Major Vascular Events In Patients Research Articles

Risk and benefit of reinitiating antiplatelet therapy after spontaneous intracerebral hemorrhage: a systematic review and meta-analysis.

This study aimed to assess the risks and benefits of reinitiating antiplatelet therapy after spontaneous intracerebral hemorrhage (ICH) through a systematic review and meta-analysis. The reinitiation of antiplatelet therapy is commonly used to reduce major vascular events in patients with occlusive vascular diseases, but its use in ICH patients may increase the risk of bleeding. A comprehensive search was conducted on databases including MEDLINE, Embase, Cochrane Library, clinicaltrials.gov, and the International Standard Randomized Controlled Trial Number Register (ISRCTN). Randomized controlled trials and cohort studies that investigated the use of reinitiation of antiplatelet therapy after hemorrhagic stroke were included. Data on ICH recurrence, major bleeding events, major occlusive cerebrovascular events, ischemic stroke, and all-cause mortality were extracted and analyzed using R software. The study included a total of 10 studies with 6,340 participants. The control group consisted of 2,964 patients who did not receive antiplatelet therapy, while the study group included 1,285 patients who received antiplatelet therapy without restrictions on the specific drug type. The meta-analysis showed that antiplatelet therapy significantly reduced the risk of ICH recurrence (RR=0.72, 95% CI: 0.59, 0.87), had no significant impact on the risk of severe bleeding events (RR=0.93, 95% CI: 0.80, 1.08), significantly lowered the risk of major occlusive cerebrovascular events (RR=0.59, 95% CI: 0.46, 0.77), had no significant effect on the risk of ischemic stroke (RR=0.77, 95% CI: 0.53, 1.12), and did not significantly influence the risk of all-cause mortality (RR=0.75, 95% CI: 0.45, 1.15). Based on the findings, reinitiating antiplatelet therapy after spontaneous ICH appears to be generally safe. However, the benefits in terms of reducing the risk of all-cause mortality are not evident and require confirmation through large-scale, long-term, prospective, randomized controlled trials.

Effect of atherosclerosis on 5-year risk of major vascular events in patients with transient ischaemic attack or minor ischaemic stroke: an international prospective cohort study

The prevalence of atherosclerosis and the long-term risk of major vascular events in people who have had a transient ischaemic attack or minor ischaemic stroke, regardless of the causal relationship between the index event and atherosclerosis, are not well known. In this analysis, we applied the ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other causes, and dissection) grading system to estimate the 5-year risk of major vascular events according to whether there was a causal relationship between atherosclerosis and the index event (ASCOD grade A1 and A2), no causal relationship (A3), and with or without a causal relationship (A1, A2, and A3). We also aimed to estimate the prevalence of different grades of atherosclerosis and identify associated risk factors. We analysed patient data from TIAregistry.org, which is an international, prospective, observational registry of patients with a recent (within the previous 7 days) transient ischaemic attack or minor ischaemic stroke (modified Rankin Scale score of 0-1) from 61 specialised centres in 21 countries in Europe, Asia, the Middle East, and Latin America. Using data from case report forms, we applied the ASCOD grading system to categorise the degree of atherosclerosis in our population (A0: no atherosclerosis; A1 or A2: atherosclerosis with stenosis ipsilateral to the cerebral ischaemic area; A3: atherosclerosis in vascular beds not related to the ischaemic area or ipsilateral plaques without stenosis; and A9: atherosclerosis not assessed). The primary outcome was a composite of non-fatal stroke, non-fatal acute coronary syndrome, or cardiovascular death within 5 years. Between June 1, 2009, and Dec 29, 2011, 4789 patients were enrolled to TIAregistry.org, of whom 3847 people from 42 centres participated in the 5-year follow-up; 3383 (87·9%) patients had a 5-year follow-up visit (median 92·3% [IQR 83·4-97·8] per centre). 1406 (36·5%) of 3847 patients had no atherosclerosis (ASCOD grade A0), 998 (25·9%) had causal atherosclerosis (grade A1 or A2), and 1108 (28·8%) had atherosclerosis that was unlikely to be causal (grade A3); in 335 (8·7%) patients, atherosclerosis was not assessed (grade A9). The 5-year event rate of the primary composite outcome was 7·7% (95% CI 6·3-9·2; 101 events) in patients categorised with grade A0 atherosclerosis, 19·8% (17·4-22·4; 189 events) in those with grade A1 or A2, and 13·8% (11·8-16·0; 144 events) in patients with grade A3. Compared with patients with grade A0 atherosclerosis, patients categorised as grade A1 or A2 had an increased risk of the primary composite outcome (hazard ratio 2·77, 95% CI 2·18-3·53; p<0·0001), as did patients with grade A3 (1·87, 1·45-2·42; p<0·0001). Except for age, male sex, and multiple infarctions on neuroimaging, most of the risk factors that were identified as being associated with grade A1 or A2 atherosclerosis were modifiable risk factors (ie, hypertension, dyslipidaemia, overweight, smoking cigarettes, and low physical activity; all p values <0·025). In patients with transient ischaemic attack or minor ischaemic stroke, those with atherosclerosis have a much higher risk of major vascular events within 5 years than do those without atherosclerosis. Preventive strategies addressing complications of atherosclerosis should focus on individuals with atherosclerosis rather than grouping together all people who have had a transient ischaemic attack or minor ischaemic stroke (including those without atherosclerosis). AstraZeneca, Sanofi, Bristol Myers Squibb, SOS Attaque Cérébrale Association.

Abstract TMP104: Effect Of Statin Therapy In Stroke Patients With Low Baseline Low-density Lipoprotein Cholesterol

Introduction: Post-stroke statin therapy is known to reduce subsequent major vascular events in patients with ischemic stroke. However, the efficacy of statin therapy in acute ischemic stroke patients with low low-density lipoprotein cholesterol (LDL-C) at baseline is not well defined. This study aimed to determine whether statin therapy would be beneficial in stroke patients with low or well-controlled LDL-C at baseline. Methods: We assessed ischemic stroke patients with baseline LDL-C &lt;100mg/dL without prior statin therapy or &lt;70mg/dL with prior statin therapy who were hospitalized between 2011 and 2020. The effect of post-stroke statin therapy on major vascular events, defined as a composite of recurrent stroke, myocardial infarction, and all-cause death within 1 year after stroke was assessed using multivariable Cox regression analyses. Results: A total of 3,350 patients (mean age 68.6 ± 13.9 years; 62.9% male; 21.5% with previous statin therapy; 37.0% with atherosclerotic stroke) were included. The mean baseline LDL-C of the patients was 73.6 ± 17.6mg/dL, which did not differ between patients with or without post-stroke statin therapy (74.0 ± 17.7mg/dL in statin users; 73.4 ± 17.6mg/dL in statin non-users). Statins were prescribed in 2,638 (78.8%) after stroke and LDL-C was significantly reduced in patients who received statin therapy (65.9 ± 21.7mg/dL in statin users; 80.2 ± 26.7mg/dL in statin non-users). Statin therapy was significantly associated with a lower risk of major vascular events (adjusted hazard ratios (aHR) 0.37 [95% confidence interval (CI) 0.31 - 0.46]). However, post-stroke LDL-C reduction (aHR 1.00 [95% CI 0.995 - 1.01]), percent LDL-C reduction (aHR 0.999 [95% CI 0.996 - 1.003]) and achieved LDL-C &lt;55mg/dL after stroke (aHR 0.96 [95% CI 0.67 - 1.37]) were not associated with the occurrence of major vascular events within 1 year after stroke. Conclusions: Post-stroke statin therapy was associated with a reduction in major vascular events after acute ischemic stroke, even in patients with low or well-controlled LDL-C. However, achieved LDL-C levels were not associated with post-stroke major vascular events in this population.

Impact of Lower Versus Higher LDL Cholesterol Targets on Cardiovascular Events After Ischemic Stroke in Patients With Diabetes.

After an ischemic stroke with evidence of atherosclerosis, lipid-lowering treatment with a target LDL cholesterol of <70 mg/dL compared with 100 ± 10 mg/dL reduced the risk of subsequent cardiovascular events. In this analysis, we explored the effect in the subgroup of patients with diabetes compared with the subgroup without, as well as in those with newly diagnosed diabetes. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned at a 1:1 ratio to a target LDL cholesterol of <70 mg/dL or 100 ± 10 mg/dL using statin or ezetimibe. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and death resulting from vascular disease. We performed a prespecified analysis to evaluate the effect in patients with diabetes. Of 2,860 patients enrolled, 643 had diabetes at baseline, with a mean age of 66.2 years and baseline LDL cholesterol of 127 mg/dL, and were followed for a median of 3 years. The primary composite end point occurred in 27 (8.2%) of 328 patients in the lower-target group and in 44 (14.0%) of 315 patients in the higher-target group (adjusted hazard ratio [HR] 0.56; 95% CI 0.34-0.89; P = 0.016). In patients without diabetes, the HR was 0.87 (95% CI 0.66-1.14; P = 0.31; interaction P = 0.15). In those with diabetes, there were three intracranial hemorrhages in both randomization groups (0.9% vs. 1.0%, respectively). Newly diagnosed diabetes occurred in 98 (9.2%) of 1,070 and in 80 (7.4%) of 1,085 patients in the lower- and higher-target groups, respectively (HR 1.27; 95% CI 0.94-1.71; P = 0.11), and baseline higher HbA1c was the unique multivariable predictor. In conclusion, after an ischemic stroke with evidence of atherosclerosis, targeting an LDL cholesterol of <70 mg/dL compared with 100 ± 10 mg/dL consistently reduced the risk of subsequent stroke and other major vascular events in patients with and without diabetes, but the higher risk in those with diabetes yielded a higher absolute risk reduction, with number needed to treat of 17.

Targeting Inflammation to Reduce Residual Cardiovascular Risk.

Patients with established cardiovascular disease are at high risk for recurrent myocardial infarction, stroke, and cardiovascular death. The term residual risk refers to this risk that persists, even after optimal treatment. Considerable progress has been made to understand the biological basis of residual risk and to devise therapies that can safely and effectively reduce risk. The presence of ongoing subclinical vascular inflammation is known to be a marker of elevated residual risk, and reductions in measures of vascular inflammation predict improved outcome in these patients. Recent trials of anti-inflammatory agents have specifically tested the hypothesis that inflammation reduction reduces residual cardiovascular risk. Most prominent among these are the CANTOS, COLCOT, and CIRT trials. CANTOS enrolled patients with prior myocardial infarction (MI) and a high-sensitivity C-reactive protein ≥ 2 mg/L and reported a 15% reduction in major adverse cardiovascular events (MACE; HR 0.85, 95% CI 0.74-0.98) with the interleukin-1β inhibitor canakinumab. In COLCOT, colchicine 0.5mg daily led to a 23% relative risk reduction (HR 0.77, 95% CI 0.61-0.96) in major vascular events in patients with recent acute coronary syndrome. By contrast, CIRT was stopped early for lack of benefit of low-dose methotrexate in preventing MACE in patients with coronary artery disease and either type 2 diabetes or the metabolic syndrome. Ongoing subclinical inflammation is an important marker of risk in patients with established cardiovascular disease, and novel therapies targeted at specific inflammatory pathways now demonstrate efficacy for the prevention of major adverse cardiovascular events.

Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial.

The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established. We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27-single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years. After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events (Ptrend=0.005) and major coronary events (Ptrend<0.0001). Individuals with intermediate and high genetic risk scores had 1.23- and 1.65-fold increased hazard for major coronary events, respectively. Elevated genetic risk was additive to major atherosclerotic risk factors and identified patients more likely to benefit from evolocumab. There was no benefit for major vascular events in patients without multiple clinical risk factors or high genetic risk (hazard ratio [HR], 1.02; absolute risk reduction [ARR], -0.2%, P=0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75-0.998], P=0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55-0.86], P=0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk (Ptrend for HR=0.017, ARR Ptrend=0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk. Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.

Blood pressure variability in subacute stage and risk of major vascular events in ischemic stroke survivors.

We aimed to investigate whether blood pressure (BP) in the subacute stage of ischemic stroke affects subsequent vascular events after acute ischemic stroke. From a prospective stroke registry database, consecutive ischemic stroke patients arriving within 48 h of onset were identified. The mean and SD of SBP per patient (SBPmean and SBPSD) in the subacute stage (from 72 h of onset to discharge), were calculated. Primary outcome was a composite of stroke, myocardial infarction and vascular death that occurred within 1 year after hospital discharge. A Cox proportional hazards model was applied to elucidate whether the increase of SBPmean and SBPSD would increase the hazards of the primary outcome. Of 4415 patients (age, 66.7 ± 13.2 years; men, 69.5%), mean ± SD of SBPmean and SBPSD in the subacute stage was 137.3 ± 15.4 and 13.3 ± 3.9 mmHg, respectively. Primary outcome events occurred in 6.9% during the first year after stroke. There was a significant dose-response relationship between the SBPSD and the risk of the primary outcome (P = 0.004), but not between SBPmean and the risk (P = 0.78). Interpolating the change of adjusted hazard ratio using restricted cubic spine function suggested an existence of a threshold effect of SBPSD and a U-shaped relationship of SBPmean for the composite event. This study shows that BP variability but not mean BP in the subacute stage of ischemic stroke may increase 1-year risk of major vascular events in patients surviving its acute stage.

Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial

BackgroundThe COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the combination of low-dose rivaroxaban and aspirin reduced major vascular events in patients with stable vascular disease. ObjectivesThe purpose of this study was to identify subsets of patients at higher risk of recurrent vascular events, which may help focus the use of rivaroxaban and aspirin therapy. MethodsCOMPASS patients with vascular disease were risk stratified using 2 methods: the REACH (REduction of Atherothrombosis for Continued Health) atherothrombosis risk score and CART (Classification and Regression Tree) analysis. The absolute risk differences for rivaroxaban with aspirin were compared to aspirin alone over 30 months for the composite of cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or vascular amputation; for severe bleeding; and for the net clinical benefit. ResultsHigh-risk patients using the REACH score were those with 2 or more vascular beds affected, history of heart failure (HF), or renal insufficiency, and by CART analysis were those with ≥2 vascular beds affected, history of HF, or diabetes. Rivaroxaban and aspirin combination reduced the serious vascular event incidence by 25% (4.48% vs. 5.95%, hazard ratio: 0.75; 95% confidence interval: 0.66 to 0.85), equivalent to 23 events prevented per 1,000 patients treated for 30 months, at the cost of a nonsignificant 34% increase in severe bleeding (1.34; 95% confidence interval: 0.95 to 1.88), or 2 events caused per 1,000 patients treated. Among patients with ≥1 high-risk feature identified from the CART analysis, rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months. ConclusionsIn patients with vascular disease, further risk stratification can identify higher-risk patients (≥2 vascular beds affected, HF, renal insufficiency, or diabetes). The net clinical benefit remains favorable for most patients treated with rivaroxaban and aspirin compared with aspirin.

More Intensive LDL-C Lowering Reduces Major Vascular Events Beyond Current Recommendations: Systematic Review and Meta-Analysis

Aims: To determine the relationship between more intensive low-density lipoprotein (LDL-C) lowering therapy and relative risk of major vascular events (MVEs) across different LDL-C levels. Methods: Randomised trials of statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that reported rates of MVEs were included. Random-effects and network meta-analyses evaluated associations between baseline LDL-C, achieved LDL-C, degree of LDL-C lowering and 10-year risk of cardiovascular (CVD) death with the relative risk (RR) of MVEs. Results: Fifty studies, totalling 316,605 patients with mean follow-up 3.6 ± 1.6 years were included. Although more intensive LDL-C lowering was associated with greater reductions in MVEs in patients with higher baseline LDL-C (p < 0.001), there was benefit in further lowering LDL-C amongst subgroups of patients with all baseline LDL-C <2.07 mmol/l (RR, 0.89; 95% CI, 0.82–0.96). In a network meta-analysis, patients with achieved LDL-C <1.50 mmol/l were most likely free from MVEs (surface under the cumulative ranking curve, 0.98), followed by 1.50–1.79, 1.80–2.59, 2.60–3.39, 3.40–4.09 and ≥4.10 mmol/l respectively. In meta-regression of primary prevention trials, LDL-C lowering therapy provided greater RR reductions in MVEs in populations with lower 10-year risk of CVD death (p = 0.030). Patients aged >75 years who received intensive LDL-C lowering therapy had significantly less MVEs. There was significantly more adverse drug reactions in the intensive LDL-C lowering arm (RR, 1.18; 95% CI, 1.10–1.27), but no significant difference in serious adverse effects. Conclusions: This meta-analysis provides new evidence that further lowering LDL-C is associated with greater reductions in MVEs beyond current recommendations.

Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: Analysis From FOURIER.

The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab. The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared. A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval [CI],1.22-1.53), 1.78 (95% CI, 1.59-1.99), and 1.39 (95% CI, 1.24-1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71-0.91), 18% (HR, 0.82; 95% CI, 0.72-0.93), and 21% (HR, 0.79; 95% CI, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85-1.05), 8% (HR, 0.92; 95% CI, 0.84-1.02), and 7% (HR, 0.93; 95% CI, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ≈1% in the low-risk groups (0.8%, 1.3%, and 1.2%). Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

Direct-acting antiviral drugs for chronic hepatitis C and risk of major vascular events: a systematic review.

Direct-acting antiviral drugs (DAAs) were recently approved for treating hepatitis C virus-related chronic hepatitis. As advanced chronic liver disease may predispose patients to thrombotic events, it is still uncertain whether DAAs may influence the actual risk of major arterial and venous thrombotic events. We performed a systematic review to assess the incidence of major vascular events in patients receiving DAAs for HCV chronic hepatitis during phase-III randomized controlled trials (RCTs). Two reviewers identified studies through Pubmed database until October 2015. Reporting and incidence of any vascular events were compared with reporting and incidence of major bleeding, anemia (a prespecified safety outcome) and headache (a common non-prespecified safety outcome). 33 RCTs, encompassing 14,764 patients, were included. Only 13 (39%) and 4 (12%) RCTs provide data on any arterial or venous events, respectively. Occurrence of anemia and headache is reported in all studies. Crude unweighted rate of major arterial events is 0.16% (95% CI 0.10-0.24) of the total included population and 0.47% in those 13 RCTs reporting data. Crude unweighted rate of major venous events is 0.03% of the total included population (95% CI 0.01-0.08) and 0.22% in those four RCTs reporting data. Crude unweighted rate of major bleeding is 0.07% (95% CI 0.03-0.1). Incidence of thrombotic events in HCV patients receiving DAAs may be low, but an incorrect estimation cannot be excluded.

Clinical Significance of Isolated Atypical Transient Symptoms in a Cohort With Transient Ischemic Attack.

Contrary to typical transient symptoms (TS), atypical TS, such as partial sensory deficit, dysarthria, vertigo/unsteadiness, unusual cortical visual deficit, and diplopia, are not usually classified as symptoms of transient ischemic attack when they occur in isolation, and their clinical relevance is frequently denied. Consecutive patients with recent TS admitted in our transient ischemic attack clinic (2003-2008) had systematic brain, arterial, and cardiac investigations. We compared the prevalence of recent infarction on brain imaging, major investigational findings (symptomatic intracranial or extracranial atherosclerotic stenosis ≥50%, cervical arterial dissection, and major source of cardiac embolism), and 1-year risk of major vascular events in patients with isolated typical or atypical TS and nonisolated TS, after exclusion of the main differential diagnoses. Among 1850 patients with possible or definite ischemic diagnoses, 798 (43.1%) had isolated TS: 621 (33.6%) typical and 177 (9.6%) atypical. Acute infarction on brain imaging was similar in patients with isolated atypical and typical TS but less frequent than in patients with nonisolated TS, observed in 10.0%, 11.5%, and 15.3%, respectively (P<0.0001). Major investigational findings were found in 18.1%, 26.4%, and 26.3%, respectively (P=0.06). One-year risk of a major vascular events was not significantly different in the 3 groups. Transient ischemic attack diagnosis should be considered and investigated in patients with isolated atypical TS.

Abstract 13635: Atorvastatin for the Prevention of Major Vascular Events in Patients Undergoing Non-Cardiac Surgery: The LOAD-Pilot Randomized Clinical Trial

Background: There is not a single established effective and safe intervention to prevent major perioperative vascular complications that commonly occur in the first 30 days after noncardiac surgery. Hypothesis: We evaluated the feasibility of a multicenter randomized controlled trial (RCT) testing the perioperative effects of statins. Methods: This is a double blind, placebo-controlled RCT testing a short course of atorvastatin 80mg before surgery, followed by 40mg 12 hours after surgery and then 40mg/day for 7 days in patients undergoing noncardiac surgery who were at risk of a major perioperative vascular complication. The primary outcome (major vascular events) was a composite of all-cause mortality, nonfatal myocardial infarction, MINS (myocardial injury after noncardiac surgery) without myocardial infarction and nonfatal stroke at 30 days after randomization. All analysis followed the intention-to-treat principle. Results: We enrolled 587 patients from 30 centers in Brazil. Mean age was 66.6 years, 37.1% were males, 22.0% had previous cardiovascular disease, 50.2% had diabetes and 89.7 % had hypertension. The majority of participants underwent general (35.9%), orthopedic (30.0%), gynecologic (8.4%), urologic (7.3%), and vascular (6.6%) surgery. A total of 51 out of 300 patients (17.0%) suffered a major vascular complication in the atorvastatin group compared to 49 out of 287 patients (17.1%) in the control group at 30 days (hazard ratio [HR] 1,02; 95% confidence interval (CI) 0.68 to 1.52; P = 0.93). No significant effect was observed on the 30-day secondary outcomes of death or myocardial infarction (8.0% versus [vs.] 7.7%, respectively; HR 0.94; 95% CI 0.52 to 1.70; P = 0.84), myocardial infarction (3.7% vs. 4.5%, respectively; HR 0.84; 95% CI 0.37 to 1.93; P = 0.68), MINS (14.0% vs.15.0%; HR 0.94; 95% CI 0.53 to 1.67; P = 0.84), and all-cause mortality (4.7% vs. 4.5%; HR 1.22; 95% CI 0.53 to 2.78; P = 0.64). Conclusions: The LOAD Trial confirms that a multicenter perioperative statin trial is feasible and highlights the need for large RCTs to establish effective and safe interventions. The study also suggests that effects of a perioperative statin on major vascular complications are, at best, moderate in size, questioning the robustness of prior data.

The “Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes”: Study protocol

Background and aimsThe rate of mortality in diabetic patients, especially of cardiovascular origin, is about twice as much that of nondiabetic individuals. Thus, the pathogenic factors shaping the risk of mortality in such patients must be unraveled in order to target intensive prevention and treatment strategies. The “Sapienza University Mortality and Morbidity Event Rate (SUMMER) study in diabetes” is aimed at identifying new molecular promoters of mortality and major vascular events in patients with type 2 diabetes mellitus (T2DM). Methods/designThe “SUMMER study in diabetes” is an observational, prospective, and collaborative study conducted on at least 5000 consecutive patients with T2DM, recruited from several diabetes clinics of Central–Southern Italy and followed up for a minimum of 5 years. The primary outcome is all-cause mortality; the secondary outcomes are cardiovascular mortality, acute myocardial infarction, stroke, and dialysis. A biobank will be created for genomic, transcriptomic, and metabolomic analysis, in order to unravel new molecular predictors of mortality and vascular morbidity. DiscussionThe “SUMMER study in diabetes” is aimed at identifying new molecular promoters of mortality and major vascular events in patients with T2DM. These novel pathogenic factors will most likely be instrumental in unraveling new pathways underlying such dramatic events. In addition, they will also be used as additional markers to increase the performance of the already existing risk-scoring models for predicting the above-mentioned outcomes in T2DM, as well as for setting up new preventive and treatment strategies, possibly tailored to specific pathogenic backgrounds. Trial registrationClinicalTrials.gov, NCT02311244; URL https://clinicaltrials.gov/ct2/show/NCT02311244?term=SUMMER&rank=5.

ROCKET AF adds more concerns about Digoxin safety in patients with atrial fibrillation

In a recent article in the Journal, we have reviewed the adverse cardiovascular outcomes observed with digoxin use in the PALLAS study.1 The PALLAS study was designed to determine if dronedarone would reduce major vascular events in patients with permanent atrial fibrillation (AF).2 However the study was stopped early because of safety reasons, as a significant number of patients on the dronedarone arm reached the co-primary end point composite of stroke, myocardial infarction, systemic embolism, or cardiovascular death. Data sub-analyses suggested that digoxin-dronedarone interaction was responsible for the higher arrhythmic death rate observed in the trial. These observations are consistent with several other studies that demonstrate the potential hazard of the use of digoxin in heart failure and/or atrial fibrillation.A more recent article published in the Lancet studied the use and outcomes of digoxin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism in Atrial Fibrillation (ROCKET AF) trial.3 The investigators concluded that digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF.

Influenza vaccination and cardiovascular risk in patients with recent TIA and stroke.

To determine whether current influenza vaccination is associated with reduced risk of major vascular events in patients with recent ischemic stroke or TIA of mainly atherothrombotic origin. Data were pooled from 2 prospective cohort studies, the OPTIC Registry (n = 3,635) and the AMISTAD Study (n = 618), and from the randomized PERFORM Trial (n = 19,120), all of which included patients with recent ischemic stroke or TIA. Influenza vaccination status was determined in 23,110 patients. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or vascular death up to 2 years. Secondary outcomes were myocardial infarction and stroke separately. Influenza vaccination had no association with the primary outcome in the propensity score-matched cohort (hazard ratio 0.97, 95% confidence interval [CI] 0.85-1.11; p = 0.67) or in the propensity score-adjusted cohort (hazard ratio 1.00, 95% CI 0.89-1.12; p = 0.99). Similarly, the risk of stroke and myocardial infarction did not differ between the vaccinated group and the unvaccinated group; in the matched cohort, the hazard ratio was 1.01 (95% CI 0.88-1.17; p = 0.89) for stroke and 0.84 (95% CI 0.59-1.18; p = 0.30) for myocardial infarction. Influenza vaccination was not associated with reduced outcome events in patients with recent atherothrombotic ischemic stroke after considering all baseline characteristics (including concomitant medications) associated with influenza vaccination.

Intracranial atherosclerosis: current understanding and perspectives.

The importance of intracranial atherosclerotic disease (ICAD) as a cause of stroke is underscored as compared to that of extracranial carotid stenosis and nonvalvular atrial fibrillation. Recent large clinical trials of ICAD, which evaluated the effectiveness of anticoagulation and stenting to prevent thromboembolism and restore hemodynamic compromise, failed to reduce major vascular events in patients with ICAD. These trials showed the importance of optimal control of risk factors to reduce major vascular events in these patients. Recent advances in risk factors for ICAD are summarized, together with possible reasons for race-ethnic differences in the prevalence of ICAD. In addition, the failure of the major clinical trials of ICAD may be caused by limitations in the understanding of ICAD. Unlike in patients with extracranial carotid stenosis or atrial fibrillation, stroke associated with ICAD occurs in association with various stroke mechanisms such as in situ thrombotic occlusion, artery-to-artery embolism, hemodynamic insufficiency, and branch occlusion. In clinical trials of ICAD, patients with all these types of ICAD were included. However, treatment effects may differ among the different types of ICAD. Treatment strategies might be selected based on clinical features (including the time after onset) and serologic and neuroimaging biomarkers (including diffusion-weighted image pattern and plaque images). Additional clinical trials considering these features are needed.

Review: Statins reduce mortality and major vascular events in patients with no history of CV disease

Source Citation Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;(1):CD004816. 23440795

Coronary Artery Disease and Risk of Major Vascular Events After Cerebral Infarction

The impact of asymptomatic coronary artery disease on the risk of major vascular events in patients with cerebral infarction is unknown. Four hundred five patients with acute cerebral infarction underwent carotid, femoral artery, thoracic, and abdominal aorta ultrasound examination. Of 342 patients with no known coronary heart disease, 315 underwent coronary angiography. We evaluated the 2-year risk of major vascular events (myocardial infarction, resuscitation after cardiac arrest, hospitalization for unstable angina or heart failure, stroke, or major peripheral arterial disease events) in patients with known coronary heart disease (n=63), and in the no known coronary heart disease group (n=315) as a function of coronary angiographic status (n=315). At 2 years, the estimated risk of major vascular events was 11.0% (95% confidence interval, 8.2-14.7). According to baseline coronary angiography, estimated risk was 3.4% in patients with no coronary artery disease (n=120), 8.0% with asymptomatic coronary artery stenosis <50% (n=113), 16.2% with asymptomatic coronary artery stenosis ≥ 50% (n=81), and 24.1% with known coronary heart disease (P<0.0001). Using no coronary artery disease as the reference, the age- and sex-adjusted hazard ratio (95% confidence interval) of vascular events was 2.10 (0.63-6.96) for asymptomatic coronary stenosis <50%, 4.36 (1.35-14.12) for asymptomatic coronary stenosis ≥ 50%, and 6.86 (2.15-21.31) for known coronary artery disease. In patients with nonfatal cerebral infarction, presence and extent of asymptomatic stenoses on coronary angiography are strong predictors of major vascular events within 2 years.

Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial

SummaryBackgroundPrevious studies have suggested that any benefits of folic acid-based therapy to lower serum homocysteine in prevention of cardiovascular events might be offset by concomitant use of antiplatelet therapy. We aimed to establish whether there is an interaction between antiplatelet therapy and the effects of folic acid-based homocysteine-lowering therapy on major vascular events in patients with stroke or transient ischaemic attack enrolled in the vitamins to prevent stroke (VITATOPS) trial.MethodsIn the VITATOPS trial, 8164 patients with recent stroke or transient ischaemic attack were randomly allocated to double-blind treatment with one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, and 500 μg vitamin B12) and followed up for a median 3·4 years (IQR 2·0–5·5) for the primary composite outcome of stroke, myocardial infarction, or death from vascular causes. In our post-hoc analysis of the interaction between antiplatelet therapy and the effects of treatment with B vitamins on the primary outcome, we used Cox proportional hazards regression before and after adjusting for imbalances in baseline prognostic factors in participants who were and were not taking antiplatelet drugs at baseline and in participants assigned to receive B vitamins or placebo. We also assessed the interaction in different subgroups of patients and different secondary outcomes. The VITATOPS trial is registered with ClinicalTrials.gov, number NCT00097669, and Current Controlled Trials, number ISRCTN74743444.FindingsAt baseline, 6609 patients were taking antiplatelet therapy and 1463 were not. Patients not receiving antiplatelet therapy were more likely to be younger, east Asian, and disabled, to have a haemorrhagic stroke or cardioembolic ischaemic stroke, and to have a history of hypertension or atrial fibrillation. They were less likely to be smokers and to have a history of peripheral artery disease, hypercholesterolaemia, diabetes, ischaemic heart disease, and a revascularisation procedure. Of the participants taking antiplatelet drugs at baseline, B vitamins had no significant effect on the primary outcome (488 patients in the B-vitamins group [15%] vs 519 in the placebo group [16%]; hazard ratio [HR] 0·94, 95% CI 0·83–1·07). By contrast, of the participants not taking antiplatelet drugs at baseline, B vitamins had a significant effect on the primary outcome (123 in the B-vitamins group [17%] vs 153 in the placebo group [21%]; HR 0·76, 0·60–0·96). The interaction between antiplatelet therapy and the effect of B vitamins on the primary outcome was significant after adjusting for imbalance in the baseline variables (adjusted p for interaction=0·0204).InterpretationOur findings support the hypothesis that antiplatelet therapy modifies the potential benefits of lowering homocysteine with B-vitamin supplementation in the secondary prevention of major vascular events. If validated, B vitamins might have a role in the prevention of ischaemic events in high-risk individuals with an allergy, intolerance, or lack of indication for antiplatelet therapy.FundingAustralia National Health and Medical Research Council, UK Medical Research Council, Singapore Biomedical Research Council, and Singapore National Medical Research Council.