Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Effects of beta-blocker therapy on hs-CRP levels in elderly patients with ischemic and non-ischemic heart failure: Results from the CIBIS-ELD trail

C reactive protein (CRP) is a biomarker indicating systemic inflammation. Elevated levels of this biomarker are associated with increased rates of cardiovascular disease, including chronic heart failure (HF). High‐sensitivity CRP assays were developed in order to measure lower levels of CRP, down to 0.3mg/l (hs‐CRP). Up to now, very little is known about the effects of beta‐blocker titration on hs‐CRP levels in ischemic and non‐ischemic HF patients. Also, little is known if this effect differs between selective and unselective blockers. Purpose: This research explored the trajectories of hs‐CRP before and after beta‐blocker (carvedilol vs bisoprolol) titration in elderly HF patients depending on the type of beta‐blocker used and the etiology of the disease (ischemic vs non‐ischemic). Methods: We measured plasma levels of hs‐CRP and NT‐proBNP in 520 HF patients ≥ 65 years (72.06±5.24 years, 38%f, LVEF 41.8±13.8%; ischemic n=243; nonischemic n=277) of the Cardiac Insufficiency Bisoprolol Study in ELDerly (CIBIS‐ELD). In this trial, patients were randomized to bisoprolol vs. carvedilol and doses were uptitrated to the target or maximally tolerated dose. hs‐CRP and NT‐proBNP levels were assessed at baseline (BL) and at follow‐up (FU), after 12 weeks. Results: In patients with ischemic HF, hs‐CRP levels decreased in the bisoprolol group (BL=0.60±0.94 mg/ dl, n=166; FU=0.43±0.694mg/dl, n=131; p=0.010), and were without a change in the carvedilol group (BL=0.60±1.69mg/dl, n=181; FU=0.57±0.982mg/ dl, n=136; p=0.731). There was also no change of hs‐CRP levels in non‐ischemic HF patients in both groups (bisoprolol: BL=0.64±1.175 mg/dl, n=197; FU=0.470±0.81mg/dl, n=152, p=0.069; carvedilol: BL=0.45±0.78mg/dl, n=198; FU=0.41±0.701 mg/ dl, n=152, p=0.420). Plasma levels of NT‐proBNP decreased in ischemic patients treated with bisoprolol, (BL=1594±2146 pg/ml, n=169; FU=1468±2110pg/ ml, n=133, p=0.04), while changes in the carvedilol group were not significant (BL=1648±1991 pg/ml, n=188; FU=1567±2119pg/ml, n=135, p=0.556). In the non‐ischemic group NT‐pro levels did not change significantly in the carvedilol group, while there was an increase in non‐ischemic patients in the bisoprolol group (BL=1427±3113 pg/ml, n=208; FU=1533±5385 pg/ml, n=166, p=0.017). Conclusion: Results indicate that bisoprolol might be associated with a decrease of hs‐CRP and NT‐proBNP levels only in ischemic HF patients, while in nonischemic HF patients there was no change of hs‐CRP and an increase of NT‐proBNP levels. In carvedilol treated patients no significant changes were shown in neither group

Effects of beta-blocker therapy on hs-CRP levels in elderly patients with ischemic and non-ischemic heart failure: results from the CIBIS-ELD trail

Congress of the European-Society-of-Cardiology (ESC), Aug 29-Sep 02, 2015, London, Englan

Prevailing surface winds in Northern Serbia in the recent and past timeperiods; modern- and past dust deposition

This study utilizes four different methodological approaches to examine the prevailing surface winds and their associated aeolian processes in Northern Serbia, focusing on the southeastern part of the Carpathian Basin. We utilized wind and atmospheric pressure data from 1939–2014 and 1960–2010 for the climatological analyses. Geomorphological data and numerical simulations were used to estimate prevailing paleowind systems. Northern Serbia is currently dominated by surface winds coming from the fourth (270°–360°) and second (90°–180°) quadrants, with frequencies of ca. 116 and 105 days/year, respectively. Comparable frequencies within Banatska Peščara are 115 and 129 days/year, respectively. Crestal orientations of the vast majority of the ≈1300 parabolic dunes here suggest that they have formed from winds derived from the second quadrant, indicating formation during the early Holocene. The remaining dunes, of the transverse type, have orientations aligned to the third quadrant. Grain size analysis of loess deposits near Banatska Peščara points to deposition driven by southeasterly winds, probably during the period between the Last Glacial Maximum (LGM) and the early Holocene. Modern wind measurements and geomorphological data showed that the prevailing winds in the recent and past periods were from the same quadrant, in and around Banatska Peščara. These results were confirmed with an explicit numerical simulation that modelled prevailing winds from the second quadrant during the LGM. Thus, the various geomorphologic and climatic data analyzed in this study show that the general air circulation patterns in the recent period are not dissimilar to those operative during the LGM

Bisoprolol vs. carvedilol in elderly patients with heart failure: rationale and design of the CIBIS-ELD trial

BACKGROUND: Chronic heart failure (CHF) is a widespread disease with severe quality of life impairment and a poor prognosis. Beta-blockers are the mainstay of CHF therapy; yet they are under-prescribed and under-dosed in clinical practice. This is particularly evident in elderly patients, which may be due to a fear of side-effects or intolerance. Beta-blockers have further not been adequately tested in patients with diastolic CHF, which is particularly common in elderly patients. Finally, comparative data on the use of different beta-blockers in patients with CHF is scarce. AIM: To compare the tolerance of bisoprolol and carvedilol in elderly patients with CHF. METHODS: CIBIS-ELD is an investigator-initiated, multi-centre, 1:1 randomised, double-blind, phase III trial comparing bisoprolol and carvedilol in patients >/=65 years with systolic or diastolic CHF. Recruitment started in April 2005 and is anticipated to be completed by April 2008 with at least 800 patients enrolled. PERSPECTIVE: This is the first large scale head to head beta-blockers trial in an elderly population with CHF. Besides determining which of two standard beta-blockers is best tolerated in elderly patients with systolic or diastolic CHF, we expect to gain further insight into the treatment of the particular population of patients with diastolic CHF

Perspectives: Rationale and design of the ISACS-TC (International Survey of Acute Coronary Syndromes in Transitional Countries) project

During the past 10 years, the health of people in Eastern Europe and the former Soviet Union has undergone changes very different from the health patterns seen in their Western counterparts. Mortality from cardiovascular disease has been decreasing continuously in the USA and many Western European countries, but it has increased or remained unchanged in many of the states of Eastern Europe. Analysis of this phenomenon has been hindered by insufficient information. The International Registry of Acute Coronary Syndromes registry study in Transitional Countries (ISACS-TC) is both a retrospective - over a 1-year period - and prospective study which was designed in order to obtain data of patients with acute coronary syndromes (ACSs) in countries with economy in transition in Central and Eastern Europe, and herewith control and optimize internationally guideline recommended therapies in these countries. Adhesion to the project was given by 112 Collaborating Centres in 17 countries with economy in transition (Albania, Bosnia and Herzegovina, Belarius, Bulgaria, Croatia, Hungary, Kosovo, Latvia, Lithuania, Macedonia, Moldova, Montenegro, Romania, Russian Federation, Serbia, Slovakia, Slovenia, and Ukraine). A total of 47 cluster sites in 11 countries in Central and Eastern Europe are currently collaborating in ISACS-TC. The registry encourages optimal individualization of evidence-based therapies and the international patient body ensures good representation of multiple practice patterns. It may help to make an additional improvement in clinical outcomes of countries with economy in transition

Surgery and outcome of infective endocarditis in octogenarians: prospective data from the ESC EORP EURO-ENDO registry

Purpose: High mortality and a limited performance of valvular surgery are typical features of infective endocarditis (IE) in octogenarians, even though surgical treatment is a major determinant of a successful outcome in IE. Methods: Data from the prospective multicentre ESC EORP EURO-ENDO registry were used to assess the prognostic role of valvular surgery depending on age. Results: As compared to &lt; 80&nbsp;yo patients, ≥ 80&nbsp;yo had lower rates of theoretical indication for valvular surgery (49.1% vs. 60.3%, p &lt; 0.001), of surgery performed (37.0% vs. 75.5%, p &lt; 0.001), and a higher in-hospital (25.9% vs. 15.8%, p &lt; 0.001) and 1-year mortality (41.3% vs. 22.2%, p &lt; 0.001). By multivariable analysis, age per se was not predictive of 1-year mortality, but lack of surgical procedures when indicated was strongly predictive (HR 2.98 [2.43–3.66]). By propensity analysis, 304 ≥ 80&nbsp;yo were matched to 608 &lt; 80&nbsp;yo patients. Propensity analysis confirmed the lower rate of indication for valvular surgery (51.3% vs. 57.2%, p = 0.031) and of surgery performed (35.3% vs. 68.4%, p &lt; 0.0001) in ≥ 80&nbsp;yo. Overall mortality remained higher in ≥ 80&nbsp;yo (in-hospital: HR 1.50[1.06–2.13], p = 0.0210; 1-yr: HR 1.58[1.21–2.05], p = 0.0006), but was not different from that of &lt; 80&nbsp;yo among those who had surgery (in-hospital: 19.7% vs. 20.0%, p = 0.4236; 1-year: 27.3% vs. 25.5%, p = 0.7176). Conclusion: Although mortality rates are consistently higher in ≥ 80&nbsp;yo patients than in &lt; 80&nbsp;yo patients in the general population, mortality of surgery in ≥ 80&nbsp;yo is similar to &lt; 80&nbsp;yo after matching patients. These results confirm the importance of a better recognition of surgical indication and of an increased performance of surgery in ≥ 80&nbsp;yo patients

Socio-Economic Variations Determine the Clinical Presentation, Aetiology and Outcome of Infective Endocarditis: a Prospective Cohort Study from the ESC-EORP EURO-ENDO (European Infective Endocarditis) Registry

Background: Infective endocarditis (IE) is a life-threatening disease associated with high mortality and morbidity worldwide. We sought to determine how socio-economic factors might influence its epidemiology, clinical presentation, investigation and management, and outcome, in a large international multi-centre registry. Methods: The EurObservationalProgramme (EORP) of the European Society of Cardiology (ESC) EURO-ENDO registry comprises a prospective cohort of 3113 adult patients admitted for IE in 156 hospitals in 40 countries between January 2016 and March 2018. Patients were separated in 3 groups, according to World Bank economic stratification (Group 1 - high income [75.6%]; Group 2 - upper-middle income [15.4%]; Group 3 - lower-middle income [9.1%]). Results: Group 3 patients were younger (median age [IQR]: Group 1 - 66 [53-75] years; Group 2 - 57 [41-68] years; Group 3 - 33 [26-43] years; p&lt;0.001) with a higher frequency of smokers, intravenous drug use and human immunodeficiency virus (HIV) infection (all p&lt;0.001) and presented later (median [IQR) days since symptom onset: Group 1 - 12 [3-35]; Group 2 - 19 [6-54]; Group 3 - 31 [12-62]; p&lt;0.001) with a higher likelihood of developing congestive heart failure (13.6%; 11.1%; and 22.6%, respectively; p&lt;0.001) and persistent fever (9.8%; 14.2%; 27.9%; p&lt;0.001). Among 2157 (69.3%) patients with theoretical indication for cardiac surgery, surgery was performed less frequently in Group 3 patients (75.5%, 76.8% and 51.3%, respectively p&lt;0.001) who also demonstrated the highest mortality (15.0%, 23.0% and 23.7%, respectively; p&lt;0.001). Conclusions: Socio-economic factors influence the clinical profile of patients presenting with IE across the world. Despite younger age, patients from the poorest countries presented with more frequent complications and higher mortality associated with delayed diagnosis and lower use of surgery