Determinants and Outcomes of Stroke Following Percutaneous Coronary Intervention by Indication
Background and Purpose—Stroke after percutaneous coronary intervention (PCI) is a serious complication, but its determinants and outcomes after PCI in different clinical settings are poorly documented.
Methods—The British Cardiovascular Intervention Society (BCIS) database was used to study 560 439 patients who underwent PCI in England and Wales between 2006 and 2013. We examined procedural-type specific determinants of ischemic and hemorrhagic stroke and the likelihood of subsequent 30-day mortality and in-hospital major adverse cardiovascular events (a composite of in-hospital mortality, myocardial infarction or reinfarction, and repeat revascularization).
Results—A total of 705 stroke cases were recorded (80% ischemic). Stroke after an elective PCI or PCI for acute coronary syndrome indications was associated with a higher risk of adverse outcomes compared with those without stroke; 30-day mortality and major adverse cardiovascular events outcomes in fully adjusted model were odds ratios 37.90 (21.43–67.05) and 21.05 (13.25–33.44) for elective and 5.00 (3.96–6.31) and 6.25 (5.03–7.77) for acute coronary syndrome, respectively. Comparison of odds of these outcomes between these 2 settings showed no differences; corresponding odds ratios were 1.24 (0.64–2.43) and 0.63 (0.35–1.15), respectively.
Conclusions—Hemorrhagic and ischemic stroke complications are uncommon, but serious complications can occur after PCI and are independently associated with worse mortality and major adverse cardiovascular events outcomes in both the elective and acute coronary syndrome setting irrespective of stroke type. Our study provides a better understanding of the risk factors and prognosis of stroke after PCI by procedure type, allowing physicians to provide more informed advice around stroke risk after PCI and counsel patients and their families around outcomes if such neurological complications occur.
- elective percutaneous coronary intervention
- nonelective percutaneous coronary intervention
- risk factor
Stroke is a serious complication after percutaneous coronary intervention (PCI). We and others have previously shown that it is associated with high in-hospital mortality1–4 and causes life-changing disabilities in those who survive.5–7 Previous studies were conducted in both single-centre8,9 and multicentre settings1,2 and reported the incidence, major determinants and outcomes of stroke after PCI.
PCI is performed either electively or in the setting of an acute coronary syndrome (ACS) as a nonelective (urgent/emergency) procedure. The clinical and procedural characteristics in these 2 settings are different,10,11 and it is conceivable that risk factors for stroke during these 2 clinical scenarios are likely to differ with different impacts on 30-day mortality and in-hospital major adverse cardiovascular events (MACE) associated with stroke. Indeed, Werner et al have recently reported differences in determinants of stroke in different clinical settings but were unable to examine this issue specifically for ischemic and hemorrhagic stroke separately.2 Better understanding of such determinants is important because these stroke subtypes have different pathophysiologies, different risk profiles, and different survival trajectories.12 These cannot be tested in randomized trial setting, and such real-world events needed to be observed and reported through registry data.
In this study, we examined the determinants and outcomes of ischemic and hemorrhagic stroke associated with PCI for ACS compared with those who underwent elective PCI using the British Cardiovascular Intervention Society registry in England and Wales, including over half a million participants. The key objectives of the current study are therefore (1) to examine (a) the determinants and (b) factors associated with mortality and MACE after ischemic and hemorrhagic stroke after PCI in the ACS and elective settings separately and (2) to compare the outcomes of the strokes after PCI between 2 clinical settings.
Data for the current study were taken from the British Cardiovascular Intervention Society (BCIS) data set, which records all PCI procedures conducted in the United Kingdom. The data contains over 100 variables on clinical, procedural, and outcome information with ≈80 000 new records added each year. In-hospital outcomes are recorded on the database, and mortality outcomes tracked through the Medical Research Information Service using the patients’ National Health Service number.
The main exposure variable for the analysis was whether the PCI procedure was performed as an elective or for ACS. The main outcomes were in-hospital MACE and 30-day mortality associated with stroke after PCI. MACE were defined as a composite of in-hospital mortality, myocardial infarction, or repeat intervention. We defined stroke-related mortality as mortality among patients who developed stroke complications after PCI. Other variables included as potential confounders are described in Methods in the online-only Data Supplement.
Statistical analyses were performed using Stata Version 13.0 (College Station, TX). Descriptive statistics were presented by indication (elective cases or PCI for ACS) and stroke subtype (ischemic and hemorrhagic stroke). Multiple imputations by chained equations were used to account for missing variables with 10 imputed data sets. All the non-outcome variables were then put into multiple logistic regression models to identify independent predictors of ischemic and hemorrhagic stroke subtypes separately according to indication of PCI. To calculate the impact of ischemic stroke and hemorrhagic stroke on in-hospital MACE and 30-day mortality, we used multiple logistic regressions controlled for all available covariates and executed separately for elective and ACS.
We then assessed the odds of these adverse outcomes in PCI for ACS using elective PCI procedure as the reference category in those who had stroke as a complication of PCI. We used a step-wise modeling approach to better understand the associations, and the following models were constructed. The models are described in Methods in the online-only Data Supplement.
To account for baseline differences across stroke groups, multiple imputations with propensity score matching (mi estimate: teffects psmatch on Stata) was used to estimate the average treatment effect. The method was used to analyze 2 separate logistic treatment models (ischemic stroke versus no stroke and any stroke versus no stroke), calculating propensity scores for group membership. Additional descriptions of the analysis methods are described in Methods in the online-only Data Supplement.
A total of 588 636 patients underwent either elective PCI or PCI for ACS in England and Wales between 2006 and 2013. After exclusion of 28 197 patients with missing information on stroke subtype, indication for PCI, age, and sex, a total of 560 439 patients were included in the analysis. More than 50% of variables (14/25) had missing data <5%, and 80% (20/25) had <10% missing values (Table I in the online-only Data Supplement). A total of 705 patients (0.13%) experienced an inpatient stroke complication after PCI, of whom 566 patients (0.10%) sustained an ischemic stroke and 139 patients (0.02%) sustained a hemorrhagic stroke.
Table 1 shows the differences in the sample characteristics between patients who had ischemic and hemorrhagic stroke and those who were not stratified by PCI setting. Older age, female sex, and requirement to use glycoprotein IIb/IIIa inhibitors were significantly associated with ischemic stroke as a complication after elective PCI. Patients with a confirmed stroke post elective PCI had a significantly higher incidence of in-hospital MACE and 30-day mortality. In the setting of PCI for ACS, the demographic profile associated with an ischemic stroke was similar, but with a wider age difference; mean age difference was 5.4 years compared with 2.2 years observed in the elective setting. Female sex, history of previous stroke, cardiogenic shock, and requirement for circulatory support, glycoprotein IIb/IIIa inhibitor use, and left main stem disease were significantly associated with the complication of hemorrhagic stroke post elective PCI. Those with hemorrhagic stroke post elective PCI had a considerably higher rate of in-hospital MACE and 30-day mortality than those without stroke.
The risk factor profile for hemorrhagic stroke in the ACS setting was similar to the risk factor profile for ischemic stroke, except for higher prevalence of valvular heart disease and left main stem disease, and greater use of thrombectomy in those with ischemic strokes, whereas patients with hemorrhagic strokes were more likely to have a diagnosis of hyperlipidemia and were more often treated with thrombolysis.
Tables 2 and 3 show the significant independent predictors of ischemic stroke and hemorrhagic stroke outcomes stratified by the clinical setting of the PCI procedure. Only female sex and the requirement for glycoprotein IIb/IIIa inhibitors significantly predicted ischemic stroke post elective PCI. Older age, female sex, previous history of stroke and coronary artery bypass graft, prior use of warfarin, presentation with ST-segment–elevation myocardial infarction, cardiogenic shock, the requirement of circulatory and ventilatory support, and thrombectomy were identified as significant predictors of ischemic stroke after PCI for ACS.
Independent predictors of hemorrhagic stroke in elective PCI included female sex, history of previous stroke, previous PCI, and glycoprotein IIb/IIIa inhibitor use, whereas older age, previous PCI, ST-segment–elevation myocardial infarction, cardiogenic shock, requirement for circulatory and ventilator support, and thrombolysis were independent predictors of hemorrhagic stroke in the PCI for ACS setting.
Table 4 and Table II in the online-only Data Supplement shows the association between the occurrence of a stroke complication and in-hospital MACE and 30-day mortality after multivariate analysis, both for the individual stroke subtypes and the combined stroke cohort. All analyses consistently show that having a stroke complication (either ischemic or hemorrhagic stroke) was significantly associated with poor outcomes assessed, regardless of the clinical setting in which it occurred. Finally, ischemic stroke complications after PCI for ACS were associated with a significantly increased risk of in-hospital MACE but not 30-day mortality after controlling for various potential confounders compared with stroke complications after elective PCI.
Table III in the online-only Data Supplement shows the results with logistic regression after propensity score matching. This analysis suggests a significant increase in in-hospital MACE for total and ischemic stroke in both settings. There were insufficient events to perform the propensity score-matching analysis for hemorrhagic stroke. After propensity score matching, there were significant increases in in-hospital MACE for ischemic and any stroke after both PCI procedures. For 30-day mortality, similar significant increases were observed, except for any stroke in elective patients.
Our analysis of the UK national PCI database of over half a million patients undergoing PCI suggests that stroke is uncommon after PCI. However, once stroke occurs as a complication of PCI, 30-day mortality and MACE are high, both in cerebral infarcts and hemorrhages. Surprisingly, the odds of both these complications are higher after an elective procedure than for ACS because patients with ACS are likely to be sicker and have a worse risk profile compared with elective patients. Patients undergoing elective PCI were usually treated with clopidogrel at the time of the procedure, whereas the majority of patients undergoing emergency PCI were more likely to be on newer oral antiplatelet therapies, such as ticagralor and prasugrel and also be treated with glycoprotein IIb/IIIa inhibitors that have more potent antiplatelet inhibition properties. This could potentially have had a protective effect in relation to ischemic stroke but also increase the risk of death after intracerebral hemorrhage in the ACS group.
Our work provides insight to the outcomes associated with this rare but devastating complication of PCI to the stroke physician, who may not frequently encounter such patients frequently treated with potent antiplatelet and anticoagulant therapies, which are necessitated during the PCI procedure. To our knowledge, this is the first article to examine the determinants and outcomes of stroke after PCI by the indication as well as by specific stroke subtype. The key strength of our work is its large sample size and our ability to control for various potential confounders in an unselected cohort of patients undergoing PCI.
Our data builds on the report of Werner et al who examined stroke risk stratified by the clinical setting of the PCI procedure2 by additionally demonstrating that risk factors for ischemic and hemorrhagic stroke also vary by the clinical setting of the PCI procedure. Cardiovascular risk factors seem to be major determinants of risk of developing ischemic stroke in ACS setting, whereas the stroke risk for elective PCI is associated with glycoprotein IIb/IIIa usage. This observation may relate to the fact that glycoprotein IIb/IIIa is used in higher thrombotic-risk patients in the elective setting (such as diabetics or those patients undergoing complex procedures) who are at higher risk of sustaining ischemic events, such as strokes.13,14 It is possible that use of these agents is a marker for the various procedural complications or complexities that led an operator to use these agents. Supporting the findings from the Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With ST-Segment–Elevation Myocardial Infarction (TOTAL),15 thrombectomy usage is also predictive of ischemic stroke after PCI for ACS. An important observation is the higher ischemic stroke risk observed for women for both indications for PCI (odds ratio 2.62 and 1.78 respectively) compared with men.
It is interesting that age seems to be predictive of stroke complications only in ACS setting but not in elective PCI setting once potential confounders were adjusted for. Similar results are observed for risk of hemorrhagic stroke. Thus, age per se is not a risk factor for a stroke complication sustained after elective PCI. Werner et al reported overall in-hospital mortality of 19.2% for patients who developed stroke (elective PCI, 10.0%; PCI for ACS, 23.2%) compared with 1.3% for those without stroke (elective PCI, 0.2%; PCI for ACS, 2.3%). These results are similar to the 30-day mortality reported in the current study of 18.9% (elective PCI, 6.7%; PCI for ACS, 21.2%) for those who developed stroke compared with 2.0% for those who did not (elective PCI, 0.3%; PCI for ACS, 3.2%).
We found the risk of adverse outcome (in-hospital MACE or 30-day mortality) to be significantly higher in patients where PCI was complicated by a stroke, regardless of stroke subtype or the clinical setting that it occurred in. Although this finding is not unexpected, we found that the greatest observed risk for adverse outcomes is associated with in-hospital strokes complicating elective PCI. This seems to be more pronounced in hemorrhagic stroke albeit with large estimates, perhaps contributed by the relatively small sample size compared with ischemic stroke. Finally, once stroke has occurred, the further risk of MACE and 30-day mortality is high, but not significantly different between the 2 settings. Considering that patients with PCI have significant cardiovascular morbidity in addition to the stroke, it is not surprising.
Our study has several strengths. The BCIS data set includes >95% of all PCI procedures performed in the United Kingdom, which therefore reflects a national, real-world experience that includes high-risk patients encountered in daily interventional practice who are often excluded from randomized controlled trials. Although stroke is a relatively rare complication of PCI, its impact on mortality and morbidity and residual long-term disability has profound consequences not only for patients and their carers but also purchasers and providers of healthcare. Our large sample size allows us to study risk factors for sustaining a stroke complication after 2 clinical settings in which PCI is performed, as well as enabling us to compare and contrast the risk of adverse outcomes by the clinical setting and also provide stroke subtype–specific prognostic information in these settings. This will enable stroke physicians to better counsel patients and their families regarding outcomes.
There are also limitations in this study. Our data set does not capture the timing and severity of stroke, stroke nature, and Activities of Daily Living score. We are unable to ascertain the temporal relationship between the predictor and stroke event. For example, it is possible that patients who undergo ventilation are more likely to develop stroke, but patients might also be ventilated as a consequence of developing stroke or patients who were admitted with a myocardial infarction may have sustained a stroke as a consequence of the coronary event rather than the procedure itself. However, the primary focus is to compare and contrast risk factors and outcomes of each stroke subtype for each type of PCI procedure. As highlighted in our previous work,4 the diagnosis of stroke is reported by individual operators with no external validation or information on how the diagnosis was reached or what imaging modalities were used to ascertain pathogenesis; hence, there is the potential for under-reporting or misclassification of neurological events. In the United Kingdom, however, it is standard practice that anyone who sustains a stroke is referred to a stroke team who would organize the relevant neuroimaging, confirm the diagnosis, and offer guidance in management of the patient. Furthermore, our reported incident stroke rates are similar in magnitude to those reported in the National Cardiovascular Data Registry (NCDR)2 and the Swedish Coronary Angiography and Angioplasty Registry (SCAAR)16 data sets derived from the United States and Sweden, respectively. Given the smaller proportion of hemorrhagic strokes within the total stroke population in this cohort, even with over half a million PCI procedures, we were not able to perform propensity score-matched analyses. Finally, although the BCIS data set captures PCI-related complications, it does not capture information as to how these were managed or whether there were differences in the management of such complications between units.
In summary, we found that stroke after both the elective and ACS setting is associated with adverse outcomes, irrespective of stroke subtype. Our study provides a better understanding of the risk factors as well as outcomes for stroke after PCI by procedure type as well as specific stroke subtype. This will inform both clinicians and patients on stroke risk associated in a specific PCI setting, but also provides important outcome information from a national perspective to enable stroke physicians to counsel patients and their families around outcomes if such neurological complications occur because stroke complications occurring in this setting will represent a small proportion of stroke physicians case mix.
P.K.M. and M.A.M. conceived the study. P.K.M. formulated study design. C.S.K. and E.K. analyzed the data. P.K.M. and M.A.M. drafted the manuscript. All authors contributed in interpretation of results and in making an important intellectual contribution to the manuscript. M.A.M. is the guarantor.
Sources of Funding
The work was supported by a grant from the North Staffs Heart Committee. MRC Health eResearch Centre Grant MR/K006665/1 supported the time and facilities of E.K.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.012700/-/DC1.
- Received January 9, 2016.
- Revision received April 3, 2016.
- Accepted April 6, 2016.
- © 2016 American Heart Association, Inc.
- Werner N,
- Bauer T,
- Hochadel M,
- Zahn R,
- Weidinger F,
- Marco J,
- et al
- Guptill JT,
- Mehta RH,
- Armstrong PW,
- Horton J,
- Laskowitz D,
- James S,
- et al
- Kwok CS,
- Kontopantelis E,
- Myint PK,
- Zaman A,
- Berry C,
- Keavney B,
- et al
- Singh M,
- Rihal CS,
- Gersh BJ,
- Lennon RJ,
- Prasad A,
- Sorajja P,
- et al
- Hoffman SJ,
- Holmes DR Jr,
- Rabinstein AA,
- Rihal CS,
- Gersh BJ,
- Lennon RJ,
- et al
- Chong E,
- Poh KK,
- Liang S,
- Soon CY,
- Tan HC
- Kwok CS,
- Skinner J,
- Metcalf AK,
- Potter JF,
- Myint PK