Pharmacological treatment of CVD

This is the first issue of the journal which is online only. We do believe most readers pick their papers of interest and read them instead of reading the whole issue from page 1 to the end of the issue. Furthermore, we save money, trees, and strain on the nature is decreased. The Covid period is certainly not over.1–3 In this issue of the journal Dr. Cosentini and co-workers from Sweden investigated the associations between the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and the risk of COVID-19 hospitalization and death. They analysed patients with Type 2 DM registered in the Swedish National Patient Registry. ‘Incident severe COVID-19’ was defined as the first hospitalization and/or death from COVID-19. A modified Poisson regression approach was applied to a 1:1 propensity score-matched population receiving vs. not receiving SGLT2i, GLP-1 RA, and DPP-4i to analyse the associations between their use and (I) incident severe COVID-19, (II) risk of 30-day mortality in patients hospitalized for COVID-19. Among 344 413 patients, 39 172 (11%) were treated with SGLT2i, 34 290 (10%) with GLP-1 RA and 53 044 (15%) with DPP-4i; 9538 (2.8%) had incident severe COVID-19 by 15th May 2021. The authors concluded that SGLT2i and DPP-4i use was associated with higher risk of incident severe COVID-19. DPP-4i use was associated with higher 30-day mortality in patients with COVID-19, whereas SGLT2i use was not. No increased risk for any outcome was observed with GLP-1 RA. Previous findings have suggested that SGLT-2 were associated with reduced all-cause mortality.3–7 In a study from the Netherlands, Dr. Souverein et al., studied the association between SGLT-2i use and all-cause mortality and the risk of sudden cardiac arrest (SCA) in patients with type 2 diabetes. They used data from the UK Clinical Practice Research Datalink, a cohort study among patients initiating a new antidiabetic drug class. Cox regression with time-dependent covariates was performed to estimate the hazard ratios (HRs) of SCA and all-cause mortality comparing SGLT-2is with other second- to third-line antidiabetic drugs. A total of 152 591 patients were included. Use of SGLT-2i was associated with reduced HR of SCA when compared with other second- to third-line antidiabetic drugs after adjustment for common SCA risk factors, although this association marginally failed to reach statistical significance [HR:0.62 (95%-CI:0.38–1.01)]. The authors concluded that SGLT-2i use was associated with reduced all-cause mortality in patients with type 2 diabetes. The association between use of SGLT-2i and reduced risk of SCA was not statistically significant. The advantages of direct oral anticoagulants (DOACs) over warfarin are well established in atrial fibrillation (AF) patients,8–12 however, studies that can guide in the selection between different DOACs are limited. In a study by Dr Barkan et al, the aim was to compare the clinical outcomes of treatment with apixaban, rivaroxaban, and dabigatran in patients with AF. The authors conducted a retrospective, nationwide, propensity scorematched-based observational study from Clalit Health Services. Data from 141 992 individuals with AF were used to emulate a target trial for head-to-head comparison of DOACs therapy. Three-matched cohorts of patients assigned to DOACs, from January 2014 through January 2020, were created. One-to-one propensity score matching was performed. Efficacy/safety outcomes were compared using Kaplan–Meier survival estimates and Cox proportional hazards models. The trial included 56 553 patients (apixaban, n = 35 101; rivaroxaban, n = 15 682; dabigatran, n = 5770). Mortality and ischaemic stroke rates in patients treated with rivaroxaban were lower compared with apixaban (HR,0.88; 95% CI,0.78–0.99; P,0.037 and HR,0.92; 95% CI,0.86- 0.99; P,0.024, respectively). No significant differences in the rates of myocardial infarction, systemic embolism, and overall bleeding were noticed between the different DOACs groups. Patients treated with rivaroxaban demonstrated lower rate of intracranial haemorrhage compared with apixaban (HR,0.86; 95% CI,0.74–1.0; P,0.044). The rate of gastrointestinal bleeding in patients treated with rivaroxaban was higher compared with apixaban (HR, 1.22; 95% CI,1.01–1.44; P, 0.016). The authors demonstrated significant differences in outcomes between the three studied DOACs. The results emphasise the need for randomized controlled trials that will compare among rivaroxaban, apixaban, and dabigatran in order to better guide the selection between them. Assessing bleeding risk during the decision-making process of starting oral anticoagulation (OAC) therapy in AF patients is essential.13,14 Several bleeding risk scores have been proposed for vitamin K antagonist users but, few studies have focused on validation of these bleeding risk scores in patients taking direct oral anticoagulants (DOACs). Dr. Marin and co-workers from Spain compared the predictive ability of HAS-BLED and ORBIT bleeding risk scores in AF patients taking rivaroxaban in the EMIR [‘Estudio observacional para la identificación de los factores de riesgo asociados a eventos cardiovasculares mayores en pacientes con fibrilación auricular no valvular tratados con un anticoagulante oral directo (Rivaroxaban)] Study. EMIR Study was an observational, multicenter, post-authorization, and prospective study that involved AF patients under OAC with rivaroxaban at least 6 months before enrolment. The authors found that in this prospective real-world AF population under rivaroxaban from EMIR registry, the HAS-BLED score had good predictive performance and calibration compared with ORBIT score for major bleeding events. ORBIT score presented worse calibration than HAS-BLED in this DOAC treated population. Thus, patients with AF treated with oral anticoagulation still suffer from cardiovascular complications including cardiovascular death, stroke, and major bleeding.13,–15 To identify risk factors for predicting stroke and bleeding outcomes in anticoagulated patients, Dr. De Caterina and co-workers assessed 2-year outcomes in patients with AF treated with edoxaban in routine care. A total of 13 133 patients with AF were included. The author group found that patients treated with edoxaban in ETNA-AF-Europe15 reported low 2-year event rates in unselected AF patients. Prior stroke, reduced kidney function, and HF identify patients at high risk of stroke, bleeding, and all-cause/cardiovascular death, respectively. Studies have found an increased risk of myocardial infarction (MI) in association with some non-steroidal anti-inflammatory drugs (NSAID).16,17 Dr. Baak et al. from USA further evaluated this association in patients without major cardiovascular risk factors and assessed potential reverse causality bias. They used a nested case-control study of patients aged 40–79 years in Clinical Practice Research Datalink GOLD who received at least one NSAID prescription between 2006 and 2019. They found 8639 MI cases and 34 556 matched controls. The authors report that risk of MI was elevated in current diclofenac users, particularly in new users of PPIs. Risk was increased in new users of ibuprofen and PPIs but declined with extended use and was lower in patients not exposed to PPIs. This suggests that some of the risk can be explained by reverse causality bias To conduct a health economic evaluation of a drug may be controversial. The journal has previously published data from the THEMIS (effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study) population.18,19 The authors used a Markov model developed to extrapolate patient outcomes over a lifetime horizon. The authors concluded that based on THEMIS results, ticagrelor plus aspirin compared with aspirin alone may be cost-effective in some European countries in patients with T2DM and CAD and no prior MI or stroke. Additionally, ticagrelor is likely to be cost-effective across European countries in patients with a history of PCI.20 In this issue of the journal, Dr. van den Broek et al. from the Netherlands, aimed to estimate the long-term cost-effectiveness of clopidogrel compared with ticagrelor in patients aged 70 years or older with NSTEMI in the POPular AGE trial.21 They used a 1-year decision tree based on the POPular AGE trial in combination with a lifelong Markov model to compare clopidogrel with ticagrelor in terms of clinical outcomes, costs and quality-adjusted life years (QALYs) in elderly patients (above 70 year) with NSTEMI. Their conclusion was that Clopidogrel is a cost-saving alternative to ticagrelor in elderly patients after NSTEMI, though regarding overall cost-effectiveness clopidogrel was not superior to ticagrelor, as it resulted in a small negative effect on QALYs. However, based on the results of the alternative base case and clinical outcomes of the POPular AGE trial, clopidogrel could be a reasonable alternative to ticagrelor for elderly NSTEMI patients with a higher bleeding risk. Patients with type 2 diabetes mellitus (T2D)have up to a four-fold higher risk of atherosclerotic CV disease (ASCVD) compared with populations without T2D.22 Finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, improves cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD).23 Dr. Filippatos and co-workers present a meta-analysis comparing finerenone with placebo in patients with and without baseline history of atherosclerotic CV disease (ASCVD). The conclusion from the study group was that Finerenone reduced the risk of CV and kidney outcomes consistently across the spectrum of CKD in patients with T2D, irrespective of prevalent ASCVD. Is RNA targeted therapeutics the future? We are very pleased to publish a current opinion paper from Dr. Granger and co-workers from USA. fRNA-targeted therapeutics, including antisense oligonucleotide technologies as well as small interfering RNAs, represent a new class of medications that may overcome several of the disadvantages of small molecule drugs or monoclonal antibodies. Specifically, upstream targeting at the mRNA level renders any disease-related protein a potential target, even those pathways previously deemed ‘undruggable’. Additional advantages include the comparably simple and cost-effective way of manufacturing and the long dosing intervals. A few agents are already approved and a wide array of cardiovascular drugs is in development, aimed at hypercholesterolaemia, hypertension, myocardial storage diseases, and the coagulation system. Here, we provide an update on the current status of RNA-targeted therapeutics in the cardiovascular arena. At last we publish a review and meta-analysis from Dr. Chaves et al. in Brazil. The authors performed a meta-analysis through a search of the EMBASE, PubMed, and Web of Science databases, 1412 articles were identified, from which 33 randomized clinical trials (RCT) and 44 preclinical were selected. Populations from RCT were stratified according to baseline BP and lipid levels. The authors performed meta-analyses of the effect of atorvastatin on systolic (SBP), diastolic, and mean BP; heart rate (HR); HR variability, and baroreflex. The conclusion from the paper was that atorvastatin lowers blood pressure independent of LDL-cholesterol levels.