Composite Cardiovascular Endpoint Research Articles

P1371HEART FAILURE HOSPITALISATIONS IN THE PIVOTAL TRIAL OF IV IRON IN HAEMODIALYSIS PATIENTS: A PRE-SPECIFIED SECONDARY ANALYSIS

Abstract Background and Aims Heart failure (HF) is a common and potentially deadly complication in patients receiving haemodialysis which is difficult to diagnose and treat. The impact of a proactive high-dose strategy compared to a reactive low-dose strategy of IV iron administration was investigated in the PIVOTAL randomised trial in incident haemodialysis patients, with fatal HF and HF hospitalisation being components of the composite primary cardiovascular endpoint as well as a pre-specified key secondary event. The aim of this analysis was to examine the effect of a proactive high-dose strategy compared to a reactive lower dose strategy on HF events in patients recruited to PIVOTAL. Method As with the primary composite cardiovascular endpoint, HF hospitalisations in PIVOTAL were recorded prospectively via an electronic database, and events were then adjudicated by a blinded Endpoint Adjudication Committee. The time-to-event analyses of the primary, secondary and post hoc outcomes were performed in the intention-to-treat population using Cox proportional hazards regression, with treatment group as the only explanatory variable. The Kaplan–Meier method was used to estimate event rates. Both fatal and non-fatal HF events were analysed as time to first event, and a recurrent event analysis was also performed for non-fatal events. Results Overall, 2141 participants were followed for a median of 2.1 years. A first fatal or non-fatal HF event occurred in 51 of 1093 patients (4.7%) in the high-dose iron group and in 70 of 1048 patients (6.7%) in the low-dose iron group (hazard ratio 0.66, 95% confidence interval 0.46 to 0.94; P<0.001) (Figure). There was a total of 63 HF events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose iron group, giving a rate ratio of 0.59 (0.40-0.87); p=0.0084. A history of HF and diabetes were independent predictors of a heart failure event. Conclusion Compared with a low-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in incident patients undergoing haemodialysis, with large relative and absolute risk reductions.

P1252ASSOCIATIONS OF SERUM SCLEROSTIN AND DKK-1 PROTEIN WITH FUTURE CARDIOVASCULAR EVENTS AND MORTALITY IN HEMODIALYSIS PATIENTS; A PROSPECTIVE COHORT STUDY

Abstract Background and Aims Sclerostin and Dickkopf-1 (Dkk-1) protein are inhibitors of the canonical Wnt/β-catenin bone pathway. Sclerostin but not Dkk-1 is associated with increased arterial stiffness. This study examined the prognostic significance of serum sclerostin and Dickkopf-related protein-1 (Dkk-1) levels for cardiovascular outcomes and mortality in hemodialysis patients. Method Serum sclerostin and Dkk-1 levels were measured with ELISA in 80 hemodialysis patients that were followed-up for a median of 45 months. Several factors that could interfere in the association of sclerostin and Dkk-1 with outcomes (including carotid-femoral pulse-wave-velocity (PWV), parathyroid hormone, calcium-phospate product and others) were assessed at baseline The primary end-point was a combination of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, hospitalization for decompensated heart failure and new-onset atrial fibrillation. Secondary end-points included cardiovascular and all-cause mortality. Results Cumulative freedom from the primary endpoint was significantly lower for higher tertiles of sclerostin (77.8%, 69.2%, and 40.7% for tertiles 1 to 3 respectively; log-rank-p=0.004). The corresponding risk for the primary outcome was gradually increasing for higher tertiles of sclerostin (Tertile 3: HR: 3.847, 95%CI: 1.502-9.851). No significant association was evident between sclerostin and all-cause mortality, whereas higher sclerostin levels presented a trend towards higher risk for cardiovascular mortality. Dkk-1 levels exhibited no association with the risk of the primary or the secondary endpoints. In stepwise Cox regression modeled analysis, sclerostin levels were associated with the primary outcome, independently of PTH, calcium-phosphate product, serum albumin, CRP and PWV levels (HR: 2.921, 95%CI: 1.401–6.090; p=0.004). Conclusion High serum sclerostin levels are associated with lower cumulative freedom and higher risk for a composite cardiovascular endpoint but not for all-cause mortality. Dkk-1 protein exhibited no association with the future risk of cardiovascular events.

The Influence of Baseline Diastolic Blood Pressure on the Effects of Intensive Blood Pressure Lowering on Cardiovascular Outcomes and All-Cause Mortality in Type 2 Diabetes.

To examine whether low baseline diastolic blood pressure (DBP) modifies the effects of intensive systolic blood pressure (SBP) lowering on cardiovascular outcomes in type 2 diabetes mellitus (T2DM). The Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial (ACCORD BP), a two-by-two factorial randomized controlled trial, examined effects of SBP (<120 vs. <140 mmHg) and glycemic (HbA1c <6% vs. 7.0-7.9% [<42 vs. 53-63 mmol/mol]) control on cardiovascular events in T2DM (N = 4,731). We examined whether effects of SBP control on cardiovascular composite were modified by baseline DBP and glycemic control. Intensive SBP lowering decreased the risk of the cardiovascular composite (hazard ratio [HR] 0.76 [95% CI 0.59-0.98]) in the standard glycemic arm but not in the intensive glycemic arm (HR 1.06 [95% CI 0.81-1.40]). Spline regression models relating the effects of the intervention on the cardiovascular composite across the range of baseline DBP did not show evidence of effect modification by low baseline DBP for the cardiovascular composite in the standard or intensive glycemic arms. The relation between the effect of the intensive SBP intervention and baseline DBP was similar between glycemic arms for the cardiovascular composite three-way interaction (P = 0.83). In persons with T2DM, intensive SBP lowering decreased the risk of cardiovascular composite end point irrespective of baseline DBP in the setting of standard glycemic control. Hence, low baseline DBP should not be an impediment to intensive SBP lowering in patients with T2DM treated with guideline-recommended standard glycemic control.

Statins and Major Adverse Limb Events in Patients with Peripheral Artery Disease: A Systematic Review and Meta-Analysis.

Statins are guidelines recommended in patients with peripheral artery disease (PAD) for the prevention of cardiovascular (CV) events. Comprehensive meta-data on the impact of statins on major adverse limb events (MALE) in PAD patients are lacking. We examined the association of statin use with MALE in patients with PAD. We performed a systematic review (registered at PROSPERO: number CRD42019137111) and metanalysis of studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of statin on MALE including amputation and graft occlusion/revascularization. Secondary endpoints were all-cause death, composite CV endpoints, CV death, and stroke. We included 51 studies with 138,060 PAD patients, of whom 48,459 (35.1%) were treated with statins. The analysis included 2 randomized controlled trials, 20 prospective, and 29 retrospective studies. Overall, 11,396 MALE events, 21,624 deaths, 4,852 composite CV endpoints, 4,609 CV deaths, and 860 strokes were used for the analysis. Statins reduced MALE incidence by 30% (pooled hazard ratio [HR]: 0.702; 95% confidence interval [CI]: 0.605-0.815) and amputations by 35% (HR: 0.654; 95% CI: 0.522-0.819), all-cause mortality by 39% (pooled HR: 0.608, 95% CI: 0.543-0.680), CV death by 41% (HR: 0.594; 95% CI: 0.455-0.777), composite CV endpoints by 34% (pooled HR: 0.662; 95% CI: 0.591-0.741) and ischemic stroke by 28% (pooled HR: 0.718; 95% CI: 0.620-0.831). Statins reduce the incidence of MALE, all-cause, and CV mortality in patients with PAD. In PAD, a high proportion of MALE events and deaths could be prevented by implementing a statin prescription in this patient population.

Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis.

Background and Purpose- The PCSK9 (proprotein convertase subtilisin-kexin type 9) monoclonal antibody evolocumab lowered LDL (low-density lipoprotein) cholesterol by 59% to 0.8 (0.5-1.2) mmol/L and significantly reduced major vascular events in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Herein, we report the results of a prespecified analysis of cerebrovascular events in the overall trial population and in patients stratified by prior stroke. Methods- FOURIER was a randomized, double-blind trial comparing evolocumab versus placebo in patients with established atherosclerosis, additional risk factors, and LDL cholesterol levels ≥1.8 (or non-HDL [high-density lipoprotein] ≥2.6 mmol/L) on statin therapy. The median follow-up was 2.2 years. We analyzed the efficacy of evolocumab to reduce overall stroke and stroke subtypes, as well as the primary cardiovascular composite end point by subgroups according to a history of stroke. Results- Among the 27 564 patients, 469 (1.7%) experienced a total of 503 strokes of which 421 (84%) were ischemic. Prior ischemic stroke, diabetes mellitus, elevated CRP (C-reactive protein), history of heart failure, older age, nonwhite race, peripheral arterial disease, and renal insufficiency were independent predictors of stroke. Evolocumab significantly reduced all stroke (1.5% versus 1.9%; hazard ratio, 0.79 [95% CI, 0.66-0.95]; P=0.01) and ischemic stroke (1.2% versus 1.6%; hazard ratio, 0.75 [95% CI, 0.62-0.92]; P=0.005), with no difference in hemorrhagic stroke (0.21% versus 0.18%; hazard ratio, 1.16 [95% CI, 0.68-1.98]; P=0.59). These findings were consistent across subgroups, including among the 5337 patients (19%) with prior ischemic stroke in whom the hazard ratios (95% CIs) were 0.85 (0.72-1.00) for the cardiovascular composite, 0.90 (0.68-1.19) for all stroke, and 0.92 (0.68-1.25) for ischemic stroke (P interactions, 0.91, 0.22, and 0.09, respectively, compared with patients without a prior ischemic stroke). Conclusions- Inhibition of PCSK9 with evolocumab added to statin in patients with established atherosclerosis reduced ischemic stroke and cardiovascular events in the total population and in key subgroups, including those with prior ischemic stroke. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633.

A scoring system for predicting individual treatment effects of statins in type 2 diabetes patients on haemodialysis.

Haemodialysis patients have high cardiovascular disease risk. Although statins reduce this risk in chronic kidney disease, randomised trials in haemodialysis patients show no benefit. Post-hoc analyses of the German Diabetes Dialysis (4D) study identified patient-specific markers associated with heterogeneous treatment effects. We combined these markers to develop a score for predicting individual effects of statins in these patients. We used data from the 4D study, enrolling 1255 haemodialysis patients with type 2 diabetes mellitus, randomised to atorvastatin or placebo and followed for a composite cardiovascular endpoint. We calculated two scores: score 1 based on all 23 predictive markers and score 2 based on 17 clinically accessible markers. Groups stratified by score 1 showed differential treatment effects: for score <26 (458 patients; 36%), the hazard ratio (95% confidence interval) was 1.54 (1.16-2.03), suggesting harm; for 26-31 (331 patients; 26%), it was 1.03 (0.72-1.48), suggesting a neutral effect; and for >31 (466 patients; 38%), it was 0.43 (0.30-0.60), suggesting a benefit. Statins also significantly reduced all-cause mortality in the benefit group. Stratification by score 2 yielded similar results but a smaller group gaining benefit (360 patients). Statin effects in haemodialysis patients can be predicted by markers associated with plausible relevant mechanisms including cholesterol metabolism, atherosclerosis, protein energy wasting, or competing risks. In clinical practice, the score could aid in risk stratification, not only to select patients who benefit from statins but also to identify those whom treatment could harm.

Does Estimated Pulse Wave Velocity Add Prognostic Information?: MORGAM Prospective Cohort Project.

The Reference Values for Arterial Stiffness Collaboration has derived an equation using age and mean blood pressure to estimated pulse wave velocity (ePWV), which predicted cardiovascular events independently of Systematic COoronary Risk Evaluation (SCORE) and Framingham Risk Score. The study aim was to investigate the independent association between ePWV and clinical outcomes in 107 599 apparently healthy subjects (53% men) aged 19 to 97 years from the MORGAM Project who were included between 1982 and 2002 in 38 cohorts from 11 countries. Using multiple Cox-regression analyses, the predictive value of ePWV was calculated adjusting for country of inclusion and either SCORE, Framingham Risk Score, or traditional cardiovascular risk factors (age, sex, smoking, systolic blood pressure, body mass index [BMI], total and high-density lipoprotein cholesterol). Cardiovascular mortality consisted of fatal stroke, fatal myocardial infarction, or coronary death, and the composite cardiovascular end point consisted of stroke, myocardial infarction, or coronary death. Model discrimination was assessed using Harrell's C-statistic. Adjusting for country and logSCORE or Framingham Risk Score, ePWV was associated with all-cause mortality (hazard ratio, 1.23 [95% CI 1.20-1.25] per m/s or 1.32 [1.29-1.34]), cardiovascular mortality (1.26 [1.21-1.32] or 1.35 [1.31-1.40]), and composite cardiovascular end point (1.19 [1.16-1.22] or 1.23 [1.20-1.25]; all P<0.001). However, after adjusting for traditional cardiovascular risk factors, ePWV was only associated with all-cause mortality (1.15 [1.08-1.22], P<0.001) and not with cardiovascular mortality (0.97 [0.91-1.03]) nor composite cardiovascular end point (1.10 [0.97-1.26]). The areas under the last 3 receiver operator characteristic curves remained unchanged when adding ePWV. Elevated ePWV was associated with subsequent mortality and cardiovascular morbidity independently of systematic coronary risk evaluation and Framingham Risk Score but not independently of traditional cardiovascular risk factors.

A PROSPECTIVE OBSERVATIONAL STUDY OF CARDIOVASCULAR COMPOSITE END POINT EVENTS AFTER PERCUTANEOUS CORONARY INTERVENTION IN THE TREATMENT OF CORONARY HEART DISEASE WITH TRADITIONAL CHINESE MEDICINE

To systematically evaluate the impact of traditional Chinese medicine (TCM) on cardiovascular composite endpoint events in patients with coronary heart disease(CHD) after percutaneous coronary intervention (PCI), so as to provide evidence-based for TCM in the long-term efficacy. This study adopts

Details on the effect of very short dual antiplatelet therapy after drug-eluting stent implantation in patients with high bleeding risk: insight from the STOPDAPT-2 trial.

Previously we briefly reported the effect of 1-month dual antiplatelet therapy (DAPT) for patients with high bleeding risk (HBR) receiving percutaneous coronary intervention (PCI) in the STOPDAPT-2 trial, but full analysis data have not been available. We conducted post hoc subgroup analysis regarding the effect of very short DAPT for HBR patients in STOPDAPT-2 trial. The primary endpoint was a 1-year composite of cardiovascular (cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) and bleeding (TIMI major/minor bleeding) outcomes. Major secondary endpoints were 1-year cardiovascular composite endpoint and bleeding endpoint. HBR was defined by the academic research consortium (ARC) HBR criteria. Among the 3009 study patients, 1054 (35.0%) were classified as HBR and 1955 (65.0%) were as non-HBR. There were no significant interactions between HBR/non-HBR subgroups and the assigned DAPT group on the primary endpoint (HBR; 3.48% vs. 5.98%, HR 0.57, 95% CI 0.32-1.03, and non-HBR; 1.81% vs. 2.36%, HR 0.78, 95% CI 0.42-1.45; P for interaction = 0.48), the major secondary cardiovascular endpoint (HBR; 3.07% vs. 4.03%, HR 0.77, 95% CI 0.40-1.48, and non-HBR; 1.41% vs. 1.61%, HR 0.89, 95% CI 0.43-1.84; P for interaction = 0.77), and the major secondary bleeding endpoint (HBR; 0.41% vs. 2.71%, HR 0.15, 95% CI 0.03-0.65, and non-HBR; 0.40% vs. 0.85%, HR 0.48, 95% CI 0.14-1.58; P for interaction = 0.22). In conclusion, the effects of 1-month DAPT for the primary and major secondary endpoints were consistent in HBR and non-HBR patients without any significant interactions. The benefit of 1-month DAPT in reducing major bleeding was numerically greater in HBR patients.Clinical trial registration Short and optimal duration of dual antiplatelet therapy after everolimus-eluting cobalt-chromium stent-2 [STOPDAPT-2]; NCT02619760.

Effects of an Antihypertensive Combination in Japanese Hypertensive Outpatients Based on the Long-acting Calcium Channel Blocker Benidipine on Vascular and Renal Events: A Sub-analysis of the COPE Trial

In the trial known as COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events), three benidipine (a Calcium Channel Blocker; CCB) regimens were compared. Hypertensive Japanese outpatients aged 40-85 years (n=3,293) who did not achieve the target blood pressure of <140/90 mmHg with benidipine 4 mg/day were treated with the diuretic thiazide (n=1,094) or a β-blocker (n=1,089) or an additional Angiotensin Receptor Blocker (ARB; n=1,110). A significantly higher incidence of hard cardiovascular composite endpoints and of fatal or non-fatal strokes was observed in the benidipine-β-blocker group compared to the benidipine-thiazide group. We further evaluated the treatment effects of the three benidipine-based regimens on vascular and renal events in a sub-analysis of the COPE patients. A total of 10 vascular events (0.8 per 1,000 person-years) including one aortic dissection (0.1 per 1,000 person-years) and nine cases of peripheral artery disease (0.8 per 1,000 person-years) were documented, as was a total of seven renal events (0.6 per 1,000 person-years). No significant differences in vascular and renal events were revealed among the three treatment groups: vascular events, p=0.92; renal events, p=0.16, log-rank test. Blood pressure-lowering therapy with benidipine combined with an ARB, β-blocker, or thiazide was similarly effective in the prevention of vascular and renal events in hypertensive outpatients, although there are not enough events to compare the difference in the three treatment groups.

Serious Adverse Events Cluster in Participants Experiencing the Primary Composite Cardiovascular Endpoint: A Post Hoc Analysis of the SPRINT Trial.

Intensively treated participants in the SPRINT study experienced fewer primary cardiovascular composite study endpoints (CVD events) and lower mortality, although 38% of participants experienced a serious adverse event (SAE). The relationship of SAEs with CVD events is unknown. CVD events were defined as either myocardial infarction, acute coronary syndrome, decompensated heart failure, stroke, or death from cardiovascular causes. Cox models were utilized to understand the occurrence of SAEs with CVD events according to baseline atherosclerotic cardiovascular disease (ASCVD) risk. SAEs occurred in 96% of those experiencing a CVD event but only in 34% (P < 0.001) of those not experiencing a CVD event. Occurrence of SAEs monotonically increased across the range of baseline ASCVD risk being approximately twice as great in the highest compared with the lowest risk category. SAE occurrence was strongly associated with ASCVD risk but was similar within risk groups across treatment arms. In adjusted Cox models, experiencing a CVD event was the strongest predictor of SAEs in all risk groups. By the end of year 1, the hazard ratios for the low, middle, and high ASCVD risk tertiles, and baseline clinical CVD group were 2.56 (95% CI = 1.39-4.71); 2.52 (1.63-3.89); 3.61 (2.79-4.68); 1.86 (1.37-2.54), respectively-a trend observed in subsequent years until study end. Intensive treatment independently predicted SAEs only in the second ASVCD risk tertile. The occurrence of SAEs is multifactorial and mostly related to prerandomization patient characteristics, most prominently ASCVD risk, which, in turn, relates to in-study CVD events.

Outpatient Registry REGION: Prospective Follow-up Data and Outcomes in Patients After Acute Cerebrovascular Accident

Aim. To estimate outcomes and risk of all-cause mortality, cardiovascular (CV) mortality, and non-fatal CV events in patients with a history of acute cerebrovascular accident (ACVA) according to data of outpatient prospective registries.Material and methods. 986 patients with a history of ACVA (aged 70.6Ѓ}10.9 years; 56.8% women) were enrolled into the outpatient registry REGION-Ryazan, including the registry of patients with ACVA of any remoteness (ACVA-AR) – 511 (aged 70.4Ѓ}10.5 years; 58.5% women) and the registry of patients, visited outpatient clinics for the first time after ACVA (ACVA-FT) – 475 (aged 70.8Ѓ}11.3 years; 54.9% women). Outcomes, risk of all-cause and CV mortality, composite CV endpoint (CV death, nonfatal myocardial infarction and ACVA), hospitalizations due to CV diseases (CVD) were evaluated during 37 (17;52) months of follow-up period.Results. 310 (31.2%) patients died during the follow-up. The most part of fatal outcomes (56.4%) was registered during the first year of follow-up, especially during the first 3 months (33.9%). Mortality among men (35.9%) was higher than among women (28.0%), р=0.008. 147 (28.8%) and 163 (34.3%) patients died in registries ACVA-AR and ACVA-FT, respectively (70.4% and 90.2% of fatal outcomes were from CV causes, respectively; р=0.04). The higher risk of death was associated with the following factors: age – hazard ratio (HR) 1.10 for each next year of age (95% confidence interval [95%CI] 1.09-1.12); sex (men) – HR 2.01 (95%CI 1.55-2.62); atrial fibrillation (AF) – HR 1.42 (95%CI 1,09-1,86); recurrent ACVA – HR 1.64 (95%CI 1.23-2.19); history of myocardial infarction (MI) – HR 1.45 (95%CI 1.09-1.93); low blood hemoglobin level – HR 2.44 (95%CI 1.59-3.79); heart rate ≥80 beats/min – HR 1.51 (95%CI 1.13-2.03); diabetes – HR 1.56 (95%CI 1.16-2.08); chronic obstructive pulmonary disease (COPD) – HR 1.89 (95%CI 1.34-2.66); no antihypertensive therapy in arterial hypertension – HR 2.03 (95%CI 1.42-2.88). The lower risk of death was associated with the following factors: prescription of ACE inhibitors (ACEI) – HR 0.60 (95%CI 0.42-0.85); angiotensin II receptor blockers (ARB) – HR 0.26 (95%CI 0.13-0.50), beta-blockers – HR 0.71 (95%CI 0.50-0.99); statins – HR 0.59 (95%CI 0.42-0.82). Factors, listed above, had significant association not only with all-cause mortality but also with CV mortality and composite CV endpoint. The higher rate of hospitalizations due to CVD was associated with younger age (incidence rate ratio [IRR] for 1 year 1.03; 95%CI 1.02-1.05; р&lt;0.001), female sex (IRR 2.40; 95%CI 1.79-3.23; р&lt;0.001), COPD (IRR 2.44; 95%CI 1.63-3.65; р&lt;0.001) and heart rate ≥80 beats/min (IRR 1.51; 95%CI 1.12-2.04; р=0.007).Conclusions. All-cause mortality in patients with a history of ACVA, enrolled in outpatient registry REGION, was 31.2% during 3-year follow-up. The proportion of CV death among the fatal cases was higher in the ACVA-FT registry than in ACVA-AR registry. The higher mortality rate was associated with the following factors: age, sex (male), recurrent ACVA, history of MI, diagnosis of AF, COPD and diabetes, low blood hemoglobin level, heart rate ≥80 beats/min, no antihypertensive therapy in arterial hypertension. The higher incidence of hospitalizations due to CVD was associated with younger age, sex (female), COPD and heart rate ≥80 beats/min. Prescription of ACEI, ARB, beta-blockers and statins was associated with lower risk of death and composite CV endpoint.

LDL cholesterol: lower, faster, younger?

Findings from recent clinical trials of LDL cholesterol lowering suggest continued benefits at lower concentrations than those previously considered acceptable. In The Lancet Diabetes & Endocrinology, Nelson Wang and colleagues emphasise this concept in their large meta-analysis 1 Wang N Fulcher J Abeysuriya N et al. 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. Lancet Diabetes Endocrinol. 2020; 8: 36-49 Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar that incorporates results of 52 randomised controlled trials of cholesterol-lowering drugs with a primary composite cardiovascular endpoint. Across three mechanistically distinct drug classes—statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors—there was a direct linear association between pharmacological LDL cholesterol lowering and relative risk reduction in cardiovascular events. A 1 mmol/L reduction in LDL cholesterol corresponded to a relative risk reduction of 19%, irrespective of baseline LDL cholesterol concentration or drug class used. Although the analysis used average LDL cholesterol concentrations in the treatment versus control groups, rather than individual participant level data, it still provides compelling evidence for the cardiovascular benefit of LDL cholesterol reduction, with no apparent lower threshold for additional benefit. 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 participantsFor 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. Full-Text PDF

Inflammation and atherosclerosis: what is on the horizon?

### Learning objectives Atherosclerosis is a chronic inflammatory process and both the innate and adaptive immune systems1 play central roles in its initiation and subsequent progression.2 Experimental models have demonstrated...

Impact of pre-existing hypertension and control status before atrial fibrillation onset on cardiovascular prognosis in patients with non-valvular atrial fibrillation: A real-world database analysis in Japan.

Hypertension is an important risk factor for non-valvular atrial fibrillation (NVAF) and its prognosis. However, there is no study to clarify the impact of pre-existing hypertension and BP control status before the onset of AF on the prognosis after the onset of AF. This retrospective real-world cohort analysis used data from the Japan Medical Data Center Co., Ltd database. The presence of NVAF and hypertension, plus the occurrence of adverse events, was based on ICD-10 codes in the database. The primary composite AF-related cardiovascular event end point included ischemic stroke, hemorrhagic stroke, and acute myocardial infarction. Of the 21523 patients identified as having new-onset NVAF between January 2005 and June 2016, 7885 had blood pressure (BP) data before the onset of NVAF available and were included in the analysis (4001 with pre-existing hypertension and 3884 without pre-existing hypertension). The rate of primary composite end point events was 10.3 and 4.4 per 1000 patient-years in patients with and without hypertension, respectively (P<.001). In addition, lower systolic BP (<120mmHg) before the onset of NVAF was associated with a lower incidence of cardiovascular events after the development of NVAF (P<.001). This highlights the importance of earlier and tighter 24-hour BP control before the onset of NVAF in patients with hypertension, not only for reducing the occurrence of new-onset of NVAF, but also for reducing both hemorrhagic and ischemic cardiovascular events after the onset of NVAF.

Time Dependent Trends in Cardiovascular Adverse Events During Follow-Up Following Carotid or Ilio-Femoral Endarterectomy

Introduction - We aimed to study if, in the presence of clinically manifest carotid or peripheral artery disease, secondary adverse cardiovascular events decreased over the last decade. Our hypothesis was supported by recent observations in the Athero-Express biobank, which showed a time-dependent decline in vulnerable plaque characteristics over the last decade in carotid and ilio-femoral derived atherosclerotic plaques. Methods - Between 2003 and 2012, in total 1697 and 530 patients were included in the Athero-Express biobank, who underwent carotid endarterectomy (CEA) or ilio-femoral endarterectomy (IFE), respectively. During three-year follow-up, composite cardiovascular endpoints were documented yearly, including: myocardial infarction (MI), coronary interventions, cerebrovascular accident (CVA), peripheral interventions and cardiovascular death. The major cardiovascular combined endpoint consisted of: MI, CVA and cardiovascular death. Results - In total, 405 (25.2%) and 236 (45.9%) patients had a composite cardiovascular endpoint within 3 years after CEA and IFE, respectively. Corrected for possible confounders, the percentage of CEA patients with a secondary cardiovascular event did not change over time (HR 0.91 (95%CI 0.65-1.28), p=0.590 for 2011-2012 vs 2003-2004). In IFE patients the incidence of secondary cardiovascular events significantly decreased only in the last two years (HR 0.62; 95%CI (0.41-0.94), p=0.024), due to a decrease in peripheral (re-)interventions in 2011-2012 (HR 0.59; 95%CI (0.37-0.94), p=0.028). No decrease in major cardiovascular events was observed in both CEA and IFE patients. Conclusion - In our cohorts of CEA and IFE patients, no consistent decrease in secondary cardiovascular events was observed despite improved measures of risk factors and stabilized atherosclerotic plaque characteristics. Especially, no differences in major cardiovascular events were observed.

FRAILTY AND THE COMPARATIVE EFFECTIVENESS AND SAFETY OF SGLT2I AND DPP4I IN OLDER ADULTS WITH TYPE 2 DIABETES

We conducted a 1:1 propensity score-matched retrospective cohort study of 83,432 patients with type 2 diabetes (mean age, 71.5 years [standard deviation, 5.0]) initiating a SGLT2i or a DPP4i in Medicare data. We estimated HRs (95% CIs) for a composite cardiovascular endpoint and severe hypoglycemia comparing the two treatments in the entire population and by the CFI-based frailty subgroups. Compared with DPP4i, SGLT2i were associated with a lower rate of the composite cardiovascular endpoint (HR, 0.70 [95% CI, 0.64-0.77]) and a similar rate of severe hypoglycemia (0.88 [0.71-1.07]) over a mean follow-up of 8.8 months. The rate of composite cardiovascular endpoint for SGLT2i vs DPP4i was consistently lower in pre-frail (0.71 [0.64-0.79]) and frail (0.67 [0.55-0.80]) subjects, but not in non-frail patients (0.98 [0.62-1.54]). The rate of severe hypoglycemia was not meaningfully different between SGLT2i and DPP4i (non-frail, 0.39 [0.12-1.16]; pre-frail, 0.83 [0.65-1.07]; frail, 1.13 [0.78-1.64]).

FRAILTY AND THE COMPARATIVE EFFECTIVENESS AND SAFETY OF SGLT2I AND SULFONYLUREA IN OLDER ADULTS WITH TYPE 2 DIABETES

We conducted a 1:1 propensity score-matched retrospective cohort study of 70,826 patients with type 2 diabetes (mean age, 71.4 years [standard deviation, 5.0]) initiating a SGLT2i or a second-generation sulfonylurea in Medicare data. We estimated HRs (95% CIs) for a composite cardiovascular endpoint and severe hypoglycemia comparing the two treatments in the entire population and by the CFI-based frailty subgroups. Compared with sulfonylureas, SGLT2is were associated with lower rates of the composite cardiovascular endpoint (HR, 0.68 [95% CI, 0.62-0.75]) and severe hypoglycemia (0.43 [0.35-0.53]) over a mean follow-up of 9.5 months. The lower rate of composite cardiovascular endpoint for SGLT2i vs sulfonylureas was observed in pre-frail (0.68 [0.61-0.77]) and frail (0.64 [0.53-0.77]) subgroups, but not in non-frail subgroup (0.95 [0.59-1.54]). The rate of severe hypoglycemia was consistently lower for SGLT2i vs sulfonylureas across frailty subgroups (non-frail, 0.37 [0.12-1.16]; pre-frail, 0.45 [0.35-0.59]; frail, 0.40 [0.28-0.58]).

FRAILTY AND THE COMPARATIVE EFFECTIVENESS AND SAFETY OF SGLT2I AND GLP1-RA IN OLDER ADULTS WITH TYPE 2 DIABETES

We conducted a 1:1 propensity score-matched retrospective cohort study of 87,218 patients with type 2 diabetes (mean age, 71.5 years [standard deviation, 5.1]) initiating a SGLT2i or a GLP1-RA in Medicare data. We estimated HRs (95% CIs) for a composite cardiovascular endpoint and severe hypoglycemia comparing the two treatments in the entire population and by the CFI-based frailty subgroups. Compared with GLP1-RA, SGLT2i were associated with similar rates of the composite cardiovascular endpoint (HR, 0.94 [95% CI, 0.86-1.03]) and severe hypoglycemia (0.87 [0.71-1.07]) over a mean follow-up of 8.6 months. The rate of composite cardiovascular endpoint was not meaningfully different between SGLT2i and GLP1-RA across non-frail (1.33 [0.80-2.23]), pre-frail (0.96 [0.85-1.08]), and frail patients (0.87 [0.73-1.04]). Similarly, the rate of severe hypoglycemia was not meaningfully different between the two treatments among non-frail (0.97 [0.20-4.80]), pre-frail (0.83 [0.64-1.08]), and frail patients (0.95 [0.67-1.34]).

FRAILTY AND THE EFFECTIVENESS AND SAFETY OF NEW GLUCOSE-LOWERING DRUGS IN OLDER ADULTS WITH TYPE 2 DIABETES

Recently, several classes of non-insulin glucose-lowering drugs, such as dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1-RA), and sodium glucose co-transporter-2 inhibitors (SGLT2i), have been approved to treat type 2 diabetes. Clinical trials have shown that GLP1RA and SGLT2i confer cardiovascular benefit, while DPP4i do not have such benefit; these drugs do not seem to increase the risk of hypoglycemia. However, due to underrepresentation of older adults with frailty and lack of frailty assessment in clinical trials, little is known about how the effectiveness and safety of these drugs change across different levels of frailty. In this symposium, we present the real-world evidence from Medicare data April 2013-December 2016 on the utilization trends of newly approved diabetes drugs (Dr. Dave) and comparative effectiveness and safety of SGLT2i vs sulfonylurea (Dr. Pawar), SGLT2i vs DPP4i (Dr. Kim), and SGLT2i vs GLP1-RA (Dr. Patorno). The outcomes were 1) composite cardiovascular endpoint of mortality, myocardial infarction, stroke, or heart failure; and 2) severe hypoglycemia, defined as emergency department visits or hospitalizations due to hypoglycemia. We applied a validated claims-based frailty index (CFI) to estimate the treatment effectiveness and safety in non-frail (CFI<0.10), pre-frail (CFI 0.10-0.19), or frail individuals (CFI≥0.20). Following individual presentations, Dr. Munshi and presenters will lead an interactive discussion about clinical implications and methodological challenges in conducting geriatric pharmacoepidemiologic studies using Medicare data. This symposium will demonstrate the utility of CFI in claims-based pharmacoepidemiologic studies and provide health care providers with new evidence to tailor diabetes pharmacotherapy based on frailty.