Kamel H, Soliman E, Heckbert S, Kronmal R, Longstreth WT, Jr, Nazarian S, Peter Okin P. P-Wave Morphology and the Risk of Incident Ischemic Stroke in the Multi-Ethnic Study of Atherosclerosis. Stroke. 2014
The Atherosclerosis Risk in Communities (ARIC) study group, already an important contributor of some of our most fundamental knowledge in cerebrovascular epidemiology, has provided us with an interesting piece of evidence that suggests a previously overlooked feature of a 12-lead electrocardiogram (ECG) called P-wave Terminal Force in V1 (PTFV1) may inform incident stroke risk. This follows on their previous work, which suggested an association between PTFV1 and incident stroke but did not control for atrial fibrillation (AF) in the cohort; a focus of this particular investigation is the role of PTFV1 after controlling for AF.
To start, what is PTFV1?!
My understanding is that PTFV1 is the degree of deflection of the terminal (or latter) aspect of a biphasic P wave. I see it most typically defined as a deflection of >40 mm2. It is a marker of morphologic and/or electrophysiologic dysfunction of the atria, related to P-wave dispersion and duration (other markers with the same implications). A better description of the relationship between these ECG markers and the cardiologic implications can be read here.
In brief, the investigators built on their previous findings of an association between PTFV1, a marker of atrial abnormality, and incident ischemic stroke. A major (and fair) criticism of their previous work is that those findings were not controlled for the presence of AF. This study, in a large cohort of > 6700 patients, was specifically designed to address this interaction, at least to the degree possible, so as to screen for an independent association between PTFV1 and incident ischemic stroke beyond the risk AF confers.
The event rate was fairly low, with only 121 strokes (1.8%) in a median of 8.5 years. AF was noted in 541 (8%) participants. However, after “adjusting for baseline confounders,” PTFV1 positivity was more strongly associated with stroke (hazard ratio [HR] per 1-SD increase, 1.21; 95% confidence interval [CI], 1.02-1.44) than AF (HR per 1-SD, 1.11; 95% CI, 1.03-1.21).
Although there are certainly some limitations to this investigation, as outlined in their discussion, this finding has interesting implications. The frustration of making a diagnosis of “cryptogenic stroke” in a patient with multiple cortical infarcts of varying ages, a morphologically abnormal left atrium and a swing-and-a-miss on prolonged outpatient telemetry is real and frequent, and the idea that any atrial abnormality – manifesting in AF or otherwise – confers ischemic stroke risk and may require treatment for risk reduction is an attractive premise for future research.
For sure, as regards incident stroke risk and ECGs, we should mind our ‘p’s and ‘q’s.
The Obese Prince and the Smoking Pauper: the interaction between smoking, hypertension and socioeconomic status on stroke risk
Despite technological progress, about 1 in 3 ischemic strokes remains cryptogenic. More than 30% of these patients will have a recurrent stroke in the next 5 years. Several studies in the last few years have brought into focus atrial fibrillation (AF) as the underlying etiology in a sizeable proportion of these patients, especially those above 60 years. The longer we look for atrial fibrillation, the more likely we are to find it. In the recently published CRYSTAL – AF trial, 12.4% patients had atrial fibrillation detected when monitored for 1 year. This is especially important, as the therapeutic implications are major.
Clinical, electrocardiographic and echocardiographic markers of atrial fibrillation may be especially important to assess in cryptogenic stroke patients, as they may point out which patients are more likely to have occult atrial fibrillation, and thus may need to be monitored longer. Left ventricular diastolic dysfunction (LVDD) is thought to be a marker of paroxysmal non-valvular AF.
In the current study, Seo et al. compared the prevalence of left ventricular diastolic dysfunction (LVDD) in cryptogenic stroke (CS) v/s stroke with AF and stroke without AF (lacunar strokes, and strokes with >50% referable large artery stenosis). Also, they compared the proportion of severe LVDD between CS patients with cardioembolism (CE)-mimic DWI pattern and non CE-mimic DWI pattern, with the aim to delineate if LVDD can be used as a marker to predict occult AF in CS patients with CE-mimic pattern on MRI. The study cohort consists of 1901 patients with acute stroke enrolled into a prospective registry at the Soonchunhyang University Hospital in Seoul, Korea between January 2004 to March 2013, with a mean age of 58 years. After excluding patients with missing workup, and patients with known sources for cardioembolism which may affect LVDD such as mechanical valve, mitral stenosis, atrial myxoma etc, 55 CS patients, 310 strokes with AF and 969 strokes without AF were included in analysis. LVDD was ascertained by 2 cardiologists and assigned grades I-III based on accepted parameters. When dichotomized at grade III, severe LVDD was much more prevalent in CS than stroke without AF, and almost comparable to stroke with AF. Moreover, among the CS patients, the presence of LVDD was much higher in CE-mimic patients than non-mimics. On the contrary, although left atrial enlargement (LAE) was predominantly detected in stroke with AF, its frequency was not different between CS and stroke without AF. In a multivariable model, LVDD was associated with stroke with AF, despite controlling for hypertension, LAE and PFO.
These findings are significant, as they validate LVDD being a marker for AF in a stroke population, despite controlling for hypertension. The fact that most of our current AF detection techniques including ambulatory cardiac telemetry or implantable devices are contingent on timing, more permanent markers are needed that precede or predict AF to save time and money. Also, in this study, LVDD proved to be a good, if not a more sensitive marker than LAE for AF. The higher prevalence of LVDD in CS with CE-mimic lesion distribution suggests that these patients likely have underlying AF as a cause for the CS. However, being a retrospective single center study, the findings cannot be generalizable to our stroke patients. Also, there may be an inherent selection bias because a significant proportion of patients, who did not have a full workup were excluded. Despite these limitations, it makes a strong argument for patients that suffer CS with CE mimic lesion patterns and have LVDD to undergo longer cardiac monitoring, as their risk of having AF is very high. In our aging population, where the prevalence of AF is predicted to double by 2050 to 5.5 million, tools to increase pre-test probability of detecting AF will help us tailor stroke care to individual stroke patients, while saving resources by avoiding unnecessary testing on others.
Intraventricular hemorrhage (IVH) results when parenchymal blood dissects or breaks the lining of the fluid filled cavities within the brain. IVH is associated with Intracerebral hemorrhage (ICH) in about 40% of cases and results in a varying but high mortality rate of 40-80%. When present, it requires placement of external ventricular drains to avoid complications such as hydrocephalus. The placement of such a drain for prolonged periods of time carries its own risks of infections such as ventricultis. Recently several studies such as the CLEAR IVH trial have been randomizing patients to receive intraventricular tissue plasminogen activator to decrease clot burden. The authors of this Meta analyses describe the pooled results of studies till date that have explored the use of intraventricular fibrinolysis (IVF).
While confounders such as the addition of renal failure to systemic disease must be acknowledged, there are many considerations raised for the treating neurologist when assessing this data. Our first year of training is usually dedicated to learning general medicine and it is all too easy to forget this realm with increasing specialization. The importance of appropriate recognition and treatment of comorbid illness such as ITP or cirrhosis is only confirmed by this data. The worse survival curve in patients with amyloid is also something to ponder. How does one decide the appropriate treatment for a patient with Afib and suspected amyloid angiopathy? In the era of rapid expansion and development of oral anticoagulants, many with unestablished methods of reversal, does this preclude the above patients from these medications? While ICH unfortunately remains a staple admission to neurologic intensive units, perhaps consideration of etiology will lead to appropriate and more accurate therapy and assessment of risk.
Pasquini M, Charidimou A, van Asch CJJ, Baharoglu MI, Samarasekera N, Werring DJ, et al. Variation in Restarting Antithrombotic Drugs at Hospital Discharge After Intracerebral Hemorrhage. Stroke. 2014
Restarting antithrombotic therapy following an intracerebral hemorrhage (ICH) has been the subject of much controversy and debate over the years. This is especially true as an increasing number of patients are prescribed antithrombotics for atrial fibrillation or thrombo-embolic disease. However, little data is currently available to support the establishment of definitive guidelines for these patients with most recommendations suggesting an individualized approach for each patient.
With that in mind, this study was designed to assess the variation in restarting antithrombotic drugs by comparing the characteristics and proportions of patients taking antithrombotic drugs at ICH onset and discharge in four hospital-based cohorts in France, the Netherlands, and in the United Kingdom using bivariate and multivariable logistic regression analysis.A total of 2138 patients, median age 72 years, 53% male) were reviewed in this study, 942 of whom were taking antithrombotics at presentation- 559 of them taking antiplatelets prior to ICH, 333 taking Vitamin K antagonists, and 50 taking both. Exclusion criteria included patients with purely extra-axial hemorrhage, patients treated with heparin, or patients with a secondary cause of ICH such as vascular malformation.
Data was collected on each patient, a study investigator with stroke expertise analyzed the images for classification into the various groups (lobar, non-lobar, unclassifiable, or multiple), and antithrombotic drug was categorized by type (antiplatelet, antithrombotic, or both). Case fatality rate was recorded at 30 days. Patients taking antithrombotic drugs had higher case fatality rate at 30 days, overall, when compared to patients not taking antithrombotics. Bivariate analysis revealed that restarting antithrombotics was more likely in younger patients, but median ICH volume was not found to differ between survivors who restarted or stopped antithrombotic agents. The proportion of patients restarting was also highest in those who were taking vitamin K antagonists before ICH. The strengths of the study included the large sample size and inclusion of multiple cohorts representing different settings. The variation between patients suggested that the cohort of origin played a role and the authors recommended that further studies be carried out to determine the best approach to guide future treatment plans.
Chen LY, Lopez FL, Gottesman RF, Huxley RR, Agarwal SK, Loehr L, et al. Atrial Fibrillation and Cognitive Decline−The Role of Subclinical Cerebral Infarcts: The Atherosclerosis Risk in Communities Study. Stroke. 2014
The implications and questions raised by the results are important given the global epidemics of stroke, dementia, and AF. Future studies will need to evaluate risk of SI in those with low CHA2DS2-VASc scores and if anticoagulation reduces risk of cognitive decline in AF patients. Other questions raised are if we should be looking for occult AF in patients with SI’s or should we treat them with anticoagulants without documented AF?