Risk Of Major Vascular Events Research Articles

Statin therapy in acute cardioembolic stroke with no guidance-based indication.

It is uncertain whether patients with cardioembolic stroke and without a guidance-based indication for statin therapy should be administered a statin for prevention of subsequent vascular events. This study was performed to determine whether the statin therapy is beneficial in preventing major vascular events in this population. Using a prospective multicenter stroke registry database, we identified patients with acute cardioembolic stroke who were hospitalized between 2008 and 2015. Patients who had other established indications for statin therapy according to current guidelines were excluded. Major vascular event was defined as a composite of stroke recurrence, myocardial infarction, and vascular death. We performed frailty model analysis with the robust sandwich variance estimator using the stabilized inverse probability of treatment weighting method to estimate hazard ratios of statin therapy on outcomes. Of 6,124 patients with cardioembolic stroke, 2,888 (male 44.6%, mean age 75.3 years, 95% confidence interval [CI] 74.8-75.8) were eligible, and 1,863 (64.5%) were on statin therapy during hospitalization. After a median follow-up of 359 days, cumulative incidences of major vascular events were 9.3% in the statin users and 20.5% in the nonusers (p < 0.001 by log-rank test). The adjusted hazard ratios of statin therapy were 0.39 (95% CI 0.31-0.48) for major vascular events, 0.81 (95% CI 0.57-1.16) for stroke recurrence, 0.28 (95% CI 0.21-0.36) for vascular death, and 0.53 (95% CI 0.45-0.61) for all-cause death. Starting statin during the acute stage of ischemic stroke may reduce the risk of major vascular events, vascular death, and all-cause death in patients with cardioembolic stroke with no guidance-based indication for statin.

Proprotein convertase subtilisin/kexin type 9: an update on the cardiovascular outcome studies.

Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme, statins, are powerful cholesterol-lowering medications and have provided outstanding contributions to the primary and secondary prevention of coronary heart disease. Low-density lipoprotein cholesterol (LDL-C) is one of the major modifiable cardiovascular risk factors, indeed, every 1.0 mmol/L (38.7 mg/dL) reduction in LDL cholesterolaemia corresponds to a 21% lowering in the risk of major vascular events. In this context, the pharmacological approach with PCSK9 monoclonal antibodies is considered a promising non-statin therapeutic option for the management of lipid disorders in patients with persistent cardiovascular risk, including patients with diabetes mellitus. Data from two large clinical trials have indisputably demonstrated the efficacy of alirocumab and evolocumab in preventive major adverse cardiovascular events in high risk, secondary-prevention patients with clinical manifestation of atherosclerotic cardiovascular diseases. Finally, PCSK9 monoclonal antibodies did not increase the risk of serious adverse events, neurocognitive events, new-onset of diabetes, muscle-related events, or myalgia.

Intensive LDL cholesterol-lowering treatment beyond current recommendations for the prevention of major vascular events: a systematic review and meta-analysis of randomised trials including 327 037 participants

The benefits of LDL cholesterol-lowering treatment for the prevention of atherosclerotic cardiovascular disease are well established. However, the extent to which these effects differ by baseline LDL cholesterol, atherosclerotic cardiovascular disease risk, and the presence of comorbidities remains uncertain. We did a systematic literature search (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, from inception up to June 15, 2019) for randomised controlled trials of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors with at least 1000 patient-years of follow-up. Random-effects meta-analysis and meta-regressions were done to assess for risk of major vascular events (a composite of cardiovascular mortality, non-fatal myocardial infarction, non-fatal ischaemic stroke, or coronary revascularisation) per 1 mmol/L (38·7 mg/dL) reduction in LDL cholesterol concentrations. 327 037 patients from 52 studies were included in the meta-analysis. Each 1 mmol/L reduction in LDL cholesterol was associated with a 19% relative risk (RR) reduction for major vascular events (RR 0·81 [95% CI 0·78-0·84]; p<0·0001). Similar reductions (per 1 mmol/L reduction in LDL cholesterol) were found in trials with participants with LDL cholesterol 2·60 mmol/L or lower, 2·61-3·40 mmol/L, 3·41-4·10 mmol/L, and more than 4·1 mmol/L (p=0·232 for interaction); and in a subgroup of patients who all had a baseline LDL cholesterol less than 2·07 mmol/L (80 mg/dL; RR 0·83 [95% CI 0·75-0·92]; p=0·001). We found greater RR reductions in patients at lower 10-year atherosclerotic cardiovascular disease risk (change in RR per 10% lower 10-year atherosclerotic cardiovascular disease 0·97 [95% CI 0·95-0·98]; p<0·0001) and in patients at younger age across a mean age of 50-75 years (change in RR per 10 years younger age 0·92 [0·83-0·97]; p=0·015). We found no difference in RR reduction for participants with or without diabetes (p=0·878 for interaction) and chronic kidney disease (p=0·934 for interaction). For each 1 mmol/L LDL cholesterol lowering, the risk reduction of major vascular events is independent of the starting LDL cholesterol or the presence of diabetes or chronic kidney disease. Patients at lower cardiovascular risk and younger age might have a similar relative reduction in risk with LDL-cholesterol lowering therapies and future studies should investigate the potential benefits of earlier intervention. None.

Microvascular complications burden (nephropathy, retinopathy and peripheral polyneuropathy) affects risk of major vascular events and all-cause mortality in type 1 diabetes: a 10-year follow-up study

BackgroundMicrovascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes.MethodsWe recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis.ResultsOut of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59–7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65–15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42–94.57], p < 0.0001). After adjustments, HRs were: 1 MC 2.05 (95% CI 0.88–4.76), 2 MC 1.98 (95% CI 0.75–5.21), 3 MC 7.02 (95% CI 2.44–20.20, p = 0.002). Forty-nine subjects (6.7%) had at least one cardiovascular event, and cumulative incidence went from no-MC 2.2% (Ref) to 1 MC 5.0%; (HR 2.27 [95% CI 0.96–5.38]), 2 MC 26.8% (HR 12.88 [95% CI 5.82–28.50]) and 3 MC 40.9% (HR 29.34 [95% CI 11.59–74.25], p < 0.0001). Upon adjustments, HRs were: 1 MC 1.59 (95% CI 0.65–3.88), 2 MC 4.33 (95% CI 1.75–10.74), 3 MC 9.31 (95% CI 3.18–27.25, p < 0.0001). Thirty-five individuals (4.8%) had at least one coronary event, which cumulative incidence increased with MC burden (p < 0.0001).ConclusionsIn type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.

Increased Thromboxane in Patients with Polycythemia Vera and Thrombosis: Evidence for Aspirin-Unsuppressible Platelet Activation In Vivo

Polycyhemia vera (PV) is a myeloproliferative neoplasm characterized by increased thromboxane (TX) production and thrombotic risk. It is reported that serum TXB2 concentrations in PV patients are twofold higher than healthy controls and that low-dose aspirin (ASA) therapy reduces the risk of major vascular events by 50 to 60%. To evaluate this unusual size of the effect of ASA we have studied platelet count, hematocrit (HCT), β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, TXB2, as primary indicator of platelet activation, the platelet function activity (PFA), as indicator of ASA platelet sensitivity, and the clotting time (CT), as parameter of thrombin formation. We studied 60 patients (38 men, 22 women; mean age 51 years, range 32-70) with PV according to WHO criteria. The mean duration of disease was 12 years. All patients were on ASA 100 mg once daily. All patients were on phlebotomy. None had inherited or acquired thrombotic risk factors. Of 60 patients, 30 had thrombosis (20 men, 10 women) and 30 had no thrombosis. Of 30 with thrombosis, 15 developed nonfatal myocardial infarction (10 men, 5 women) defined by chest pain of typical intensity and duration and ST-segment elevation in any limb lead on electrocardiography, 10 had nonfatal stroke (8 men, 2 women) confirmed with the use of magnetic resonance imaging, and 5 (2 men , 3 women) had deep venous thrombosis confirmed by ultrasonography. Platelet count and HCT were measured by automated analyzer. β-TG and PF4 were determined by ELISA. TXB2 was measured by radioimmunoassay technique. ASA platelet sensitivity was measured by Platelet Function Analyzer (PFA-100). CT was measured by thromboelastometry. The mean platelet count was 430±170x109/L. The mean HCT value was 42±3%. The patients with thrombosis had high β-TG, PF4 and TXB2 (110±45 IU/ml, 45±21 IU/ml, and 1.700±1.990 nmol/L, respectively), shortened C/EPI closure time (T, unit: s, n.v. 84-160 s) (55±10 s) and shortened CT (CT, unit: s. n.v. 100-240 s) (45±20 s) whereas the patients without thrombosis had normal β-TG, PF4 and TXB2 (20±11 IU/ml, 6±2 IU/ml, and 800±280 nmpl/L, respectively), prolonged C/EPI closure time (249±40 s) and normal CT (110±20 s). These findings might suggest that in PV patients and thrombotic complications might need a platelet-selective dosage of ASA. Disclosures No relevant conflicts of interest to declare.

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.

P656Risk of major gastrointestinal bleed in relation to vascular disease risk in 0.5M UK Biobank participants

Abstract Background Low-dose aspirin is of established benefit for secondary prevention of cardiovascular events but in primary prevention the benefit is finely balanced with the hazard of major bleeds, and in particular gastrointestinal (GI) bleeds. Purpose To investigate non-vascular, non-genetic risk factors for major GI bleeds and derive a score for GI bleed risk which may help identify who will receive most net benefit from aspirin. Methods In the UK Biobank prospective study of 0.5M participants aged 40–69 at recruitment, prior history of cardiovascular disease, bleeds and other medical conditions was ascertained from self-reported diagnoses and electronic heath records (EHR) prior to recruitment. Major GI bleed during 6 years of follow-up was defined based on coded diagnoses and duration of hospital stay. Non-vascular risk factors for bleed were identified from amongst 100 baseline and prior disease factors using a stepwise regression with adjustment for established vascular risk factors, aspirin and warfarin use. 10-way cross-validation was used when making risk scores. Results Among the primary prevention population without prior intracranial bleed, serious extracranial bleed or gastrointestinal ulcer in the 6 months prior to recruitment, 1682 (0.06%/y) participants had a major GI bleed (1006 upper GI, 676 lower GI) with a mean stay in hospital of 3.2 days. Antiplatelet use (in 11%) and anticoagulant use (in 1%), were associated with 1.5 and 4 fold risks of GI bleed, respectively. Stepwise regression identified a non-vascular risk score for major bleed with a 4-fold risk ratio across fifths (Figure). But the score was also associated with a 2-fold risk ratio for major vascular events. Conclusions Major GI bleeds cause substantial morbidity. A 4-fold difference in bleed risk across quintiles was distinguishable by a score based largely on EHR prior disease information and frailty measures. This score is applicable in other contexts and will be applied in the ASCEND randomised trial of daily aspirin to provide randomized evidence of the net benefit of aspirin in different risk categories. However, vascular risk factors predicted risk of GI bleeds, and non-vascular risk factors for GI bleed predicted risk of major vascular events; so the net benefit from aspirin may vary only modestly across categories by vascular and bleed risks.

Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials.

Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; P<0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; P<0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; P=0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; P<0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; P=0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; P<0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]). In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

Suggested clinical approach for the diagnosis and management of ‘statin intolerance’ with an emphasis on muscle‐related side‐effects

Hyperlipidaemia is a major risk factor for cardiovascular morbidity and mortality. 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors ('statins') are first-line therapies for hyperlipidaemia. For each 1.0 mmoL/L reduction in low-density lipoprotein (LDL)-cholesterol, statins reduce the risk of major vascular events by 21% and all-cause mortality by 9%. Owing to their clinical effectiveness and excellent safety profile, many Australians are prescribed statins. There has been widespread reporting of possible side-effects, particularly muscle pains. Conversely, statin cessation relating to possible side-effects exposes patients to increased risk of vascular events and death. Although there is clinical consensus for diagnosing rare side-effects (e.g. myopathy or rhabdomyolysis), confirming that statins cause other less common side-effects (e.g. memory impairment) is difficult as strong randomised trial evidence related to statins and non-muscle-related side-effects is lacking. A stepwise approach to possible statin intolerance, consistent definitions and a simple flowchart may improve diagnosis and management. An increasing array of potential treatments is emerging, including intermittent statin dosing, new LDL-lowering drugs, LDL apheresis and supplements. Optimal statin use and management of statin intolerance should improve cardiovascular care and clinical outcomes.

Serious Adverse Effects of Extended-release Niacin/Laropiprant: Results From the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial

PurposeThe Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial of patients at high risk of vascular disease found that adding extended-release niacin-laropiprant to intensive statin-based LDL-lowering therapy had no benefit on cardiovascular outcomes. However, the trial also identified previously unrecognized serious adverse effects (including new-onset diabetes, bleeding, and infection). Our objective was to explore the safety profile of niacin-laropiprant and examine whether any patients were at lower (or higher) risk of its adverse effects. MethodsHPS2-THRIVE was a randomized, double-blind trial of niacin-laropiprant (2000/40 mg/d) versus placebo among 25,673 patients at high risk of vascular disease. Information on all serious adverse events was collected during a median of 3.9 years of study treatment. Effects of niacin-laropiprant on new-onset diabetes, disturbances of diabetes control, bleeding, infection, and gastrointestinal upset were estimated by (1) time after randomization, (2) severity, (3) baseline characteristics, (4) baseline risk of the adverse event of interest, and (5) risk of major vascular event. FindingsThe hazard ratio (HR) for new-onset diabetes with niacin/laropiprant was 1.32 (95% CI, 1.16–1.51; P < .001), which corresponded to an absolute excess of 4 people (95% CI, 2–6) developing diabetes per 1000 person-years in the study population as a whole. Among the 8299 participants with diabetes at baseline, the HR for serious disturbances in diabetes control was 1.56 (95% CI, 1.35–1.80), corresponding to an absolute excess of 12 (95% CI, 8–16) per 1000 person-years. The HR was 1.38 (95% CI, 1.17–1.63; P < .001) for serious bleeding, corresponding to an absolute excess of 2 (95% CI, 1–3) per 1000 person-years and 1.22 (95% CI, 1.11–1.34; P < .001) for serious infection, corresponding to an absolute excess of 4 (95% CI, 2–6) per 1000 person-years. The excess risks of these serious adverse events were larger in the first year after starting niacin-laropiprant therapy than in later years (except for the excess of infection, which did not appear to attenuate with time), and the risks of nonfatal and fatal events were similarly increased. The absolute excesses of each of these adverse effects were similar regardless of the baseline risk of the outcome. ImplicationsPractitioners or patients considering the use of niacin (in addition to, or instead of, a statin) despite the lack of evidence of cardiovascular benefits (at least when added to effective statin therapy) should take account of the significant risks of these serious adverse effects when making such decisions. ClinicalTrials.gov identifier: NCT00461630.

Impact of ADCY9 Genotype on Response to Anacetrapib.

Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to cholesteryl ester transfer protein (CETP) inhibitor therapy differs by ADCY9 genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification) demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with preexisting atherosclerotic vascular disease. In the present study, we examined the impact of ADCY9 genotype on response to anacetrapib in the REVEAL trial. Individuals with stable atherosclerotic vascular disease who were treated with intensive atorvastatin therapy received either anacetrapib 100 mg daily or matching placebo. Cox proportional hazards models, adjusted for the first 5 principal components of ancestry, were used to estimate the effects of allocation to anacetrapib on major vascular events (a composite of coronary death, myocardial infarction, coronary revascularization, or presumed ischemic stroke) and the interaction with ADCY9 rs1967309 genotype. Among 19 210 genotyped individuals of European ancestry, 2504 (13.0%) had a first major vascular event during 4 years median follow-up: 1216 (12.6%) among anacetrapib-allocated participants and 1288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotype: hazard ratio (HR) = 0.92 (95% CI, 0.81-1.05) for GG; HR = 0.94 (95% CI, 0.84-1.06) for AG; and HR = 0.93 (95% CI, 0.76-1.13) for AA genotype carriers, respectively; genotypic P for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events or meaningful differences in lipid response to anacetrapib. The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib. The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib. URL: https://www. gov. Unique identifier: NCT01252953. URL: http://www.isrctn.com. Unique identifier: ISRCTN48678192. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2010-023467-18.

Microvascular Complications Burden Affects Risk of Major Vascular Events and All-Cause Mortality in Type 1 Diabetes: A 10-Year Follow-Up Study

Background: To which extent the presence of one or more microvascular complication (MC) affects cardiovascular (CV) outcomes and mortality in diabetes is still debated. We evaluated the relationship between MC and incidence of major CV events and all-cause mortality in type 1 diabetes. Methods: We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10*8±2*5 years. Hazard Ratios (HR) for outcomes were determined by unadjusted and adjusted Cox regressions. Findings: Out of 774 individuals, 54·9% had no-MC, 32·3% 1 MC, 9·7% 2 MC and 3·1% 3 MC. A total of 54 deaths occurred. Death rate increased from no-MC 2·1% (Ref) to 1-MC 7·2% (HR 3·54 [95% CI 1·59–7·87]), 2-MC 14·7% (6·41 [2·65–15·49]) and 3-MC 66·7% (41·73 [18·42–94·57]; p<0·0001). After adjustments, HRs were: 1-MC 2·05 (0·88–4·76), 2-MC 1·98 (0·75–5·21), 3-MC 7·02 (2·44–20·20; p=0·002). Forty-nine subjects had at least one CV event, and cumulative incidence went from no-MC 2·2% (Ref) to 1-MC 5·0%; (2·27 [0·95–5·38]), 2-MC 26·8% (12·88 [5·82–28·50]) and 3-MC 40·9% (29·34 [11·59–74·25]; p<0·0001). Upon adjustments, HRs were: 1-MC 1·59 (0·65–3·88), 2-MC 4·33 (1·75–10·74), 3-MC 9·31 (3·18–27·25; p<0·0001). Thirty-five individuals had at least one coronary event, which cumulative incidence increased with MC burden (p<0·0001). Interpretation: In type 1 diabetes, MC burden increases in an independent dose-dependent manner the risk of major CV outcomes and all-cause mortality. The presence and number of MC should be considered in stratifying overall CV risk in type 1 diabetes. Funding Statement: This work was supported by a grant from the Regione Toscana, Italy. (December 19, 2011), ID number D55E11002680005. Declaration of Interests: MG has received travel grants from AstraZeneca and Novo Nordisk. MA has received speaker/advisory honoraria from Abbott Laboratories. FC has received travel grants from Novo Nordisk. GD reports past participation in advisory boards from AstraZeneca, Eli Lilly and Co and Novartis Pharmaceuticals. SDP reports past participation in advisory boards and/or receiving research grants from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk, Sanofi, Servier, and Takeda Pharmaceuticals. GP has received travel grants and speaker/advisory honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, Merck Sharp & Dohme, Mundipharma Pharmaceuticals, Novo Nordisk, and Takeda Pharmaceuticals. All other authors (EG, RG, DL, MR, and PF) declare no competing interests. Ethics Approval Statement: The Ethics Committee of the University of Pisa approved the study protocol, consent procedures and data analysis plan.

MiR-3188 (rs7247237-C>T) Single-Nucleotide Polymorphism Is Associated With the Incidence of Vascular Complications in Chinese Patients With Type 2 Diabetes.

miR-3188, one of the earliest discovered microRNAs, is involved in regulating the mTOR-p-PI3K/AKT pathway, thus affecting the progression of diabetic complications. In this study, we observed that the miR-3188 (rs7247237-C>T) polymorphism not only affected the production of nitric oxide (NO) production in endothelial cells, but also significantly associated with the incidence of vascular complications in Chinese patients with type 2 diabetes. Mechanistic analyses indicate that miR-3188 (rs7247237-T) polymorphism inhibited its own expression and upregulated the expression of gstm1 and trib3, which impairs NO production in human endothelial cells through inactivating AKT/eNOS signal transduction pathway. In addition, our clinical retrospective study indicated that, compared with patients with the CC genotype (n = 351), patients with rs7247237 TT + CT genotypes (n = 580) exhibited an increased risk of major vascular events during intensive glucose control treatment (hazard ratio = 1.560; 95% CI: 1.055-2.307, P = 0.025). Simultaneously, the risk of major vascular events was marginally decreased in patients with the CC genotype during intensive glucose control treatment compared with standard treatment (hazard ratio = 0.666; 95% CI: 0.433-1.016, P = 0.053). Our findings indicate that the miR-3188 (rs7247237-C>T) polymorphism is associated with the incidence of vascular complications in Chinese patients with type 2 diabetes, likely due to its remarkable effect on miR-3188 expression.

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

SummaryBackgroundAntiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.MethodsThe REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).FindingsBetween May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).InterpretationThese results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.FundingBritish Heart Foundation.

Statins Reduce Major Vascular Events in All Age Groups

According to this study: Statin therapy significantly reduces the risk of major vascular events in all age groups, but the proportional reductions in risk decreased slightly with increasing age.

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.

Statins reduce risk of major vascular events in all ages, study finds

Statins reduce risk of major vascular events in all ages, study finds

PCSK9 inhibitors: clinical evidence and implementation.

The gene encoding PCSK9 was first identified and linked to the phenotype of familial hypercholesterolaemia approximately 15 years ago. Soon after, studies uncovered the role of PCSK9 in the regulation of LDL-receptor recycling and identified loss-of-function variants ofPCSK9 that were associated with low circulating levels of LDL cholesterol (LDL-C) and a reduced risk of coronary artery disease. With amazing rapidity, monoclonal antibodies against PCSK9 were developed and studied in large clinical programmes. These PCSK9 inhibitors lowered plasma LDL-C levels by approximately 60%, even in patients already receiving maximum-dose statin therapy. In the past year, three cardiovascular outcome trials were completed and showed that PCSK9 inhibitors significantly reduce the risk of major vascular events. Reassuringly, this benefit comes with no major offsetting adverse events, such as an excess of myalgias, elevation of hepatic aminotransferases levels in the plasma, incident diabetes mellitus or neurocognitive adverse events. The clinical benefit of PCSK9 inhibitors seen in these trials occurred in the setting of reducing LDL-C levels to unprecedentedly low levels, suggesting that more aggressive LDL-C targets should be adopted. New technologies to inhibit PCSK9 are now being harnessed and might further revolutionize our treatment of dyslipidaemia.

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.