) funded investigators. Potential conflicts of interest were declared by MJR (Canadian Academy of Geriatric Psychiatry (board president); consultancy at the Canadian Medical Association), JD (CMA Driver’s Guide (editor-in-chief)); MG (case reviewer for the CMPA and other legal entities), AK (guideline development committee for the ACC/AHA and HRS guidelines; board membership for the Canadian Cardiovascular Society and Heart Rhythm Society; consultancy at Medtronic), SRR (guideline development committee for the ACC/AHA guidelines; American Autonomic Society (board president); Association for Clinical and Translational Sciences (secretary); Medical Advisory Board for various patient groups including Dysautonomia International, PoTS-UK, Red Lily Foundation, and the Dysautonomia Information Network; consultancy at Lundbeck Pharmaceuticals and GE Healthcare); RKS (guideline development committee for the ACC/AHA and HRS guidelines); RSS (guideline

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development committee for the ESC Syncope Guidelines 2009, CCS Syncope Approaches 2011 (chair), HRS Syncope Consensus 2015 (chair), CCS Pediatric Syncope 2016, and ACC AHA HRS Syncope Guidelines 2017 (vice chair); Saskatchewan Health Research Foundation board member); CS (CMA Driver’s Guide (chapter lead author); CCS Guidelines 2004 (lead); consultancy for the MTO Medical Advisory Board); and VT (CCS position paper on ‘Standardized approaches to the investigation of syncope’ (writing panel member); Evidence Review Committee for the ACC/AHA and HRS guidelines); International Panel on ‘Standardized Reporting Guidelines for Emergency Department Syncope Risk Stratification Research’ (co-chair)). All other authors have no disclosures.

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24

25

Figure Legends Figure 1. PRISMA Flow Chart This diagram outlines the literature search and study selection process utilized during this review.

Tables Table 1.

Methodological Considerations

Table 2.

Main Results and Annualized Point Estimates of MVC Risk

25

Table 1. Methodological Considerations

Author (Year)

Non-Syncope Control Group

Syncope Group Characteristics

Sample Size

Source

Sample Size

General Population: UK, Canada, & USA(b)

Not Provided

Follow-Up / Observation Period (a)

Time Between Syncope Event and Crash

Study Design

Self-Report

0.772 years per person

Not reported

Prospective

Data Collection Method

a) VASOVAGAL SYNCOPE ≥3 lifetime syncopal spells and positive tilt test; or VVS diagnosis using the CSS

n = 418

Bhatia et al. (1999)

≥1 syncope episode (past 6 months) and positive tilt test

n = 155

N/A

N/A

Self-Report

22 months (median)

Not reported

Prospective

Sheldon et al. (1995)

NMS diagnosis and positive tilt test

n = 209

N/A

N/A

Self-Report

5 years

Not reported

Prospective

n = 559

N/A

N/A

Self-Report

35 months (mean)

Not reported

Prospective

N/A(d)

N/A

Self-Report

38±26 months (mean)

Not reported (e)

Prospective

Tan et al. (2016)

(b)

b) ICDs / ARRHYTHMIC SYNCOPE Akiyama et al. (2001)

Patients with VF/VT(c)

Trappe et al. (1998)

Patients with VF, SMVT, or both

(c)

n = 171

c) SYNCOPE NOT YET DIAGNOSED OR ALL-CAUSE SYNCOPE Numé et al. (2016)

All patients diagnosed with a first-time primary diagnosis of syncope from hospital or ER(f)

n= 41,039

General Population: All Danish residents 20082012 ≥ 18 years old

n= 4,224,262

Administrative Data

5 years

±48 hours

Prospective

Koepsell et al. (1994)

Members of a large pre-paid health plan(g) with an active diagnosis of syncope or dizziness (etiology unknown), and who were older adults (i.e., 65 years and above), active drivers, and either: injured in a MVC that they caused over a twoyear period (i.e., 1987 or 1988) (syncope cases); or not

n = 96(i)

Members of a large prepaid health plan(g) with an active diagnosis of a neurological condition other than syncope or dizziness (etiology unknown), and who were older adults (i.e., 65 years and above), active drivers, and either: injured in a MVC that they caused

n = 584(j)

Self-Report and Administrative Data(k)

2 years

0 days

Retrospective

injured in an MVC within one-year of the matched case MVC (syncope controls).(h)

over a two-year period (i.e., 1987 or 1988) (nonsyncope cases); or not injured in an MVC within one-year of the matched case MVC (non-syncope controls).(h)

Silva et al. (2016)

Consecutive patients who were admitted in the ED or hospital with transient LOC, with the causes of transient LOC subsequently classified as: reflex syncope, cardiogenic syncope, syncope due to orthostatic hypotension, transient LOC with CNS origin, psychogenic pseudo-syncope, and unexplained syncope

n = 125

N/A

N/A

Self-Report

18 months

≤18 months

Prospective

Folino et al. (2012)

Consecutive patients with syncope while driving (reflex syncope); ≥2 or more episodes of LOC; normal cardiological and neurological evaluation; absence of relevant structural heart disease; and absence of significant SVA or VA.

n = 40

N/A(l)

N/A

Self-Report

1793±573 days (mean)

0 days (m)

Prospective

Martikainen et al. (2011)

Consecutive patients with suspected LOC referred to a specialist

n = 56

N/A

N/A

Self-Report

1 year

≤1 year

Prospective

Maas et al. (2003)

Patients referred for investigation of syncope who hold a driving license

n = 104

N/A

N/A

Self-Report

1 year

0 days

Prospective

N/A = not applicable; ICDs = implantable cardioverter-defibrillators; VVS = vasovagal syncope; CSS = Calgary Syncope Score; NMS = neurally-mediated syncope; VT = ventricular tachyarrhythmia; VF = ventricular fibrillation; SMVT = sustained monomorphic ventricular tachycardia; ER = emergency room; NYD = not yet diagnosed; LOC = loss of consciousness; SVA = supraventricular arrhythmia; VA = ventricular arrhythmia; ED = emergency department; IQR = interquartile range. The superscript letters in this table (a through m) correspond to additional information provided in the Supplemental Results S5.

Table 2. Main Results and Annualized Point Estimates of MVC Risk Annual MVC Risk: Comparison Groups Non-Syncope Controls

General Population Author (Year)

Country

Main Results

Annual MVC Risk: Syncope Patients

UK(a,b)

Canada (a,b)

USA(a,b)

UK, Canada, & USA Combined

Denmark (a)

USA(d)

2008-12

1987-88

(b,c)

2013

2012

2009

2009, 2012-13

a) VASOVAGAL SYNCOPE Tan et al. (2016)

Canada, Columbia, Germany, USA, and Australia

2 out of 418 patients (0.48%) had syncope while driving (0.62% per patient-year), of which 1 had MVC.

0.31% / driver-year (
)

Bhatia et al. (1999)

USA(e)

0 out of 49 patients who continued to drive had an MVC despite an increase in the number of hours driven per week. The tilt table may have been therapeutic.

0.00% / driver-year (
)

Sheldon et al. (1995)

Canada(f)

4 MVCs over 5 years, two of which caused driver injury.

0.26% / driver-year (
)

0.49% / driver-year

0.56% / driver-year

2.29% / driver-year

1.11% / driver-year

b) ICDs / ARRHYTHMIC SYNCOPE Akiyama et al. (2001)

USA and Canada(g)

Annual risk of 3.4% (95% CI: 2.5 – 4.3) MVC per patient-year (h)

3.4% / driver-year ()

Trappe et al. (1998)

Germany

11 accidents in 11 drivers, none related to syncopal symptoms (1 of the 11 accidents was at-fault), corresponding to 6% over a mean follow-up of 38 ± 28 months.

1.9% / driver-year ()

c) SYNCOPE NOT YET DIAGNOSED OR ALL-CAUSE SYNCOPE Numé et al. (2016)

Denmark

Crude MVC incidence rate of 20.6 (95% CI: 19.7-21.6) per 1000 person-years for syncope and 12.1

1.6% / year(k,l) ()

1.0% / year(l)

(95% CI: 12.0-12.1) per 1000 person-years for controls, with a Rate Ratio of 1.83 (95% CI: 1.741.91)(i). 5-year crash risk (cumulative incidence) of 8.2% (95% CI: 7.5-8.8%) for syncope and 5.1% (95% CI: 4.7-5.4%) for age- and sex-matched controls(j). Koepsell et al. (1994)

USA(m)

About 38 cases with syncope or dizziness had an MVC injury over 2 years. Relative risk (RR) of MVC injury (Odds Ratio (OR)) was 1.8 (95% CI: 0.7-5.0) for syncope patients and 1.2 (95% CI: 0.7-1.9) for patients with dizziness (etiology unknown). Regarding patients with other neurological conditions, RR of MVC injury was lowest for seizures (OR: 0.3; 95% CI: 0.033.4) and highest for dementia (OR: 2.8; 95% CI: 0.4-17.0). Overall RR of MVC Injury (OR) for all neurological conditions combined was 1.1 (95% CI: 0.8-1.7).

Not Provided(n)

Silva et al. (2016)

Portugal

25 out of 125 patients had recurrence of transient LOC: 8% (2/25) of these had MVCs, corresponding to 1.6% (2/125) risk of MVC for the whole sample during the 18-month follow-up period(o)and an annualized rate of 1.06% per patient-year; 60% (15/25) had some sort of accident or injury (but, they were not only attributable to driving, e.g. injuries due to falls).

1.06% / driver-year

Folino et al. (2012)

Italy

Cross-sectionally, 3 out of 40 (7.5%) patients who experienced syncope while driving crashed their vehicles as a consequence. Prospectively, 8 out of 40 (20%) had recurrences of syncope, but none while driving and none were

0.0% / driveryear (
)

Not Provided(n)

hospitalized, for a 0.0% MVC risk during follow-up as well as per patient-year. Martikainen et al. (2011)

Finland

2 out of 29 (6.9%) of the patients who drove at the time of the 1-year follow-up had an MVC(p), corresponding to a 6.9% annualized MVC risk.

6.9% / driveryear ()

Maas et al. (2003)

Germany

1 out of 104 (0.96%) patients had an MVC resulting from syncope while driving in the past. Within the one-year follow-up, none of the patients had an MVC, corresponding to an MVC risk of 0.0% during follow-up as well as per patient-year.

0.0% / driveryear (
)

Note: Up and down arrows indicate MVC risk point estimates that appear to be conceivably above or below those of the general population respectively. LOC = loss of consciousness; MVC = motor vehicle collision. The superscript letters in this table (a through p) correspond to additional information provided in the Supplemental Results S6.

Literature Search •

Records identified through other sources

Databases: MEDLINE (1946– 2019 April 15), CINAHL (1981 – 2017 January 09), EMBASE (1947 – 2017 January 08), PsychInfo (1806 – January Week 1 2017), and TRID (2011 – 2017 January 08)

• Reference Lists:

From searching reference lists of included studies and relevant reviews (n = 4)

Records identified through database searching (n = 887) Excluded (n = 387) • Duplicate records (n = 351) • Missing abstracts (n = 36)

Records screened on the basis of titles (n = 500)

Records screened on the basis of abstracts (n = 433)

Excluded (n = 67) • • • •

Conference presentations/proceedings (n = 38) Irrelevant reviews (n = 19) Case studies (n = 7) No primary data (e.g. letters, opinions, etc.) (n = 3)

Excluded (n = 406) • Irrelevant topic or study design (n = 406)

Full-text studies assessed for eligibility (n = 27)

Excluded (n = 11) • • • •

Studies available for data extraction (n = 20)

Irrelevant outcomes (n = 5) Relevant reviews (n = 4) Irrelevant population (n = 1) Case studies (n = 1)

Late Exclusions (n = 9) • No extractable crash data or relevant syncope patients (n = 6)

• Numerator-denominator malposition (n = 1) • Insufficient information to confirm eligibility (n = 2)

Studies included in narrative synthesis (n = 11)