Risk Of Subsequent Ischemic Events Research Articles

Blood pressure during long-term cilostazol-based dual antiplatelet therapy after stroke: a post hoc analysis of the CSPS.com trial

We determined the associations of follow-up blood pressure (BP) after stroke as a time-dependent covariate with the risk of subsequent ischemic stroke, as well as those of BP levels with the difference in the impact of long-term clopidogrel or aspirin monotherapy versus additional cilostazol medication on secondary stroke prevention. In a sub-analysis of a randomized controlled trial (CSPS.com), patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone, or a combination of cilostazol with aspirin or clopidogrel. The percent changes, differences, and raw values of follow-up BP were examined. The primary efficacy outcome was the first recurrence of ischemic stroke. In a total of 1657 patients (69.5 ± 9.3 years, female 29.1%) with median 1.5-year follow-up, ischemic stroke recurred in 74 patients. The adjusted hazard ratio for ischemic stroke of a 10% systolic BP (SBP) increase from baseline was 1.19 (95% CI 1.03–1.36), that of a 10 mmHg SBP increase was 1.14 (1.03–1.28), and that of SBP as the raw value with the baseline SBP as a fixed (time-independent) covariate was 1.14 (1.00–1.31). Such significant associations were not observed in diastolic BP-derived variables. The estimated adjusted hazard ratio curves for the outcome showed the benefit of dual therapy over a wide SBP range between ≈120 and ≈165 mmHg uniformly. Lower long-term SBP levels after ischemic stroke were associated with a lower risk of subsequent ischemic events. The efficacy of dual antiplatelet therapy including cilostazol for secondary stroke prevention was evident over a wide SBP range.

Dyspnea-Related Ticagrelor Discontinuation After Percutaneous Coronary Intervention

BackgroundNearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases. ObjectivesThe authors sought to evaluate the incidence, predictors, and outcomes of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI). MethodsIn the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, after 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The occurrence of dyspnea associated with ticagrelor discontinuation was evaluated among all patients enrolled in the trial. A landmark analysis was performed at 3 months after PCI, that is, the time of randomization. Predictors of dyspnea-related ticagrelor discontinuation were obtained from multivariable Cox regression with stepwise selection of candidate variables. ResultsThe incidence of dyspnea-related ticagrelor discontinuation was 6.4% and 9.1% at 3 and 15 months after PCI, respectively. Independent predictors included Asian race (lower risk), smoking, prior PCI, hypercholesterolemia, prior coronary artery bypass, peripheral artery disease, obesity, and older age. Among 179 patients who discontinued ticagrelor because of dyspnea after randomization, ticagrelor monotherapy was not associated with a higher risk of subsequent ischemic events (composite of all-cause death, myocardial infarction, or stroke) compared with ticagrelor plus aspirin (5.0% vs 7.1%; P = 0.566). ConclusionsIn the TWILIGHT trial, dyspnea-related ticagrelor discontinuation occurred in almost 1 in 10 patients and tended to occur earlier rather than late after PCI. Several demographic and clinical conditions predicted its occurrence, and their assessment may help identify subjects at risk for therapy nonadherence.

Peridevice Leak After Left Atrial Appendage Occlusion: Incidence, Mechanisms, Clinical Impact, and Management.

Left atrial appendage occlusion is an increasingly adopted stroke prevention strategy in patients with atrial fibrillation. However, peridevice leaks after the procedure are not infrequent and have recently been shown to confer a higher risk for subsequent ischemic events. In this paper, the authors review the available research on the frequency, mechanisms, clinical significance, and management of peridevice leak after percutaneous left atrial appendage occlusion.

Defining Key Features of Complex Coronary Lesions: An Evidence Based Review of Clinical Practice. Part II: Chronic Total Occlusions, Graft Interventions, In-Stent Restenosis, and Antithrombotic Strategies.

Clinicians have long recognized that certain features of coronary artery lesions increase the complexity of intervention. Complex lesions are associated with worse cardiovascular outcomes and a higher risk of subsequent ischemic events. These lesions are categorized by their angiographic features. These features include bifurcation lesions, left main coronary artery disease, calcified lesions, in-stent restenosis, chronic total occlusions and graft interventions. This two-part review aims to highlight the current evidence in the percutaneous management of these lesions. Part two of this review focuses on the indications to treat chronic total occlusions, interventions of failed grafts, tools used to treat in-stent restenosis, as well as antithrombotic strategies.

Defining Key Features of Complex Coronary Lesions: An Evidence Based Review of Clinical Practice. Part I: Bifurcations, Left Main Disease, and Calcifications.

Clinicians have long recognized that certain features of coronary artery lesions increase the complexity of intervention. Complex lesions are associated with worse cardiovascular outcomes and a higher risk of subsequent ischemic events. These lesions are categorized by their angiographic features. These features include bifurcation lesions, left main coronary artery disease, calcified lesions, in-stent restenosis, chronic total occlusions and graft interventions. This two-part review aims to highlight the current evidence in the percutaneous management of these lesions. Part one of this review focuses on the best techniques to treat bifurcation lesions, indications for intervention of left main coronary artery disease and additional tools used to treat calcified lesions.

Global assessment improves risk stratification for major adverse cardiac events across a wide range of triglyceride levels: Insights from the KP REACH study

ObjectivePatients with risk factors for or established atherosclerotic cardiovascular disease (ASCVD) remain at high risk for subsequent ischemic events despite statin therapy. Triglyceride (TG) levels may contribute to residual ASCVD risk, and the performance of global risk assessment calculators across a broad range of TG levels is unknown. MethodsWe performed a retrospective cohort study of Kaiser Permanente Northern California members aged ≥45 years with ≥1 ASCVD risk factor (primary prevention cohort) or established ASCVD (secondary prevention cohort) between 2010 and 2017 who were receiving statin therapy and had a low-density lipoprotein cholesterol between 41–100 mg/dL. Global ASCVD risk assessment was performed using both the Kaiser Permanente ASCVD Risk Estimator (KPARE) and the ACC/AHA ASCVD Pooled Cohort Equation (PCE). Outcomes included major adverse cardiovascular events (MACE) defined as myocardial infarction, stroke, or peripheral artery disease, and expanded MACE (MACE + coronary revascularization + hospitalization for unstable angina). ResultsAmong 373,389 patients in the primary prevention cohort, median TG was 122 mg/dL (IQR 88–172 mg/dL) and there were 0.2 MACE events and 0.3 expanded MACE events per 100-person years. Among 97,832 patients in the secondary prevention cohort, median TG level was 116 mg/dL (IQR 84–164 mg/dL) and there were 9.6 MACE events and 22.0 expanded MACE events per 100-person years. KPARE and the ACC/AHA PCE stratified patients for MACE and expanded MACE over the entire range of TGs. ConclusionIn a cohort receiving statin therapy for primary or secondary prevention, we found global assessment further improves risk stratification for initial and/or recurrent ASCVD events irrespective of baseline TG level.

Abstract 10627: Benefits of Icosapent Ethyl in Patients with Prior Peripheral Artery Disease: REDUCE-IT PAD

Introduction: REDUCE-IT found significant benefit in 8179 statin-treated patients randomized to icosapent ethyl (IPE). Whether that benefit extends to patients with peripheral artery disease (PAD) was unknown. Methods: The primary endpoint was time to cardiovascular (CV) death, myocardial infarction (MI), stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. Total (first plus recurrent) events were also assessed. PAD was an inclusion criterion in the established CV disease cohort. Prespecified and post hoc analyses by baseline history of PAD history were performed. Results: Of 5785 (70.7%) REDUCE-IT patients enrolled with established CV disease, 688 had PAD. IPE demonstrated statistically similar risk reduction in first (interaction P [p int ]=0.58) and total (p int =0.78) primary endpoints in patients with established CV disease with or without PAD, though PAD patients had higher first (placebo: 32.8% with vs 24.5% without PAD) and total (placebo: 162.3 vs 101.7 per 1000 patient-years) event rates. The primary endpoint event rate with PAD was 26.2% with IPE vs 32.8% with placebo (HR 0.78; 95% CI 0.59, 1.03; P=0.08) and total events were 112.8 per 1000 patient-years with IPE vs 162.3 with placebo (RR 0.68; 95% CI 0.48, 0.95; P=0.03) (Figure). Primary endpoint absolute risk reductions (ARR) and numbers needed to treat (NNT) suggest benefit for patients with (ARR 6.6%; NNT 15) and without (6.1%; 16) PAD. Safety did not differ substantially by PAD history and was generally consistent with the overall study. Conclusions: In REDUCE-IT, patients with PAD were at very high risk of subsequent ischemic events. IPE provided consistent CV benefit in patients with or without PAD.

Systolic Blood Pressure and Outcomes in Stable Outpatients with Recent Symptomatic Artery Disease: A Population-Based Longitudinal Study.

Objectives: The most appropriate targets for systolic blood pressure (SBP) levels to reduce cardiovascular morbidity and mortality in patients with symptomatic artery disease remain controversial. We compared the rate of subsequent ischemic events or death according to mean SBP levels during follow-up. Design: Prospective cohort study. FRENA is an ongoing registry of stable outpatients with symptomatic coronary (CAD), cerebrovascular (CVD) or peripheral artery disease (PAD). Setting: 24 Spanish hospitals. Participants: 4789 stable outpatients with vascular disease. Results: As of June 2017, 4789 patients had been enrolled in different Spanish centres. Of these, 1722 (36%) had CAD, 1383 (29%) CVD and 1684 (35%) PAD. Over a mean follow-up of 18 months, 136 patients suffered subsequent myocardial infarction, 125 had ischemic stroke, 74 underwent limb amputation, and 260 died. On multivariable analysis, CVD patients with mean SBP levels 130–140 mm Hg had a lower risk of mortality than those with levels <130 mm Hg (hazard ratio (HR): 0.39; 95% CI: 0.20–0.77), as did those with levels >140 mm Hg (HR: 0.46; 95% CI: 0.26–0.84). PAD patients with mean SBP levels >140 mm Hg had a lower risk for subsequent ischemic events (HR: 0.57; 95% CI: 0.39–0.83) and those with levels 130–140 mm Hg (HR: 0.47; 95% CI: 0.29–0.78) or >140 mm Hg (HR: 0.32; 95% CI: 0.21–0.50) had a lower risk of mortality. We found no differences in patients with CAD. Conclusions: In this real-world cohort of symptomatic arterial disease patients, most of whom are not eligible for clinical trials, the risk of subsequent events and death varies according to the levels of SBP and the location of previous events. Especially among patients with large artery atherosclerosis, PAD or CVD, SBP <130 mm Hg may result in increased mortality. Due to potential factors in this issue, Prospective, well designed studies are warranted to confirm these observational data.

Abstract MP48: Intracranial Dolichoectasia in Patients With Symptomatic Intracranial Atherosclerotic Disease: The Myriad Study

Background: It is unknown whether intracranial atherosclerotic disease (IAD), in addition to vessel narrowing, also contributes to the abnormal dilation and increased tortuosity of intracranial vessels, a condition known as intracranial dolichoectasia (IDE). We aim to determine the degree to which these two arteriopathies coexist and whether IDE correlates with subsequent ischemic events in patients with recently symptomatic moderate-to-severe IAD. Methods: The study included 99 patients (mean age 6311 years; 57% men) enrolled in the Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) study. Intracranial vessels diameter, length, and tortuosity were determined by semiautomatic vessel segmentation and were considered abnormal if ≥2 standard deviations from the study population mean. Either ectasia (increased diameter) or dolichosis (increased tortuosity) defined IDE. We assessed the correlation of IDE in the symptomatic vessel with the composite outcome of either new infarcts in the territory of the affected vessel on brain MRI performed at 6-8 weeks from the index event or stroke recurrence during 12-month follow up. Results: IDE prevalence was 34% (isolated ectasia 8%, isolated dolichosis 18%, and both ectasia and dolichosis 8%) and 14% of symptomatic vessels. Patients with and without IDE had similar demographics and vascular risk factors prevalence (Table). I Twenty-two out of 85 (26%) patients with brain MRI at 6-8 weeks had new infarct(s) in the territory and 9% of the entire cohort had stroke recurrence during follow-up. Coexistence of IAD and IDE in the target vessel was not associated to subsequent ischemic events (21.4% versus 29.4%; P=0.54). Conclusion: IDE is a common finding in patients with moderate-to-severe IAD. Superimposed IDE did not increase the already heightened risk of subsequent ischemic events in patients with symptomatic IAD. ClinicalTrials.gov Identifier: NCT02121028

Conservative treatments for acute nonarteritic central retinal artery occlusion: Do they work?

Acute central retinal arterial occlusion has a very poor visual prognosis. Unfortunately, there is a dearth of evidence to support the use of any of the so-called “conservative” treatment options for CRAO, and the use of thrombolytics remains controversial. In this review, we address a variety of these “conservative” pharmacologic treatments (pentoxifylline, isosorbide dinitrate, and acetazolamide) and nonpharmacologic approaches (carbogen, hyperbaric oxygen, ocular massage, anterior chamber paracentesis, laser embolectomy, and hemodilution) that have been proposed as potential treatments of this condition. We conclude that the available evidence for all treatments is insufficient to conclude that any treatment will influence the natural history of this disorder. Management of CRAO patients should instead focus on reducing the risk of subsequent ischemic events, including cerebral stroke. Certain patients may be considered for acute treatment with thrombolytics, although further research must clarify the efficacy, safety, and optimal use of these therapies.

Proton pump inhibitors and risk for recurrent ischemic events or death in outpatients with symptomatic artery disease

Bagkground and aimsThe influence of proton pump inhibitors (PPIs) on outcome in patients with symptomatic artery disease remains controversial. MethodsFRENA is a prospective registry of consecutive outpatients with symptomatic coronary (CAD), cerebrovascular (CVD) or peripheral artery disease (PAD). We compared the risk for subsequent ischemic events or death according to the use of PPIs. ResultsAs of December 2016, 5170 patients were recruited: 1793 (35%) had CAD, 1530 (30%) CVD and 1847 (35%) had PAD. Overall, 2289 patients (44%) were regularly using PPIs. During a median follow-up of 36 months, 172 patients suffered a recurrent myocardial infarction, 139 had ischemic stroke, 71 underwent limb amputation and 267 died (cardiovascular death, 109). On multivariable analysis, patients using PPIs were at a lower risk for subsequent limb amputation (hazard ratio [HR]: 0.53; 95%CI: 0.30–0.94), a similar risk for myocardial infarction (HR: 0.78; 95%CI: 0.55–1.10) or stroke (HR: 0.93; 95%CI: 0.64–1.35) and at a higher risk of death (HR: 1.37; 95%CI: 1.04–1.79). ConclusionsAmong stable outpatients with symptomatic artery disease, the use of PPIs was associated with a lower risk for subsequent ischemic events but a higher risk for death.

Clinical consequences of bleeding among individuals with a recent acute coronary syndrome: Insights from the APPRAISE-2 trial

In this post hoc analysis, we evaluated 7,392 high-risk patients (median follow-up 241 days) with a recent ACS randomized to apixaban or placebo in APPRAISE-2. Clinical events during a 30-day period after Thrombolysis in Myocardial Infarction (TIMI) major/minor bleeding were analyzed using unadjusted and adjusted Cox proportional-hazards models. In total, 153 (2.1%) patients experienced TIMI major/minor bleeding during follow-up. Bleeding risk for patients on triple therapy (apixaban, thienopyridine, and aspirin) was increased compared with those on dual therapy (apixaban plus aspirin: hazard ratio [HR] 2.02, 95% CI 1.08-3.79; thienopyridine plus aspirin: HR 1.99, 95% CI 1.41-2.83). Those receiving apixaban/aspirin had similar bleeding risk compared with those receiving thienopyridine/aspirin (HR 1.01, 95% CI 0.53-1.95). Patients who experienced TIMI major/minor bleeding had an increased risk of 30-day all-cause mortality (HR 24.7, 95% CI 15.34-39.66) and ischemic events (HR 6.7, 95% CI 3.14-14.14). In a contemporary cohort of high-risk patients after ACS, bleeding was associated with a significantly increased risk of subsequent ischemic events and mortality regardless of antithrombotic or anticoagulant strategy. Patients receiving apixaban plus aspirin had a similar bleeding risk compared with those receiving thienopyridine plus aspirin. Interventions to improve outcomes in patients after ACS should include strategies to optimize the reduction in ischemic events while minimizing the risk of bleeding.

Dual Antiplatelet Therapy: How Long Is Long Enough?

The optimal duration of dual antiplatelet therapy (DAPT) has been a topic of considerable interest in recent years, as the risk of stent thrombosis has decreased with newer generation stents and the impact of significant bleeding events on clinical outcomes is increasingly apparent. The purpose of this review is to highlight the landmark studies examining short-duration (6months or less) and extended-duration (greater than 12months) DAPT as well as provide information about prediction tools to help guide individualized patient treatment decisions. Short-duration DAPT is acceptably safe when clinically necessary, though recent trials demonstrate non-significant trends towards increased risk of ischemic events with shorter durations. Extended-duration DAPT clearly confers a reduced risk of subsequent ischemic events but at an increased risk of bleeding. Understanding the perceived ischemic and bleeding risks for each individual patient is paramount in deciding targeted DAPT duration. For patients at a higher bleeding risk with a low ischemic risk, short-duration DAPT (6months) is acceptable. For patients with continued ischemic risk factors and a low bleeding risk, extended-duration DAPT (up to 30months) is recommended. The PRECISE DAPT and DAPT prediction tools are helpful in making this determination.

Efficacy and safety of short-term dual antiplatelet therapy (≤6 months) after percutaneous coronary intervention for acute coronary syndrome: A systematic review and meta-analysis of randomized controlled trials.

Patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) are at increased risk for subsequent ischemic events. Short-term dual antiplatelet therapy (DAPT) (≤6 months) is inferior to standard or long-term DAPT in patients who undergo PCI for ACS events. We conducted a systematic review and meta-analysis of randomized controlled trials that compared short-term (≤6 months) to long-term (≥12 months) DAPT after PCI for ACS. We searched MEDLINE, EMBASE, SCOPUS, and the Cochrane Central Register of Controlled Trials database. Ten randomized controlled trials, including a total of 12 696 patients, met our inclusion criteria. For short-term DAPT, duration of therapy ranged from 3 to 6 months, while long-term DAPT ranged from 12 to 24 months. The majority of studies used clopidogrel and second-generation drug-eluting stents. No statistically significant difference was found between short-term and long-term DAPT with regard to myocardial infarction (odds ratio 1.21; 95% confidence interval 0.94-1.57; P = 0.14), stent thrombosis (odds ratio 1.54; 95% confidence interval 1.00-2.38; P = 0.052), or major bleeding events (odds ratio 0.74; 95% confidence interval 0.49-1.11; P = 0.14). There was no significant difference in all-cause mortality, cardiac death, or net adverse cardiac and cerebrovascular events. Our meta-analysis demonstrated that short-term DAPT (<6 months) after PCI for ACS was not associated with increased risk of myocardial infarction or stent thrombosis when compared to long-term DAPT.

Efficacy of Carotid Endarterectomy for Mild (

Carotid endarterectomy (CEA) is known to reduce stroke risk in patients with symptomatic, moderate to severe carotid stenosis but has no apparent impact in patients with symptomatic, mild (less than 50%) carotid stenosis. However, recent development of noninvasive imaging modalities has shown that a certain subgroup of patients are at high risk for further ischemic events despite antiplatelet therapy. This study, therefore, aimed to clarify the patients' clinical features and explore the impact of CEA for them. This prospective cohort study included 74 patients who underwent CEA for symptomatic carotid stenosis between April 2012 and December 2016. Of these, 16 (22%) had mild (less than 50%) carotid stenosis. Their demographic, radiologic, intraoperative, and pathologic findings were precisely analyzed, and their outcome after CEA was examined for 38.5 ± 13.3 months. Of these 16 patients, 12 had already been treated with antiplatelets against previous ischemic cerebrovascular or coronary artery diseases. Plaque magnetic resonance imaging revealed that all patients had vulnerable plaque, including lipid-rich plaque (n= 6) and intraplaque hemorrhage (n= 10). Intraoperative observations confirmed this. Histologic analysis revealed that inflammatory cells and fragile angiogenesis were widely found in the specimens. Only 1 patient experienced transient (less than 30 days) neurologic deficit after CEA, and none of them repeated cerebrovascular events during the follow-up period. It is not rare the patients who are at high risk for subsequent ischemic events because of vulnerable plaque despite mild (less than 50%) carotid stenosis. Magnetic resonance imaging is quite useful to noninvasively detect such vulnerable plaque. CEA is a promising procedure to treat these patients.

Autonomic Nervous System and Stress to Predict Secondary Ischemic Events after Transient Ischemic Attack or Minor Stroke: Possible Implications of Heart Rate Variability.

Transient ischemic attack (TIA) and minor stroke have high risks of recurrence and deterioration into severe ischemic strokes. Risk stratification of TIA and minor stroke is essential for early effective treatment. Traditional tools have only moderate predictive value, likely due to their inclusion of the limited number of stroke risk factors. Our review follows Hans Selye’s fundamental work on stress theory and the progressive shift of the autonomic nervous system (ANS) from adaptation to disease when stress becomes chronic. We will first show that traditional risk factors and acute triggers of ischemic stroke are chronic and acute stress factors or “stressors,” respectively. Our first review shows solid evidence of the relationship between chronic stress and stroke occurrence. The stress response is tightly regulated by the ANS whose function can be assessed with heart rate variability (HRV). Our second review demonstrates that stress-related risk factors of ischemic stroke are correlated with ANS dysfunction and impaired HRV. Our conclusions support the idea that HRV parameters may represent the combined effects of all body stressors that are risk factors for ischemic stroke and, thus, may be of important predictive value for the risk of subsequent ischemic events after TIA or minor stroke.

Updating the Evidence of the Interaction Between Clopidogrel and CYP2C19-Inhibiting Selective Serotonin Reuptake Inhibitors: A Cohort Study and Meta-Analysis.

We previously found that patients who initiate clopidogrel while treated with a cytochrome P450 (CYP) 2C19-inhibiting selective serotonin reuptake inhibitor (SSRI) have a higher risk of subsequent ischemic events than patients treated with other SSRIs. It is not known whether initiating an inhibiting SSRI while treated with clopidogrel will also increase risk of ischemic events. The aim of this study was to assess clinical outcomes following initiation of a CYP2C19-inhibiting SSRI versus initiation of other SSRIs among patients treated with clopidogrel and to update existing evidence on the clinical impact of clopidogrel-SSRI interaction. Using five US databases (1998-2013), we conducted a cohort study of clopidogrel initiators who encountered treatment with SSRI during their clopidogrel therapy. Patients were matched by propensity score (PS) and followed for as long as they were exposed to both clopidogrel and index SSRI group. Outcomes were a composite ischemic event (myocardial infarction, ischemic stroke, or a revascularization procedure, whichever came first) and a composite major bleeding event (gastrointestinal bleed or hemorrhagic stroke, whichever came first). Results were combined via random-effects meta-analysis with previous evidence from subjects initiating clopidogrel while on SSRI therapy. The PS-matched cohort comprised 2346 clopidogrel users starting CYP2C19-inhibiting SSRI therapy and 16,115 starting other SSRIs (mean age 61years; 59% female). Compared with those treated with a non-inhibiting SSRI, the hazard ratio (HR) for patients treated with a CYP2C19-inhibiting SSRI was 1.07 (95% confidence interval [CI] 0.82-1.40) for the ischemic outcome and 1.00 (95% CI 0.42-2.36) for bleeding. The pooled estimates were 1.11 (95% CI 1.01-1.22) for ischemic events and 0.80 (95% CI 0.55-1.18) for bleeding. We observed similar estimates of association between the two studies. The updated evidence still indicates a small decrease in clopidogrel effectiveness associated with concomitant exposure to clopidogrel and CYP2C19-inhibiting SSRIs.

Pioglitazone Prevents Diabetes in Patients With Insulin Resistance and Cerebrovascular Disease.

The Insulin Resistance Intervention after Stroke (IRIS) trial recently found that pioglitazone reduced risk for stroke and myocardial infarction in patients with insulin resistance but without diabetes who had had a recent ischemic stroke or transient ischemic attack (TIA). This report provides detailed results on the metabolic effects of pioglitazone and the trial's prespecified secondary aim of diabetes prevention. A total of 3,876 patients with recent ischemic stroke or TIA, no history of diabetes, fasting plasma glucose (FPG) <126 mg/dL, and insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR) score >3.0 were randomly assigned to pioglitazone or placebo. Surveillance for diabetes onset during the trial was accomplished by periodic interviews and annual FPG testing. At baseline, the mean FPG, HbA1c, insulin, and HOMA-IR were 98.2 mg/dL (5.46 mmol/L), 5.8% (40 mmol/mol), 22.4 μIU/mL, and 5.4, respectively. After 1 year, mean HOMA-IR and FPG decreased to 4.1 and 95.1 mg/dL (5.28 mmol/L) in the pioglitazone group and rose to 5.7 and 99.7 mg/dL (5.54 mmol/L), in the placebo group (all P < 0.0001). Over a median follow-up of 4.8 years, diabetes developed in 73 (3.8%) participants assigned to pioglitazone compared with 149 (7.7%) assigned to placebo (hazard ratio [HR] 0.48 [95% CI 0.33-0.69]; P < 0.0001). This effect was predominately driven by those with initial impaired fasting glucose (FPG >100 mg/dL [5.6 mmol/L]; HR 0.41 [95% CI 0.30-0.57]) or elevated HbA1c (>5.7% [39 mmol/mol]; HR 0.46 [0.34-0.62]). Among patients with insulin resistance but without diabetes who had had a recent ischemic stroke or TIA, pioglitazone decreased the risk of diabetes while also reducing the risk of subsequent ischemic events. Pioglitazone is the first medication shown to prevent both progression to diabetes and major cardiovascular events as prespecified outcomes in a single trial.

Abstract TP232: Symptomatic Plaque with Low-grade Stenosis Which Retains Hyperintensity After an Ischemic Event may Indicate a High Risk of a Subsequent Ipsilateral Ischemic Event

Introduction: Intraplaque hemorrhage (IPH) has been reported to be a characteristic feature of a vulnerable plaque, indicated by an area of high signal intensity on carotid MRI. It has been reported that symptomatic low-grade stenosis with IPH is strongly associated with ischemic events, but there are limited data regarding the dynamics of the carotid plaque signal. The aim of this study was to assess the time-dependent change of carotid plaque in the symptomatic patient with low-grade stenosis. Methods: Thirty-eight symptomatic patients with carotid low-grade stenosis (0.31 between time points was considered significant. We then investigated changes in rSI and subsequent ipsilateral ischemic events. Result: Of the 38 patients, there were strong-positive and positive plaque at baseline in 22 and 12 patients, respectively. During a mean follow-up period of 42.5 months, 26 positive plaques (74%) at baseline kept an rSI of &gt;1.25, and all of 4 negative plaques at baseline changed positive. Strong-positive plaques at baseline showed a lower tendency to be negative than positive plaque (p=0.08). Twenty-one of the 38 patients (55%) experienced a total of 26 recurrent ischemic events. In patients who experienced recurrent ischemic events, 19 plaques (73%) were strong-positive and 5 plaques (19%) were positive. Compared to the most recent carotid MRI, rSI at the event was stable in 18 patients (69%) and increased in 8 patients (31%). Conclusions: Most symptomatic plaque with low-grade stenosis retained its hyperintensity after ischemic events and had a high rate of subsequent ipsilateral ischemic events. A sustaining high signal intensity might be associated with an increased risk of subsequent ischemic events. Follow-up observation by carotid MRI has the potential to increase the accuracy of stroke risk stratification in the management of carotid low-grade stenosis.

Thrombotic complications associated with early and late nonadherence to dual antiplatelet therapy.

This study sought to assess the frequency and clinical impact of dual antiplatelet therapy (DAPT) nonadherence. There are limited data on the impact of DAPT nonadherence during the first year after a second-generation drug-eluting stent placement. After successful Endeavor zotarolimus-eluting stent implantation, 2,265 patients were enrolled in a registry with limited exclusions and monitored during 12 months of prescribed DAPT. Predictors of any nonadherence (ANA) at 6 months were analyzed by multivariable analysis, and the association between ANA at 6 or 12 months with the endpoints of death, myocardial infarction, and stent thrombosis was assessed. The study population included 30% female patients, 34% with diabetes and 36% with acute coronary syndromes. ANA occurred in 208 patients (9.6%) before 6 months and 378 patients (18.5%) before 1 year. Major bleeding (odds ratio [OR]: 12.83, 95% confidence interval [CI]: 7.55 to 21.80, p < 0.001) was the only predictor of ANA at 6 months. In time-dependent analyses, ANA before 6 months was associated with an increased risk of death or myocardial infarction (7.6% vs. 3.0%, p < 0.001) and a numerical increase in stent thrombosis (2.0% vs. 0.9%, p = 0.12). After adjustment for baseline differences, ANA within 6 months remained associated with death or MI (OR: 1.95, 95% CI: 1.02 to 3.75). ANA occurring after 6 months did not increase the risk of subsequent ischemic events. DAPT ANA occurs frequently and is associated with increased risk for thrombotic complications if it occurs within the first 6 months. Major bleeding was a significant correlate of DAPT ANA within 6 months. (EDUCATE: The MEDTRONIC Endeavor Drug Eluting Stenting: Understanding Care, Antiplatelet Agents and Thrombotic Events; NCT01069003).