Validation of SCORE2 on a sample from the Russian population and adaptation for the very high cardiovascular disease risk region.

SCORE2 (Systematic COronary Risk Evaluation 2) is a risk assessment scale for cardiovascular events, presented in 2021 by the European Society of Cardiology. Both for training and validation of the SCORE2 model, representative samples from the Russian population were not used. Therefore, we aimed to validate SCORE2 on a such sample. For this purpose, we used a sample from the ESSE-RF epidemiological study consisting of 7251 participants aged 40-69 years without history of CVDs. We performed the validation by comparing SCORE2 risk estimates for ESSE-RF participants with the observed incidence of cardiovascular events in the study, adjusted for event information losses. The validation demonstrated that SCORE2 risk estimates were accurate for Russian men and inaccurate for Russian women. Together with the quantitative assessment of risk, SCORE2 offers its interpretation in terms of 10-year CVD risk group: low-moderate, high, and very high. For Russian men we considered the original interpretation of the SCORE2 estimates to be questionable because almost none of the men would be categorized as having "low-to-moderate" 10-year CVD risk. This problem would be typical for all countries of the very high CVD risk region. Therefore, we proposed a new interpretation of the SCORE2 risk estimates for men from the very high risk region. According to the proposed interpretation, the fraction of men in ESSE-RF in "low-to-moderate" 10-year CVD risk increased from 2% to 18% and the fraction of men in "very high" CVD risk decreased from 63% to 20% as compared to the original interpretation. The proposed interpretation would allow a more personalized approach to CVD treatment and optimize the burden on primary healthcare in the very high risk region countries.

Lipoprotein(a) in an adult sample from the Russian population: distribution and association with atherosclerotic cardiovascular diseases.

Introduction: Lipoprotein(a) (Lp(a)) is recognized as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). The aim of this study was to estimate the distribution of Lp(a) levels in working age adults from the Russian population and to assess its association with ischemic heart disease (IHD), myocardial infarction (MI), stroke, diabetes mellitus (DM), and arterial hypertension (AH). Material and methods: This substudy of the population-based study "Epidemiology of Cardiovascular Diseases and their Risk Factors in Some Regions of the Russian Federation" (ESSE-RF) included 8461 subjects aged 25-64 years (63.7% women) without lipid-lowering drugs. Atherosclerotic cardiovascular disease was self-reported. Lp(a), apolipoproteins AI and B, and lipid and glucose levels in blood serum were determined. Results: The prevalence of Lp(a) ≥ 30 mg/dl was 20.5% and 23.0%, and prevalence of Lp(a) ≥ 50 mg/dl was 13.3% and 15.2%, in men and women, respectively. An association of Lp(a) with IHD, MI, and AH, but not with stroke and DM, was shown. A cut-off level of Lp(a) of 9 mg/dl was determined, above which there was increased frequency of MI (by 59.2%, p = 0.02), IHD (by 33.4%, p < 0.001), and AH (by 11.6%, p < 0.001). In the multivariate analysis only the association of Lp(a) with IHD (1.19 (1.01-1.41), p = 0.038) and MI (1.57 (1.06-2.38), p = 0.028) remained significant. Conclusions: Lipoprotein(a) level ≥ 30 mg/dl was detected in every fifth adult aged 25-64 years. Increased risk of MI and IHD starts at an Lp(a) serum level above 9 mg/dl.

A Novel Integrated Biomarker for Evaluation of Risk and Severity of Coronary Atherosclerosis, and Its Validation.

OBJECTIVE: To assess the feasibility of a combination of biochemical and imaging parameters for estimation of risk and severity of coronary atherosclerosis (CA), and to verify the created integrated biomarker (i-BIO) on independent cohort. METHODS: Two cohorts of patients admitted to the hospital for coronary angiography and ultrasound carotid dopplerography were enrolled into the study (n = 205 and n = 216, respectively). The extent of CA was assessed by Gensini Score (GS). RESULTS: According to GS, participants were distributed as follows: atherosclerosis-free (GS = 0), CA of any stage (GS > 0), subclinical CA (GS < 35), severe CA (GS ≥ 35). Based on the analysis of mathematical models, including biochemical and imaging parameters, we selected and combined the most significant variables as i-BIO. The ability of i-BIO to detect the presence and severity of CA was estimated using ROC-analysis with cut-off points determination. Risk of any CA (GS > 0) at i-BIO > 4 was 7.3 times higher than in those with i-BIO ≤ 4; risk of severe CA (GS ≥ 35) at i-BIO ≥ 9 was 3.1 times higher than at i-BIO < 9. Results on the tested cohort confirmed these findings. CONCLUSIONS: The i-BIO > 4 detected CA (GS > 0) with sensitivity of 87.9%, i-BIO ≥ 9 excluded patients without severe CA (GS < 35), specificity 79.8%. Validation of i-BIO confirmed the feasibility of i-BIO > 4 to separate patients with any CA with sensitivity 76.2%, and of i-BIO ≥ 9 to exclude atherosclerosis-free subjects with specificity of 84.0%.

Lipoprotein Profile in Populations from Regions of the Russian Federation: ESSE-RF Study.

This study aimed to describe the dyslipidemia prevalence and pattern among adult populations from different regions (n = 13) of the Russian Federation (RF). Randomly selected samples (n = 22,258, aged 25-64) were studied according to the ESSE-RF protocol. Lipoprotein parameters were estimated by routine methods. Statistical analyses were performed using R software (v.3.5.1). The overall dyslipidemia prevalence was 76.1% (76.9/75.3% for men/women). In women, total cholesterol (TC) and low-density lipoprotein (LDL)-C levels gradually increased with age (from 4.72 to 5.93 and from 2.76 to 3.79 mmol/L, respectively); in men, they reached a maximum by 45-54 (5.55 and 3.55 mmol/L, respectively) and then decreased. No differences in high-density lipoprotein (HDL)-C in men of different ages were found, but slight decreases in HDL-C and apo AI were observed in women by 55-64 years. No pronounced associations between education and lipid levels in men were observed; higher-educated women showed significantly better lipoprotein profiles. Similar associations between lipids and income level were detected. Women from rural areas had higher TC and triglycerides than urban residents. Regardless of sex, rural residents had higher HDL-C and apo AI, and reduced apo B/apo AI. Conclusion: Information on the peculiarities of dyslipidemia prevalence and lipoprotein profile depending on sex, age, residential place, and socioeconomic status is useful for assessing the global ASCVD risk, and for risk modeling based on national data.

Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4·5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial.

BACKGROUND: Non-immunogenic staphylokinase is modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity, and selectivity to fibrin. We aimed to assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with acute ischaemic stroke within 4·5 h after symptom onset. METHODS: We did a randomised, open-label, multicentre, parallel-group, non-inferiority trial in 18 clinical sites in Russia. We included patients aged 18 years and older with a diagnosis of acute ischaemic stroke (up to 25 points on the National Institutes of Health Stroke Scale). The study drug had to be administered within 4·5 h after the onset of symptoms. Patients were randomly assigned to receive either non-immunogenic staphylokinase (10 mg) or alteplase (0·9 mg/kg, maximum 90 mg), both administered intravenously. The randomisation sequence was created by an independent biostatistician using computer-generated random numbers. 84 blocks (block size of four) of opaque sealed envelopes were numbered sequentially from 1 to 336 and were opened in numerical order. Patients were unaware of their assigned treatment and were assessed by the study investigators who were also unaware of the treatment assignment on all trial days. Emergency department staff, who administered the assigned drug and opened the envelopes, were not masked to treatment. The primary efficacy endpoint was a favourable outcome, defined as a modified Rankin scale (mRS) score of 0-1 on day 90. The margin of non-inferiority was established as 16% for the difference in mRS score of 0-1 on day 90. Non-inferiority was tested using Welch's t-test for the primary outcome only. Endpoints were analysed in the per-protocol population, which comprised all randomly assigned patients who completed treatment without any protocol violations; this population was identical to the intention-to-treat population. This trial is completed and registered at ClinicalTrials.gov, NCT03151993. FINDINGS: Of 385 patients recruited from March 18, 2017, to March 23, 2019, 336 (87%) were included in the trial. 168 (50%) patients were randomly assigned to receive non-immunogenic staphylokinase and 168 (50%) to receive alteplase. The median duration of follow-up was 89 days (IQR 89-89). 84 (50%) of 168 patients in the non-immunogenic staphylokinase group had a favourable outcome at day 90 compared with 68 (40%) of 168 patients in the alteplase group (odds ratio [OR] 1·47, 95% CI 0·93 to 2·32; p=0·10). The difference in the rate of favourable outcome at day 90 was 9·5% (95% CI -1·7 to 20·7) and the lower limit did not cross the margin of non-inferiority (pnon-inferiority <0·0001). Symptomatic intracranial haemorrhage occurred in five (3%) patients in the non-immunogenic staphylokinase group and in 13 (8%) patients in the alteplase group (p=0·087). On day 90, 17 (10%) patients in the non-immunogenic staphylokinase group and 24 (14%) patients in the alteplase group had died (p=0·32). 22 (13%) patients in the non-immunogenic staphylokinase group had serious adverse events, compared with 37 (22%) patients in the alteplase group (p=0·044). INTERPRETATION: Non-immunogenic staphylokinase was non-inferior to alteplase for patients with acute ischaemic stroke. Mortality, symptomatic intracranial haemorrhage, and serious adverse events did not differ significantly between groups. Future studies are needed to continue to assess the safety and efficacy of non-immunogenic staphylokinase in patients with acute ischaemic stroke within the 4·5 h time window, and to assess the drug in patients with acute ischaemic stroke outside this time window with reperfusion CT or magnetic resonance angiography followed by thrombectomy if necessary. FUNDING: The Russian Academy of Sciences.

Prognostic value of changes in arterial stiffness in men with coronary artery disease.

BACKGROUND: Men with coronary artery disease (CAD) have been shown to have enhanced arterial stiffness. Arterial function may change over time according to treatment, but the prognostic value of these changes has not been investigated. OBJECTIVES: The aim of the present study was to assess whether an improvement in large artery rigidity in response to treatment, could predict a more favorable prognosis in a population of men with CAD. METHODS: A total of 161 men with CAD (mean age 56.8 ± 10.9 years) being treated with conventional therapy underwent brachial-ankle pulse wave velocity (PWVba) measurements at baseline and after six months. Follow-up period was 3.5 years. End-points were major adverse cardiac events (MACE): acute myocardial infarction, unstable angina, coronary intervention, or cardiac death. RESULTS: During the three-year follow-up period (since initial six-month follow-up), 30 patients experienced MACE. After six-month follow-up, PWVba had not improved (ΔPWVba ≥ 0%, relative to baseline) in 85 (52.8%) of 161 men (Group 1), whereas it had improved (ΔPWVba < 0%) in the remaining 76 men (47.2%) (Group 2). During follow-up, we noticed 24 cardiovascular events in Group 1 and six events in Group 2 (P < 0.001). Cox proportional hazards analyses demonstrated that independent of conventional risk factor changes, absence of PWVba decrease was a predictor of MACE (RR 3.99; 95% CI:1.81-8.78; P = 0.004). The sensitivity of ΔPWVba was 80% and its specificity was 54%. CONCLUSIONS: This study demonstrates that an improvement in arterial stiffness may be obtained after six months of conventional therapy and clearly identifies patients who have a more favorable prognosis.