Lipoprotein apheresis for lipoprotein(a)-associated progressive atherosclerotic cardiovascular disease: 12-years follow-up.

Should Lipoprotein(a) be Measured in Youth?

The German Lipoprotein Apheresis Registry-Summary of the eleventh annual report

Lipoprotein(a) [Lp(a)] levels are increased in dialysis patients, suggesting that they may play a role in the elevated atherosclerotic cardiovascular disease (ASCVD) risk in this population. Few prospective studies of Lp(a) level, apolipoprotein(a) [apo(a)] size, and ASCVD have been performed in the dialysis population. An inception cohort of 833 incident dialysis patients were followed prospectively. Baseline Lp(a) was measured by apo(a) size-independent ELISA and apo(a) size by Western blot after SDS-agarose gel electrophoresis. A combined prospective nonfatal and fatal ASCVD end point included myocardial infarction, coronary revascularization, cerebrovascular accident, carotid endarterectomy, peripheral revascularization, gangrene, or limb amputation. Survival analyses were performed with adjustment for baseline demographics, comorbid conditions, ASCVD risk factors, albumin, lipids, and C-reactive protein. Median follow-up was 27.4 mo, with 297 ASCVD events, 130 non-ASCVD deaths, and seven losses to follow-up over 1649 person-years. In multivariate Cox regression models, both high Lp(a) concentration (>/=53 nmol/L) and low molecular weight (LMW) apo(a) isoforms (</=22 Kringle-IV repeats) predicted ASCVD events (relative hazard [RH] = 1.38, P = 0.02; RH = 1.58, P < 0.0005, respectively). In models that included both Lp(a) concentration and apo(a) size, only apo(a) size remained associated with ASCVD. Among those with both LMW apo(a) and Lp(a) level >123 nmol/L, the relative hazard (RH) of ASCVD was 1.73 (P < 0.0005), compared with high molecular weight apo(a) and Lp(a) level <123 nmol/L. No interactions by age, race, gender, diabetes, or ASCVD were present. Both LMW apo(a) size and high Lp(a) level predict ASCVD risk in dialysis patients, but the association of ASCVD with LMW isoforms is stronger than the association with high Lp(a) concentration.

ObjectiveTo evaluate the association of atherosclerotic cardiovascular disease (ASCVD) risk factors with incident ASCVD events among type 2 diabetes (T2D) individuals with microvascular complications.MethodsWe included T2D participants with only microvascular complications from the UK Biobank cohort at baseline (2006–2010). Multivariable-adjusted Cox proportional hazards models were used to study the association between ASCVD risk factors with adjudicated incident ASCVD in T2D participants with only microvascular complications. A restricted cubic spline approach was employed to evaluate potential nonlinear associations between ASCVD risk factors and ASCVD.ResultsWe studied 4,129 T2D individuals with microvascular complications at baseline. Over a median follow-up of 11.7 years, a total of 1,180 cases of incident ASCVD were documented, of which 1,040 were CHD, 100 were stroke, and 40 were both CHD and stroke events. After multivariable-adjustment, high-density lipoprotein cholesterol (HDL-C) level was linearly associated with a decreased risk of incident ASCVD [hazard ratio (HR): 0.49, 95% Confidence interval (CI): 0.32–0.75, Plinear = 0.011] and each 10 nmol/L increase of lipoprotein(a) [Lp(a)] level (HR: 1.02, 95% CI: 1.00-1.04, Plinear = 0.012) was linearly associated with an increased risk of incident ASCVD in T2D participants with only microvascular complications.ConclusionHDL-C levels and Lp(a) levels (per 10 nmol/L) showed an independent linear relation with ASCVD risk among T2D individuals with only microvascular complications at long-term follow-up.

Background Atopic dermatitis (AD) is associated with substantial impairment in quality of life, including sleep disturbances, anxiety, and depression, which may increase the risk of cardiovascular disease (CVD). However, the association between CVD and AD is not well established. Objectives To evaluate incidence rates (IRs) of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) in patients with and without AD in a population-based cohort study in Denmark, and to assess IRs of malignancies, major adverse cardiovascular events (MACE), VTE, and the distribution of Atherosclerotic Cardiovascular Disease (ASCVD) risk factors in patients with AD and rheumatoid arthritis (RA) in a nested cohort analysis. Methods Data from all individuals aged ≥12 years (≥18 years in the nested cohort analysis) between January 1, 2000, and December 31, 2018, were extracted from the Danish National Patient Registry. Patients with ≥1 AD diagnosis during the study period were matched on sex and age with 10 individuals from the general population. The nested cohort analysis included patients diagnosed with RA as an additional comparison population. In the overall cohort, IRs of VTE, DVT, and PE were assessed; the nested cohort analysis evaluated the distribution of ASCVD risk factors and incidence of malignancies, MACE, and VTE in patients with and without ASCVD risk factors (age ≥65 years, and history of smoking, coronary artery disease, stroke, DVT, PE, and malignancy). The follow-up period was from the first diagnosis during the study period until the occurrence of death or an endpoint, the first instance of migration, or December 31, 2018. IRs are shown per 100 patient-years (PY) of exposure with 95% confidence intervals. Results The population-based cohort comprised 190,751 patients, including 17,341 patients with AD and 173,410 age- and sex-matched controls. The IR/100 PY of VTE was similar between the AD cohort (0.14 [95% CI, 0.12-0.16]) and the general population (0.11 [0.11-0.12]). The IR/100 PY for VTE was higher in patients with AD aged ≥65 years (0.71 [0.56-0.90]) than the age-matched general population (0.50 [0.46-0.54]) and lower in the younger AD cohorts (12 to &amp;lt;18 years, 0.02 [0.00-0.08]; 18 to &amp;lt;65 years, 0.12 [0.09-0.13]). The IRs/100 PY of DVT and PE were comparable between the AD cohort (DVT, 0.08 [0.06-0.09]; PE, 0.06 [0.05-0.08]) and the general population (DVT, 0.06 [0.06-0.07]; PE, 0.05 [0.05-0.05]).. The nested cohort analysis comprised 195,807 patients, including 13,432 with AD, 48,055 with RA, and 134,320 age- and sex-matched controls. Distribution of risk factors for malignancies (excluding nonmelanoma skin cancer [NMSC]), MACE, and VTE was comparable in the AD cohort and general population, but higher in patients with RA. The IR/100 PY for malignancies (excluding NMSC) was higher in patients with AD with a history of malignancy (11.41 [9.83-13.25]) than those without (0.44 [0.40-0.48]), and in those aged ≥65 years (3.09 [2.75-3.48]) versus &amp;lt;65 years (0.36 [0.33-0.40]). Similarly, the IR/100 PY for MACE was higher in patients with AD aged ≥65 years (2.30 [2.01-2.63]) versus &amp;lt;65 years (0.15 [0.13-0.17]), and patients with a history of ASCVD (5.02 [4.37-5.76]) versus without (0.15 [0.13-0.18]). Patients with AD with a history of VTE (including DVT/PE) and inherited thrombophilia had a greater risk of VTE than patients without these risk factors. Conclusions In these 2 large cohort studies of adults and adolescents with AD, IRs of VTE, DVT, and PE were comparable with the general Danish population. The risk of VTE, malignancy, and MACE was higher in patients with AD with a history of risk factors for ASCVD. This underscores the need for appropriate monitoring and reporting of cardiovascular events in patients with AD, and active management of risk factors with early and effective therapeutic intervention.

Lipoprotein(a) (Lp(a)) is an independent cardiovascular risk factor playing a causal role for atherosclerotic cardiovascular disease (CVD). Lipoprotein apheresis (LA) is a safe well-tolerated outpatient treatment to lower LDL-C and Lp(a) by 60–70%, and is the ultimate escalating therapeutic option in patients with hyperlipoproteinemias (HLP) involving LDL particles. Major therapeutic effect of LA is preventing cardiovascular events. Lp(a)-HLP associated with progressive CVD has been approved as indication for regular LA in Germany since 2008. The Pro(a)LiFe-study investigated with a prospective multicenter design the long-term preventive effect of LA on incidence rates of cardiovascular events prospectively over a period of 5 years in 170 consecutive patients who commenced regular LA. During a median period of 4.7 years of the pre-LA period, Lp(a) associated progressive CVD became apparent. Apolipoprotein(a) (apo(a)) isoforms and polymorphisms at the apo(a) gene (LPA) were analyzed to assess hypothetical clinical correlations. 154 patients (90.6%) completed 5‑years follow-up. Significant decline of the mean annual major adverse cardiac event (MACE) rate was observed from 0.41 ± 0.45 two years prior to regular LA to 0.06 ± 0.11 during 5 years with regular LA (p < 0.0001). 95.3% of patients expressed at least one small apo(a) isoform. Calculation of isoform specific concentrations allowed to confirm the equivalence of 60 mg/dl or 120 nmol/l as Lp(a) thresholds of the German LA guideline. Results of 5 years prospective follow-up confirmed that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP and afore progressive CVD.

Tofacitinib is a Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA) and has been investigated for psoriasis (PsO). This post hoc analysis examined baseline cardiovascular (CV) disease risk and its association with the occurrence of major adverse cardiovascular events (MACE) and malignancies in tofacitinib-treated patients with PsA and PsO. Included three phase III/long-term extension (LTE) PsA trials and seven phase II/phase III/LTE PsO trials of patients receiving ⩾ 1 dose of tofacitinib. Incidence rates (IRs: patients with events/100 patient-years) for MACE and malignancies (excluding non-melanoma skin cancer) were determined in subgroups according to history of atherosclerotic CV disease (ASCVD), baseline 10-year risk of ASCVD (in patients without history of ASCVD), and baseline metabolic syndrome (MetS). For patients with PsA (N = 783) and PsO (N = 3663), respectively, tofacitinib exposure was 2038 and 8950 patient-years (median duration: 3.0 and 2.4 years), and 40.9% and 32.7% had MetS. Excluding missing CV risk profile data, 51/773 (6.6%) and 144/3629 (4.0%) patients had history of ASCVD, and in patients without history of ASCVD, around 20.0% had intermediate/high baseline 10-year ASCVD risk. For PsA and PsO, IRs of MACE were greatest in those with history of ASCVD or high baseline 10-year ASCVD risk. For PsA, five of six patients with MACE had baseline MetS. Malignancy IRs in patients with PsA were greatest in those with intermediate/high baseline 10-year ASCVD risk. Of these, eight of nine patients with malignancies had baseline MetS. In the PsO cohort, IR of malignancies was notably greater with high versus low/borderline/intermediate baseline 10-year ASCVD risk. In tofacitinib-treated patients with PsA/PsO, increased ASCVD risk and baseline MetS were associated with higher IRs for MACE and malignancies. Our results support assessing CV risk in patients with PsA/PsO and suggest enhanced cancer monitoring in those with increased ASCVD risk. NCT01877668/NCT01882439/NCT01976364/NCT00678210/NCT01710046/NCT01241591/NCT01186744/NCT01276639/NCT01309737/NCT01163253. People who have psoriatic arthritis or psoriasis may have more heart-related problems and cancer if they have a higher risk of cardiovascular disease: A study in people with psoriatic arthritis or psoriasis receiving tofacitinib Why was this study done? • People with psoriatic arthritis (PsA) and psoriasis (PsO) are more likely than the general population to have a disease affecting the heart and blood vessels [cardiovascular (CV) disease].• People who are more likely to have CV disease may also be more likely to have certain types of cancer.• Tofacitinib is a medicine to treat people with PsA and has been tested in people with PsO.• We wanted to know if the risk of CV disease affects the number of heart-related problems (including heart attack, stroke, or death) and cancer in people with PsA and PsO. What did the researchers do? • We used results from 10 clinical trials.• In these trials, people with PsA and PsO were taking tofacitinib 5 or 10 mg twice a day.• After the trials had ended, we measured people's risk of CV disease using a risk calculator. This risk calculator showed if they had a low, borderline, intermediate, or high risk of CV disease over the next 10 years. We also checked if they had had CV disease before treatment.• We checked if people had a group of conditions linked to CV disease: diabetes, high blood pressure, and obesity.• We counted the cases of heart-related problems and cancer in people once they started taking tofacitinib. What did the researchers find? In people with PsA and PsO taking tofacitinib:• There were more cases of heart-related problems and cancer in people who had intermediate or high risk of CV disease.• There were more cases of heart-related problems in people who had had CV disease before.• More people with diabetes, high blood pressure, and obesity had heart-related problems and cancer than people without those conditions. What do the findings mean? • It is important to measure risk and assess history of CV disease in people with PsA and PsO, including those taking tofacitinib.• We should test for cancer in people with high risk of CV disease.

Background: CAD (Coronary Artery Disease) and diabetes is strongly associated with high low-density lipoproteins (LDL) levels. Objective: Understand evaluation practices and treatment for dyslipidemia with statin intensity in T2DM participants as per ADA guidelines. Methods: A subset analysis of real world, prospective, cross sectional, observational LEADD study in T2DM participants conducted at 226 sites. “n”=number of participants analyzed for each parameter. Available lipid profile was recorded and stratified based on age and Atherosclerotic cardiovascular disease (ASCVD) risk factors and ASCVD as per ADA guidelines for percentages achieving LDL-C target and high intensity of statin. Results: A total of 4002 participants enrolled with mean (±SD) Hb1Ac 8.15 ± 1.7%, LDL- C levels 117.7 ± 37.6 mg/dl. Rosuvastatin was given in 87% (n=2419/2757) participants. Participants &amp;lt;40 years, ASCVD risk factors and ASCVD were present in 95% (n=207/217) and 3.2% (n=7/217), in &amp;gt;40 years it was 86.7% (n=2908/3354) and 12.8% (n= 432/3354). Mean (±SD) LDL- C levels in ASCVD risk factors and ASCVD participants in &amp;lt;40 years was 129±37.9 mg/dl and 121±42mg/dl, in &amp;gt;40 years it was 120.9±36mg/dl and 118±41mg/dl. 64% (n= 155/162) and 80% (n= 4/5) participants &amp;lt;40 years with ASCVD risk factors and ASCVD, in &amp;gt;40 years 91.4% (n= 1925/2104) and 87.9% (278/316) were not on target LDL - C levels. In &amp;lt;40 years 15.6% (n = 22/141) and 83% (n = 5/6) statin receiving participants in the ASCVD risk factors and ASCVD group and in &amp;gt;40 years 87% (n = 1869/2143) and 77.8% (n = 271/348) were not receiving high intensity statins. Conclusion: Adherence to ADA guidelines for diabetic participants despite having ASCVD risk factors/ASCVD was sub-optimal in study participants, when high intensity statins is required for dyslipidemia to achieve desired outcomes in them. The findings need further research. Disclosure A. Unnikrishnan: Other Relationship; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dr. Reddys Laboratories, Eli Lilly and Company, Eris Pharmaceuticals, Ipca Laboratories Ltd., MSD, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi. A.K. Das: None. B.D. Saboo: None. S. Kalra: None. V. Ayyar: None. M.H. Tiwaskar: None. Funding Diabetes Care India; Dr. Reddy's Laboratories

BackgroundDiabetic dyslipidemia is a risk factor for coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). American Diabetes Association (ADA) provides internationally accepted guidelines to manage dyslipidemia in T2DM.ObjectiveTo assess if ADA guidelines are followed for managing dyslipidemia in patients with T2DM in India.MethodsThis was a subset analysis of a prospective, cross sectional, observational study (LEADD Study) conducted at 199 sites across India to evaluate dyslipidemia management practices in T2DM patients (N=4002), in a real-world setting. The data was stratified based on age and atherosclerotic cardiovascular disease (ASCVD) and ASCVD risk factors to record the percentages of T2DM patients achieving LDL-C target and treated optimally with the Guideline directed intensity of statin. Analysis was conducted using descriptive statistics.ResultsAs per ADA 2018 targets: LDL-C levels (<100mg/dL) were seen in 30.6% of participants. High intensity statins were prescribed to 13.4% of the participants with LDL levels ≥100 mg/dL. ASCVD risk assessment details were available for 89.2% of participants. Data was not available for smoking and albuminuria. In participants <40 years of age, 80% and 64.2% with ASCVD and ASCVD risk factors, respectively, did not achieve target LDL-C levels. In this age group, 15.6% and 83.3% of participants with ASCVD risk factors and ASCVD group, respectively, were not receiving statins in the recommended dose. In participants ≥40 years of age, 88.0% and 91.5% with ASCVD and ASCVD risk factors, respectively, did not have LDL-C levels as per ADA 2018 targets. In this age group, 87.2% and 77.9% of participants with ASCVD risk factors and ASCVD, respectively, were not receiving statins in the recommended dose.ConclusionThe sub-analysis of LEADD study shows sub-optimal adherence to ADA 2018 guidelines for management of diabetic dyslipidemia.

Lipoprotein(a) – Marker for cardiovascular risk and target for lipoprotein apheresis

High lipoprotein(a) (Lp(a)) level is an independent cardiovascular risk factor with higher prevalence among patients with atherosclerotic cardiovascular disease (ASCVD). The actual problem is that most currently available lipid-lowering drugs are unable to abolish Lp(a) pathogenicity. Lipoprotein apheresis (LA) is an effective method for elimination of atherogenic lipoproteins, but it is approved only in some countries for treatment of elevated Lp(a) level in the presence of progressive ASCVD. In recent years, new studies on LA were published and the purpose of this review is to present the information on optimal management of Lp(a) hyperlipoproteinemia by LA in the modern era. Most clinical studies designed to treat Lp(a) hyperlipoproteinemia with different LA systems are small in size but demonstrate that the elimination of Lp(a) from bloodstream leads to reduction of inflammatory and prothrombotic process in a few months and to atherosclerotic plaques regression in 1.5years. Treatment with LA for 2 to 5years in terms of clinical trials and in real-world setting provides further evidence that Lp(a) reduction by 60-80% is associated with proportional decreasing of rate and risk of cardiovascular events. Specific Lp(a) apheresis is the only possible method that solely targets Lp(a). In most countries, non-specific LA is used for treatment Lp(a) hyperlipoproteinemia in very high-risk subjects with progressive ASCVD. PCSK9 inhibitors have only modest effect on significantly elevated Lp(a), whereas large population-based studies requested sustained and prolonged reduction of Lp(a) levels by 50-100mg/dL to gain proportional decreasing of major adverse cardiovascular events.

Purpose Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated cardiovascular benefits in patients with diabetes and atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the impact of early initiation of SGLT2 inhibitor on cardiovascular outcomes in diabetic patients with known and at risk of ASCVD. Methods We retrospectively analyzed 29,309 consecutive patients with type 2 diabetes prescribed empagliflozin (N=18,979, 64.8%) and dapagliflozin (N=10,330, 35.2%) between August 2015 and August 2020 in 16 public hospitals in Hong Kong. Patients with diagnosis of diabetes to first prescription of SGLT2 inhibitors (Dx-to-Rx time) ≤12 months were matched with &amp;gt;12 months using propensity score derived from logistic regression. 3,370 matched patients were divided into 4 groups: (i) patients with known ASCVD involving 1 territory (coronary artery, peripheral artery or cerebrovascular disease); (ii) known ASCVD involving &amp;gt;1 territories; (iii) CV risk factor(s) other than diabetes and (iv) no known ASCVD or additional CV risk factors. Incidence rates of 3-point major adverse cardiovascular events (MACE, including non-fatal stroke, non-fatal myocardial infarction and cardiovascular death) were compared between Dx-to-Rx time ≤12 months and &amp;gt;12 months across 4 subgroups during a median follow-up of 2.8 years (IQR 2.2 to 3.4). Results Of 29,309 patients (mean age 54.9±11.6 years, female 41.0%), 22.9% had single territory and 6.1% multi-territories ASCVD, 53.3% with additional CV risk factors and 17.7% neither risk factor nor ASCVD. Overall, 19.0% of patients had Dx-to-Rx time ≤12 month; 19.3%, 15.7%, 17.6% and 30.0% in each group, respectively. Overall, Dx-to-Rx time ≤12 months was associated with lower rates of MACE (hazard ratio (HR) =0.27, 95% CI: 0.17–0.42). Subgroup analysis showed similar results in patients with CV risk factors of or known ASCVD but not in patients with neither risk factor nor ASCVD (P for interaction=0.001, Table 1). Conclusion Early initiation of SGLT2 inhibitor was associated with significant lower MACE rates in diabetic patients with known ASCVD or additional CV risk factors. The impact was more marked in patients with additional CV risk factors. Our findings suggested early initiation in diabetic patients with known ASCVD and additional CV risk factors. Funding Acknowledgement Type of funding sources: None.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder mainly caused by mutations in the low-density lipoprotein (LDL) receptor or associated genes, resulting in elevated serum cholesterol levels and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Early diagnosis and timely treatment can substantially lower the risk of ASCVD. In this sense, cascade screening could be one of the most useful options. However, few data exist regarding the impact of cascade screening for FH on the reduction of risk of ASCVD events. We aimed to evaluate the prognostic impact of cascade screening for FH. Methods: We retrospectively investigated the health records of 1,050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened, who were referred to our institute. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiovascular events (MACE). The median period of follow-up was 12.3 years (interquartile range [IQR] = 9.1-17.5 years), and MACE included death from any causes or hospitalization due to ASCVD events. Results: During the observation period, 246 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P &lt; 2.2 х 10 –16 ), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.36; 95%CI = 0.22 to 0.60; P = 6.3 х 10 –5 ) when compared with the probands, even after adjusting for those known risk factors. Conclusions: The identification of patients with FH via cascade screening appeared to result in better prognoses.

Lipoprotein apheresis in isolated hyperlipoproteinemia(a): a validated treatment or an illusion of validity?

Introduction: The impact of atherosclerotic cardiovascular disease (ASCVD) risk factors on pregnancy outcomes in women with pre-existing heart disease (HD) has not been examined. Aim: To determine the risk of major adverse cardiovascular events (MACE), preeclampsia and fetal events in women with HD stratified according to the presence of ASCVD risk factors. Methods: We studied a consecutive cohort of pregnant women with heart disease. ASCVD risk factors included any of the following: obesity, hypertension, dyslipidemia, diabetes or smoking. Primary outcomes were MACE (heart failure, cardiac arrest, CV death, stroke and myocardial infarction), preeclampsia and adverse fetal events (pre-term birth, small for gestational age, intraventricular hemorrhage, neonatal death and respiratory distress syndrome). Univariate logistic regression was used to determine the odds of adverse outcomes. Results: In total, 1656 pregnancies (congenital heart disease n=1041, acquired heart disease n= 420, isolated arrhythmia n=195) were included. At least one ASCVD risk factor was present in 24% of pregnancies. Overall, MACE occurred in 7.1%, preeclampsia in 4.3% and adverse fetal events in 30.1% of the pregnancies. Compared to pregnancies in women without ASCVD risk factors, those with ASCVD risk factors were more likely to have pregnancies complicated by MACE (9.7% vs 6.3%, p= 0.025), preeclampsia (8.3% vs 3.4%, p &lt; 0.001), and fetal events (38.5% vs 27.5%, p &lt;0.001). There were differences in maternal and fetal outcomes with or without ASCVD risk factors when stratified by diagnosis (acquired heart disease, congenital heart disease, isolated arrhythmias) (Figure 1). Conclusions: The presence of ASCVD risk factors in women with heart disease is associated with worse maternal and fetal outcomes. Modification of ASCVD risk factors may improve pregnancy outcomes.