Post hoc analyses of clinical trials show that PCSK9 inhibitors might lower lipoprotein(a), but whether this effect contributes to reductions in cardiovascular risk remains unknown. We aimed to ...assess whether genetically proxied PCSK9 inhibition influences lipoprotein(a) (Lp(a)), and whether any such effect could mediate its effects on coronary artery disease (CAD) and ischemic stroke (IS).
To explore associations between the genetic proxies for PCSK9 inhibitors and Lp(a) levels, we used UK Biobank data (310,020 individuals). We identified 10 variants in the PCSK9 gene associated with lower PCSK9 and LDL-C levels as proxies for PCSK9 inhibition. We explored the effects of genetically proxied PCSK9 inhibition on Lp(a) levels, as well as on odds of CAD (60,801 cases, 184,305 controls) and IS (60,341 cases, 454,450 controls) in two-sample Mendelian randomization analyses. In mediation analyses, we assessed the effects of genetically proxied PCSK9 inhibition on CAD and IS mediated through reductions in Lp(a) levels.
Genetically proxied PCSK9 inhibition (1-SD decrement in PCSK9 concentration; corresponding to 20.6 mg/dl decrement in LDL-C levels) was associated with a 4% decrease in log-Lp(a) levels (beta: −0.038, 95%CI: −0.053 to −0.023). We estimated a 0.8% reduction in the odds for CAD (OR: 0.992, 95%CI: 0.989–0.995) and a 0.5% reduction in the odds for atherosclerotic IS (OR: 0.995, 95%CI: 0.992–0.998) due to reductions in Lp(a) levels through genetically proxied PCSK9 inhibition, corresponding to 3.8% and 3.2% of the total effects, respectively.
Genetic proxies for PCSK9 inhibition are associated with lower Lp(a) levels. However, Lp(a) lowering explains only a small proportion of the total effects of genetic proxies for PCSK9 inhibitors on risk of CAD and IS.
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•12 genetic variants in the PCSK9 gene were identified as proxies for PCSK9 inhibition.•Genetically proxied PCSK9 inhibition is associated with lower Lp(a) levels.•Lp(a) lowering explains only a small proportion of the effects of genetically proxied PCSK9 inhibition on cardiovascular risk.
Venous thromboembolism (VTE) can occur simultaneously with a cryptogenic stroke (CS) linked to patent foramen ovale (PFO), given paradox thromboembolism as potential stroke cause. However, little is ...known on the frequency of concomitant VTE and CS. We aimed to review the literature on the frequency of VTE in patients with CS linked to PFO (primary aim) and of ischemic stroke (IS) among patients with pulmonary embolism (PE) (secondary aim).
We performed a Medline search for cohort studies, written in English, with the following characteristics: (a) enrolling patients hospitalized for an acute ischemic stroke undergoing a work-up for deep venous thrombosis (DVT) and/or PE. To be included in this review, a study had to have at least a subgroup of patients with PFO; (b) the time interval between the index stroke and the work-up had to be within 40 days and the studies had to differentiate between DVT and PE. For the secondary aim, studies had to include patients with acute PE, known PFO-status and routine brain imaging on admission or within 1 year.
We found eight studies reporting on the frequency of VTE after an acute CS linked to PFO. Concerning DVT, the reported frequency ranged between 7 and 27%; concerning PE, it lied between 4.4 and 37%. Six studies assessed the frequency of ischemic brain lesions among patients with an acute PE. In all studies, the presence of PFO was associated with ischemic brain lesions, both at baseline and follow-up.
VTE can be detected in patients with CS linked to PFO. While -based on the presented literature-routine screening for VTE in patients with CS linked to PFO does not appear justified, history taking, and clinical exam should consider concomitant VTE. Whenever clinically suspected, the threshold to trigger ancillary testing for VTE should be low. Among patients with an acute PE and PFO, vigilance for new neurologic deficits should be increased, with a low threshold for brain imaging.
Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it ...is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk.
Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation.
Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death.
Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.
Lipoprotein (a) Lp(a) serum levels are highly genetically determined and promote atherogenesis. High Lp(a) levels are associated with increased cardiovascular morbidity. Serum Lp(a) levels have ...recently been associated with large artery atherosclerosis (LAA) stroke. We aimed to externally validate this association in an independent cohort.
This study stems from the prospective multicentre CoRisk study (CoPeptin for Risk Stratification in Acute Stroke patients NCT00878813), conducted at the University Hospital Bern, Switzerland, between 2009 and 2011, in which Lp(a) plasma levels were measured within the first 24 hours after stroke onset. We assessed the association of Lp(a) with LAA stroke using multivariable logistic regression and performed interaction analyses to identify potential effect modifiers.
Of 743 patients with ischaemic stroke, 105 (14%) had LAA stroke aetiology. Lp(a) levels were higher for LAA stroke than non-LAA stroke patients (23.0 nmol/l vs 16.3 nmol/l, p = 0.01). Multivariable regression revealed an independent association of log10and#xA0;Lp(a) with LAA stroke aetiology (aOR 1.47 95% CI 1.03and#x2013;2.09, p = 0.03). The interaction analyses showed that Lp(a) was not associated with LAA stroke aetiology among patients with diabetes.
In a well-characterised cohort of patients with ischaemic stroke, we validated the association of higher Lp(a) levels with LAA stroke aetiology, independent of traditional cardiovascular risk factors. These findings may inform randomised clinical trials investigating the effect of Lp(a) lowering agents on cardiovascular outcomes. The CoRisk (CoPeptin for Risk Stratification in Acute Patients) study is registered on ClinicalTrials.gov.
NCT00878813.
INTRODUCTION: There is limited understanding of the pathomechanistic relationship between leptomeningeal collateral formation and ischaemic stroke aetiology. We aimed to assess the association of ...leptomeningeal collateral status and ischaemic stroke aetiology, using the widely recognised “Trial of Org 10172 in Acute Stroke Treatment” (TOAST) classification categorising strokes into five distinct aetiologies. METHODS: Retrospective study of consecutively admitted adult ischaemic stroke patients at a Swiss stroke centre. Leptomeningeal collateral status was assessed on admission with single-phase CT-angiographies using a validated 4-point score. Patients were categorised into large-artery atherosclerosis (LAA), cardioembolic (CE), small-vessel disease (SVD) and cryptogenic (CG) according to the TOAST classification. We performed ordinal and binary (poor collaterals filling ≤50% of the occluded territory vs good collaterals filling >50% of the occluded territory collateralisation) logistic regression to evaluate the impact of TOAST aetiology on collateral status. RESULTS: Among 191 patients, LAA patients had better collateral status compared to non-LAA aetiology (LAA: 2 vs CE: 2 vs SVD: 3 vs CG: 2, pLAA vs non-LAA = 0.04). In weighted multivariate logistic regression, LAA and SVD independently predicted better collateral status (binary models adjusted odds ratio; aOR: LAA: 3.72 1.21–11.44 and SVD: 4.19 1.21–14.52; ordinal models adjusted common odds ratio; acOR: LAA: 2.26 95% CI: 1.23–4.15 and SVD: 1.94 1.03–3.66), while CE predicted worse collateral status (binary models aOR: CE: 0.17 0.07–0.41; ordinal models acOR: CE: 0.24 0.11–0.51). CONCLUSION: The aetiology of ischaemic stroke is associated with leptomeningeal collateral status on single-phase CT-angiography, with LAA and SVD predicting better and CE predicting worse collateral status.
Background
Cerebral microbleeds (CMBs) may have a differential impact on clinical outcome in stroke patients with atrial fibrillation (AF) treated with different types of oral anticoagulation (OAC).
...Methods
Observational single-center study on AF-stroke-patients treated with OAC. Magnetic-resonance-imaging was performed to assess CMBs. Outcome measures consisted of recurrent ischemic stroke (IS), intracranial hemorrhage (ICH), death, and their combined analysis. Functional disability was assessed by mRS. Using adjusted logistic regression and Cox proportional-hazards models, we assessed the association of the presence of CMBs and OAC type (vitamin K antagonists VKAs vs. direct oral anticoagulants DOACs) with clinical outcome.
Results
Of 310 AF-stroke patients treated with OAC DOACs:
n
= 234 (75%); VKAs:
n
= 76 (25%), CMBs were present in 86 (28%) patients; of these, 66 (77%) received DOACs. In both groups, CMBs were associated with an increased risk for the composite outcome: VKAs: HR 3.654 1.614; 8.277;
p
= 0.002; DOACs: HR 2.230 1.233; 4.034;
p
= 0.008. Patients with CMBs had ~50% higher absolute rates of the composite outcome compared to the overall cohort, with a comparable ratio between treatment groups VKAs 13/20(65%) vs. DOACs 19/66(29%);
p
< 0.01. The VKA-group had a 2-fold higher IS VKAs:4 (20%) vs. DOACs:6 (9%);
p
= 0.35 and a 10-fold higher ICH rate VKAs: 3 (15%) vs. DOACs: 1 (1.5%);
p
= 0.038. No significant interaction was observed between type of OAC and presence of CMBs. DOAC-patients showed a significantly better functional outcome (OR 0.40 0.17; 0.94;
p
= 0.04).
Conclusions
In AF-stroke patients treated with OAC, the presence of CMBs was associated with an unfavorable composite outcome for both VKAs and DOACs, with a higher risk for recurrent IS than for ICH. Strokes were numerically higher under VKAs and increased in the presence of CMBs.
Clinical trial registration
http://www.clinicaltrials.gov
, Unique identifier: NCT03826927.
Background:
Approximately one in four stroke patients suffer from recurrent vascular events, underlying the necessity to improve secondary stroke prevention strategies. Immune mechanisms are causally ...associated with coronary atherosclerosis. However, stroke is a heterogeneous disease and the relative contribution of inflammation across stroke mechanisms is not well understood. The optimal design of future randomized control trials (RCTs) of anti-inflammatory therapies to prevent recurrence after stroke must be informed by a clear understanding of the prognostic role of inflammation according to stroke subtype and individual patient factors.
Aim:
In this narrative review, we discuss (1) inflammatory pathways in the etiology of ischemic stroke subtypes; (2) the evidence on inflammatory markers and vascular recurrence after stroke; and (3) review RCT evidence of anti-inflammatory agents for vascular prevention.
Summary of review:
Experimental work, genetic epidemiological data, and plaque-imaging studies all implicate inflammation in atherosclerotic stroke. However, emerging evidence also suggests that inflammatory mechanisms are also important in other stroke mechanisms. Advanced neuroimaging techniques support the role of neuroinflammation in blood–brain barrier dysfunction in cerebral small vessel disease (cSVD). Systemic inflammatory processes also promote atrial cardiopathy, incident and recurrent atrial fibrillation (AF). Although several inflammatory markers have been associated with recurrence after stroke, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) are presently the most promising markers to identify patients at increased vascular risk. Several RCTs have shown that anti-inflammatory therapies reduce vascular risk, including stroke, in coronary artery disease (CAD). Some, but not all of these trials, selected patients on the basis of elevated hsCRP. Although unproven after stroke, targeting inflammation to reduce recurrence is a compelling strategy and several RCTs are ongoing.
Conclusion:
Evidence points toward the importance of inflammation across multiple stroke etiologies and potential benefit of anti-inflammatory targets in secondary stroke prevention. Taking the heterogeneous stroke etiologies into account, the use of serum biomarkers could be useful to identify patients with residual inflammatory risk and perform biomarker-led patient selection for future RCTs.
IMPORTANCE: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC). OBJECTIVE: To ...determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32 375 controls without recent DOAC use. Data were collected from January 2008 to December 2021. EXPOSURES: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation. MAIN OUTCOMES AND MEASURES: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses. RESULTS: Of 33 207 included patients, 14 458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion. CONCLUSIONS AND RELEVANCE: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion.
To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF).
We analysed consecutive patients with AF with ...an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke.
Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy.
Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed.
ISRCTN48292829.
In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major ...bleedings remain uncertain.
This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment.
After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA
DS
-VASc score after the index event (odds ratio OR, 1.2 95% CI, 1.0-1.3 for each point increase;
=0.05) and hypertension (OR, 2.3 95% CI, 1.0-5.1;
=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 95% CI, 1.0-1.2 for each year increase;
=0.002), history of major bleeding (OR, 6.9 95% CI, 3.4-14.2;
=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 95% CI, 1.4-5.5;
=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 95% CI, 0.8-1.7).
Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.
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