Reduction In Major Cardiovascular Events Research Articles

A novel digital twin strategy to enable the translation of evidence from randomized control trials to new populations

Abstract Background Randomized clinical trials (RCTs) are essential to guide medical practice; however, their generalizability to a given population is often uncertain. Between the SPRINT and ACCORD trials, only SPRINT found a significant reduction in major cardiovascular events (MACE) with intensive blood pressure control, but ACCORD did not, without clear evidence of whether this reflected differences in enrolled patients. Purpose To use a novel RCT digital twin-based approach to demonstrate the translation of an RCT to a different population, leveraging the differences in populations and treatment effects in SPRINT and ACCORD. Methods We developed a statistically informed Generative Adversarial Network (GAN) model that leverages relationships between covariates and outcomes using Directed Acyclic Graphs (DAGs). This model can generate a digital twin of an RCT (RCT-Twin) conditioned on covariate distributions from a second patient population while maintaining these relationships (Fig A). Using this, we generated the (i) RCT-Twin of SPRINT, which was conditioned on the 10 most disparate covariates drawn from ACCORD, and (ii) an RCT-Twin of ACCORD conditioned on SPRINT. To demonstrate treatment effect estimates of each RCT conditioned on the other RCT’s patient population, we evaluated the cardiovascular event-free survival of 10 iterations of these cross-trained RCT-Twins against the original trials. Results Using 9361 SPRINT participants and conditioning on 4733 ACCORD participants, we generated 10 ACCORD-conditioned SPRINT-Twin datasets. We confirmed that the RCT-Twins were consistently balanced between treatment and controls across all measured covariates (mean absolute standardized mean difference (MASMD) 0.019, SD 0.018), as expected for real RCTs. We also confirmed that covariates of the ACCORD-conditioned SPRINT-Twins were closer to ACCORD than SPRINT (MASMD 0.0082 vs 0.46, SD 0.016 vs 0.20), suggestive of successful conditioning. Most importantly, across iterations, ACCORD-conditioned SPRINT-Twin datasets reproduced the overall non-significant effect size seen in ACCORD (5-year MACE hazard ratio (95% confidence interval) of 0.88 (0.73-1.06) in ACCORD vs median 0.87 (0.68-1.13) in the ACCORD-conditioned SPRINT-Twins, Fig B), while the SPRINT-conditioned ACCORD-Twin datasets reproduced the significant effect size seen in SPRINT (0.75 (0.64-0.89) vs median 0.79 (0.72-0.86) in the SPRINT-conditioned ACCORD-Twins, Fig C). Conclusions Our novel conditioned digital twin approach simulates RCT-derived effects in different patient populations by translating these effects to the covariate distributions of the patients. This key methodological advance may enable the direct translation of RCT-derived effects into disparate patient populations and may enable causal inference in real-world settings.

Long-Term Effect of Salt Substitution for Cardiovascular Outcomes : A Systematic Review and Meta-analysis.

Salt substitution is a simple yet increasingly promising strategy to improve cardiovascular outcomes. To evaluate the long-term effects of salt substitution on cardiovascular outcomes. PubMed, EMBASE, Cochrane CENTRAL, and CINAHL searched from inception to 23 August 2023. Trial registries, citation analysis, and hand-search were also done. Randomized controlled trials (RCTs) comparing provision of or advice to use a salt substitute with no intervention or use of regular salt among adults for 6 months or longer in total study duration. Two authors independently screened articles, extracted data, and assessed risk of bias. Primary outcomes include mortality, major cardiovascular events (MACE), and adverse events at 6 months or greater. Secondary and post hoc outcomes include blood pressure, cause-specific mortality, and urinary excretion at 6 months or greater. Random-effects meta-analyses were done and certainty of effect estimates were assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). Of the 16 included RCTs, 8 reported on primary outcomes. Most (n = 7 of 8) were done in China or Taiwan, 3 were done in residential facilities, and 7 included populations of older age (average 62 years) and/or with higher-than-average cardiovascular risk. In this population, salt substitute may reduce risk for all-cause mortality (6 RCTs; 27 710 participants; rate ratio [RR], 0.88 [95% CI, 0.82 to 0.93]; low certainty) and cardiovascular mortality (4 RCTs; 25 050 participants; RR, 0.83 [CI, 0.73 to 0.95]; low certainty). Salt substitute may result in a slight reduction in MACE (3 RCTs; 23 215 participants; RR, 0.85 [CI, 0.71 to 1.00]; very low certainty), with very low-certainty evidence of serious adverse events (6 RCTs; 27 995 participants; risk ratio, 1.04 [CI, 0.87 to 1.25]). The evidence base is dominated by a single, large RCT. Most RCTs were from China or Taiwan and involved participants with higher-than-average cardiovascular risk; therefore, generalizability to other populations is very limited. Salt substitution may reduce all-cause or cardiovascular mortality, but the evidence for reducing cardiovascular events and for not increasing serious adverse events is uncertain, particularly for a Western population. The certainty of evidence is higher among populations at higher cardiovascular risk and/or following a Chinese diet. National Health and Medical Research Council. (PROSPERO: CRD42022327566).

O054 What Measure of CPAP Treatment is most closely Associated with Reduced Risk of Future Major Cardiovascular Events (MACE)?

Abstract Introduction Obstructive sleep apnoea (OSA) is associated with future Major Adverse Cardiovascular Events (MACE). Continuous positive airway pressure (CPAP) is the standard treatment for OSA, but it is not known which measure of CPAP treatment is most closely associated with reduction in future MACE. We compared associations between a novel and a commonly used measure of CPAP treatment and future MACE. Materials and Methods Participants: 2717 adults with moderate-severe OSA attending a tertiary sleep clinic 2006-2010 completed baseline assessments and followed-up for 7years. CPAP treatment: Month-long CPAP trial and periodic review post-trial. Outcomes Time to cardiac death or non-fatal hospitalisations due to MACE, or end of follow-up, using Cox proportional hazards models. Predictors Average nightly CPAP use and the SARAH index (Sleep-Adjusted Residual AHI), using all available device downloads SARAH index=([AHITreatment×HoursTreatment]+[AHIUntreated×HoursUntreated])/HoursTotalSleepTime Covariates Demographics/comorbidities associated with MACE. Results MACE occurred in 18% participants. Average nightly use: Compared to zero use, each tertile of increasing use predicted reduction in risk of MACE (tertile-0:ref, tertile-I:HR 0.632, 95%CI 0.484-0.824, p<0.001, tertile-II:HR 0.772, 95%CI 0.602-0.990, p=0.042, tertile-III:HR 0.708, 95%CI 0.553-0.905, p=0.006). SARAH A dose-response decreasing risk of MACE with decreasing SARAH index tertiles (tertile-I:ref, tertile-II:HR 0.827, 95%CI 0.658-1.039, p= 0.102, tertile-III:HR 0.772, 95%CI 0.614-0.969, p=0.026). Conclusions Average nightly CPAP use and SARAH index were associated with a decreased risk of future MACE. The SARAH index showed a dose-response relationship with MACE; suggesting that it may be a better estimate of residual OSA-related cardiovascular stress.

Major cardiovascular events increase in long-term proprotein convertase subtilisin/kexin type 9 inhibitors therapy: the Tuscany cost-effective study.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a breakthrough in the treatment of hypercholesterolemia. The aim of this study was to perform a multicentre prospective analysis on the effects of PCSK9i since their distribution in Italy. During the study period (July 2017 to February 2022) 246 patients (mean age 61 ± 11 years, male 73%) who were evolocumab (142/246) or alirocumab (104/246) new users were enrolled in the CERTI (Costo Efficacia Regione Toscana Inibitori PCSK9) study. Lipid value, adverse events (AEs), major cardiovascular events (MACEs) and intima-media thickness were analysed. PCSK9i therapy allowed a significant improvement in patients' lipid profile [total cholesterol -35%, P < 0.001; triglycerides -9%, P < 0.05; low-density lipoprotein (LDL) cholesterol -51%, P < 0.001; Lp(a) levels -4%, P < 0.05], maintained during the follow-up. No significant variations in intima-media thickness were observed. In the subgroup of patients with more than 1 year of PCSK9i therapy (165/246 patients) we highlighted: a 66% reduction in MACEs compared with the year before recruitment; a progressive increase in MACEs during the follow-up (MACEs event/rate at first year 0.08 vs. MACEs event/rate at year 5: 0.47); a patients cluster with late MACEs older, with higher prevalence of hypertension, smoking habit and peripheral vascular disease. During the follow-up, we recorded AEs in 31% of patients, which mainly resulted in reduction/discontinuation of lipid-lowering therapy for 50 patients or in discontinuation/shift of PCSK9i (respectively 8 and 6 cases). Our data agree with the large evidence on the effectiveness/tolerability of PCSK9i therapy; however, although PCSK9i represents a good cholesterol-lowering therapeutic option, our study shows a progressive increase in MACEs during the late follow-up that deserve further research.

Present and Future of Dyslipidaemia Treatment-A Review.

One of the greatest burdens on the healthcare systems of modern civilization is cardiovascular diseases (CVDs). Therefore, the medical community is looking for ways to reduce the incidence of CVDs. Simple lifestyle changes from an unhealthy to a healthy lifestyle are the cornerstone of prevention, but other risk factors for cardiovascular disease are also being currently targeted, most notably dyslipidaemia. It is well known that lowering serum lipid levels, and in particular lowering elevated LDL-cholesterol, leads to a reduction in major cardiovascular events. Although the focus to date has been on LDL-cholesterol levels and lowering them with statin therapy, this is often not enough because of increased concentrations of other lipoprotein particles in the serum and residual cardiovascular risk. Since lowering LDL-cholesterol levels is successful in most cases, there has been a recent focus on lowering residual cardiovascular risk. In recent years, new therapeutic options have emerged that target triglyceride-rich lipoproteins, lipoprotein (a) and apolipoproteins C and B. The effects of these drugs on serious adverse cardiovascular events are not yet known, but recent studies with some of these drugs have shown significant results in lowering total lipid levels. The aim of this review is to present the current therapeutic options for the treatment of dyslipidaemia and to describe the newly approved drugs as well as the drugs that are still in development. Although at this stage we cannot say with certainty whether these agents will be approved and widely used, it is safe to say that our views on the treatment of dyslipidaemia are certainly changing.

Effects of continuous positive airway pressure on cardiac events and metabolic components in patients with moderate to severe obstructive sleep apnea and coronary artery disease: a meta-analysis.

This meta-analysis aimed to systematically assess the effects of continuous positive airway pressure (CPAP) in secondary prevention of major cardiovascular events (MACEs) in patients with moderate-to-severe obstructive sleep apnea and coronary artery disease. PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched for observational studies and randomized controlled trials that compared CPAP with usual care in patients with moderate-to-severe obstructive sleep apnea with coronary artery disease. The primary outcomes were MACEs, all-cause death, acute coronary syndrome, rehospitalization for heart failure, repeat revascularization, and arrhythmia. A total of 11 studies (5 randomized controlled trials and 6 observational studies) with 5,410 patients reported outcomes of MACEs. Treatment with CPAP was associated with a modest risk reduction in MACEs (risk ratio [RR] 0.87, 95% confidence interval [CI] 0.78 to 0.98; P = .02). Similarly, CPAP significantly reduced the risk of all-cause and cardiovascular death by 23% (RR 0.77, 95% CI 0.60 to 0.99; P = .04; I2 = 0%). Subgroup analysis revealed that CPAP adherence time ≥ 4 hours/night had a greater benefit on MACEs by 42% (RR 0.58, 95% CI 0.42 to 0.79; P < .001; I2 = 0%) and repeat revascularization by 44% (RR 0.56, 95% CI 0.34 to 0.92; P = .02; I2 = 0%). Also, CPAP had a positive effect on systolic and diastolic blood pressure. CPAP therapy might prevent subsequent MACEs and all-cause death among patients with moderate to severe obstructive sleep apnea and concomitant coronary artery disease. CPAP use exceeding 4 hours/night may add more benefits on MACEs, repeat revascularization, and blood pressure. Registry: PROSPERO database; Name: Effects of Continuous Positive Airway Pressure on Cardiovascular Events and Metabolic Components in Patients with Obstructive Sleep Apnea and Coronary Artery Disease; URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID= CRD42020213546; Identifier: CRD42020213546. Yang D, Li L, Dong J, Yang W, Liu Z. Effects of continuous positive airway pressure on cardiac events and metabolic components in patients with moderate to severe obstructive sleep apnea and coronary artery disease: a meta-analysis. J Clin Sleep Med. 2023;19(12):2015-2025.

The Novel Role of Noncoding RNAs in Modulating Platelet Function: Implications in Activation and Aggregation.

It is currently believed that plaque complication, with the consequent superimposed thrombosis, is a key factor in the clinical occurrence of acute coronary syndromes (ACSs). Platelets are major players in this process. Despite the considerable progress made by the new antithrombotic strategies (P2Y12 receptor inhibitors, new oral anticoagulants, thrombin direct inhibitors, etc.) in terms of a reduction in major cardiovascular events, a significant number of patients with previous ACSs treated with these drugs continue to experience events, indicating that the mechanisms of platelet remain largely unknown. In the last decade, our knowledge of platelet pathophysiology has improved. It has been reported that, in response to physiological and pathological stimuli, platelet activation is accompanied by de novo protein synthesis, through a rapid and particularly well-regulated translation of resident mRNAs of megakaryocytic derivation. Although the platelets are anucleate, they indeed contain an important fraction of mRNAs that can be quickly used for protein synthesis following their activation. A better understanding of the pathophysiology of platelet activation and the interaction with the main cellular components of the vascular wall will open up new perspectives in the treatment of the majority of thrombotic disorders, such as ACSs, stroke, and peripheral artery diseases before and after the acute event. In the present review, we will discuss the novel role of noncoding RNAs in modulating platelet function, highlighting the possible implications in activation and aggregation.

Practical issues in pragmatic trials: the implementation of the Diuretic Comparison Project.

The US Department of Veterans Affairs Point of Care Clinical Trial Program conducts studies that utilize informatics infrastructure to integrate clinical trial protocols into routine care delivery. The Diuretic Comparison Project compared hydrochlorothiazide to chlorthalidone in reduction of major cardiovascular events in subjects with hypertension. Here we describe the cultural, technical, regulatory, and logistical challenges and solutions that enabled successful implementation of this large pragmatic comparative effectiveness Point of Care clinical trial. Patients were recruited from 72 Veterans Affairs Healthcare Systems using centralized processes for subject identification, obtaining informed consent, data collection, safety monitoring, site communication, and endpoint identification with minimal perturbation of the local clinical care ecosystem. Patients continued to be managed exclusively by their clinical care providers without protocol specified study visits, treatment recommendations, or data collection extraneous to routine care. Centralized study processes were operationalized through the application layer of the electronic health record via a data coordinating center staffed by clinical nurses, data scientists, and statisticians without site-based research coordinators. Study data was collected from the Veterans Affairs electronic health record supplemented by Medicare and National Death Index data. The study exceeded its enrolled goal (13,523 subjects) and followed subjects for the 5-year study duration. The key determinant of program success was collaboration between researchers, regulators, clinicians, and administrative staff at the site level to customize study procedures to align with local clinical practice. This flexibility was enabled by designation of the study as minimal risk and determination that clinical care providers were not engaged in research by the Veterans Affairs Central Institutional Review Board. Cultural, regulatory, technical, and logistical problems were identified and solved through iterative collaboration between clinical and research entities. Paramount among these problems was customization of the Veterans Affairs electronic health record and data systems to accommodate study procedures. Leveraging clinical care for large-scale clinical trials is feasible but requires a rethinking of traditional clinical trial design (and regulation) to better meet requirements of clinical care ecosystems. Study designs must accommodate site-specific practice variation to reduce the impact on clinical care. A tradeoff thus exists between designing trial processes tailored to expedite local study implementation versus those to produce a more refined response to the research question. The availability of a uniform and flexible electronic health record in the Department of Veterans Affairs played a major role in the success of the trial. Conducting Point of Care research in other healthcare systems without such research-friendly infrastructure presents a more formidable challenge.

The association of energy and macronutrient intake at breakfast and cardiovascular disease in Chinese adults: From a 14-year follow-up cohort study.

We aimed to examine the associations between energy and macronutrient intakes at breakfast and the incidence of cardiovascular events among Chinese adults. There were 12,937 participants from the China Health and Nutrition Survey who met the study criteria and completed six rounds of questionnaires in 1997, 2000, 2004, 2006, 2009, and 2011. Combined weighing methods with 24-h dietary recall were used to measure dietary intake throughout the day. Intakes of macronutrients at breakfast were calculated using energy provided by nutrients as a percentage of breakfast energy. We calculated hazard ratios using a multivariable Cox frailty model with random intercepts to account for household clustering. During follow-up, we documented 453 (3.6 per 1,000 person-years) major cardiovascular events, 195 (1.5 per 1,000 person-years) myocardial infarctions, and 293 (2.3 per 1,000 person-years) strokes. In Chinese adults, more breakfast carbohydrates or less proteins intake was associated with the reduced risk of cardiovascular diseases. Especially for women, higher intake of breakfast carbohydrates was associated with a lower risk of major cardiovascular events (quintile 5 vs. quintile 1, HR 0.47 [95%CI 0.30-0.74]; p trend = 0.0008) and stroke (quintile 5 vs. quintile 1, HR 0.48 [95%CI 0.26-0.88]; p trend = 0.0006). Higher intake of breakfast proteins was associated with a higher risk of major cardiovascular events (quintile 5 vs. quintile 1, HR 1.77 [95%CI 1.12-2.79]; p trend = 0.1162), myocardial infarction (quintile 5 vs. quintile 1, HR 2.49 [95%CI 1.21-5.11]; p trend = 0.2641). There was a significant association between breakfast fat intake and cardiovascular diseases in the adult population, but less significant correlation was found in Chinese men or women. Breakfast fat intake was positively associated with the risk of major cardiovascular events (quintile 5 vs. quintile 1, HR 1.74 [95%CI 1.27-2.36]; p trend = 0.0070), myocardial infarction (quintile 5 vs. quintile 1, HR 2.03 [95%CI 1.23-3.37]; p trend = 0.0168), and stroke (quintile 5 vs. quintile 1, HR 1.64 [95%CI 1.12-2.41]; p trend = 0.0732). There was a significant reduction in major cardiovascular events and stroke when breakfast energy intake was moderated, even if the independence of skipping breakfast. High carbohydrate intake and low protein and fat intake at breakfast may contribute to cardiovascular health while maintaining a moderate energy intake.

Secondary Cardiovascular Prevention after Acute Coronary Syndrome: Emerging Risk Factors and Novel Therapeutic Targets.

The control of cardiovascular risk factors, the promotion of a healthy lifestyle, and antithrombotic therapy are the cornerstones of secondary prevention after acute coronary syndrome (ACS). However, many patients have recurrent ischemic events despite the optimal control of traditional modifiable risk factors and the use of tailored pharmacological therapy, including new-generation antiplatelet and lipid-lowering agents. This evidence emphasizes the importance of identifying novel risk factors and targets to optimize secondary preventive strategies. Lipoprotein(a) (Lp(a)) has emerged as an independent predictor of adverse events after ACS. New molecules such as anti-PCSK9 monoclonal antibodies, small interfering RNAs, and antisense oligonucleotides can reduce plasma Lp(a) levels and are associated with a long-term outcome benefit after the index event. The inflammatory stimulus and the inflammasome, pivotal elements in the development and progression of atherosclerosis, have been widely investigated in patients with coronary artery disease. More recently, randomized clinical trials including post-ACS patients treated with colchicine and monoclonal antibodies targeting cytokines yielded promising results in the reduction in major cardiovascular events after an ACS. Gut dysbiosis has also raised great interest for its potential pathophysiological role in cardiovascular disease. This evidence, albeit preliminary and needing confirmation by larger population-based studies, suggests the possibility of targeting the gut microbiome in particularly high-risk populations. The risk of recurrent ischemic events after ACS is related to the complex interaction between intrinsic predisposing factors and environmental triggers. The identification of novel risk factors and targets is fundamental to customizing patient clinical management with a precision medicine perspective.

Atorvastatin

Atorvastatin

ANMCO Position paper: Evidence and practical indications for the use of low-dose rivaroxaban in stable coronary artery disease and peripheral artery disease

In patients with atherosclerotic disease, the occurrence of atherothrombotic events is the main determinant of morbidity and mortality. Growing evidence suggests the involvement of the coagulation pathway in the atherosclerotic process and the benefit of antithrombotic agents, such as direct oral anticoagulants, which interfere with both platelet aggregation and the coagulation cascade. The COMPASS trial has shown that in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD), low-dose rivaroxaban (2.5 mg twice daily) added to acetylsalicylic acid (ASA) 100 mg reduces major vascular events and mortality, with an increase in major bleeding but not in fatal bleeding or involving a critical organ. The reduction in major cardiovascular events has been confirmed in the overall population with CAD and in both patients with and without a previous percutaneous coronary revascularization, and also in patients with previous coronary bypass surgery. In patients with PAD, the combination of rivaroxaban 2.5 mg twice daily and ASA was found to reduce both major adverse cardiovascular events and major adverse limb events, including major limb amputations. In clinical practice, the use of rivaroxaban 2.5 mg co-administered with ASA has been approved in both patients with CAD and symptomatic PAD at high risk of ischemic events. However, in Italy, the national health system reimbursement is provided only for patients with PAD. In patients treated with rivaroxaban 2.5 mg, assessment and monitoring of bleeding risk is crucial to achieve the maximum clinical benefit.

Resistant hypertension: integrated strategies between pharmacological treatment and renal denervation

The achievement of adequate blood pressure (BP) control and the management of resistant hypertension still represent two burning "unmet needs" in the field of cardiovascular diseases, thus originating a continuous search for more efficacious pharmacological and non-pharmacological strategies including radiofrequency and ultrasound renal denervation (RDN). The most recent guidelines recommend a combination therapy of two or more antihypertensive agents, preferably in a single-pill formulation, as first-line strategy to achieve an effective and early BP control also improving adherence to prescribed treatments. In the last few years several sham-controlled trials have confirmed both the BP-lowering efficacy and safety of RDN in a broad range of patients with hypertension, showing a significant reduction of office and ambulatory BP levels without a relevant increase of procedure-related adverse events such as renal artery stenosis and worsening renal function. These results have been recently confirmed by the analyses of 3-year follow-up data. According to these findings, RDN may represent a useful tool in addition to pharmacological treatment with more compelling indications for patients with resistant hypertension, those who are non-adherent or intolerant to multiple antihypertensive drugs or express a preference to undergo RDN. Further studies are necessary to explore the efficacy of RDN on prevention of hypertension-mediated organ damage and reduction of major cardiovascular events.

Inclisiran and cardiovascular events: a patient-level analysis of phase III trials.

Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. Patient-level, pooled analysis of ORION-9, -10 and -11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58-0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50-1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41-1.81)]. This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

Cardiovascular Risk Reduction After Renal Denervation According to Time in Therapeutic Systolic Blood Pressure Range

BackgroundRenal denervation (RDN) has been shown to lower blood pressure (BP), but its effects on cardiovascular events have only been preliminarily evaluated. Time in therapeutic range (TTR) of BP is associated with cardiovascular events. ObjectivesThis study sought to assess the impact of catheter-based RDN on TTR and its association with cardiovascular outcomes in the GSR (Global SYMPLICITY Registry). MethodsPatients with uncontrolled hypertension were enrolled and treated with radiofrequency RDN. Office and ambulatory systolic blood pressure (OSBP and ASBP) were measured at 3, 6, 12, 24, and 36 months postprocedure and used to derive TTR. TTR through 6 months was assessed as a predictor of cardiovascular events from 6 to 36 months using a Cox proportional hazard regression model. ResultsAs of March 1, 2022, 3,077 patients were enrolled: 42.2% were female; mean age was 60.5 ± 12.2 years; baseline OSBP was 165.6 ± 24.8 mm Hg; and baseline ASBP was 154.3 ± 18.7 mm Hg. Patients were prescribed 4.9 ± 1.7 antihypertensive medications at baseline and 4.8 ± 1.9 at 36 months. At 36 months, mean changes were −16.7 ± 28.4 and −9.0 ± 20.2 mm Hg for OSBP and ASBP, respectively. TTR through 6 months was 30.6%. A 10% increase in TTR after RDN through 6 months was associated with significant risk reductions from 6 to 36 months of 15% for major adverse cardiovascular events (P < 0.001), 11% cardiovascular death (P = 0.010), 15% myocardial infarction (P = 0.023), and 23% stroke (P < 0.001). ConclusionsThere were sustained BP reductions and higher TTR through 36 months after RDN. A 10% increase in TTR through 6 months was associated with significant risk reductions in major cardiovascular events from 6 to 36 months. (Global SYMPLICITY Registry [GSR] DEFINE; NCT01534299)

ODP212 Inpatient Euglycemic DKA due to SGLT2 Inhibitors – Lessons From a Case Series and Strategies to Decrease Incidence

Abstract Background In the past decade, sodium-glucose co-transporter 2 inhibitors (SGLT2i) have revolutionized diabetes mellitus (DM) care due to reduction of major cardiovascular events, heart failure hospitalizations, renal disease progression, and all-cause mortality. SGLT2i are now recommended by the ADA as a second-line agent for many patients with DM. A rare but concerning side effect of SGLT2i is euglycemic DKA (eDKA), which has often been noted in postoperative patients. For patients undergoing elective or routine (non-urgent) procedures, the FDA has recommended cessation three days prior to surgery, a plan already implemented in our pre-operative clinic since 2018. For patients undergoing emergent procedures, careful medication planning cannot be performed. Research Questions We reviewed cases of perioperative eDKA to identify clinical characteristics and factors associated with development of eDKA, and develop strategies to reduce such events. Methods Electronic health record (EHR) data was extracted to identify all patients between 12/1/2013 and 3/30/2021 who underwent procedures and had been prescribed an SGLT2i prior to these procedures. The resulting list was streamlined to a subset of patients who either had DKA listed as a hospital diagnosis, post-operative serum bicarbonate ≤ 16 mmol/L, or post-operative serum pH ≤ 7.20. Clinical documentation and laboratory data for these patients was reviewed to determine those with eDKA. Results A total of 2183 procedures (on 1307 total patients) met extraction criteria with the majority (1726, 79.1%) being non-emergent. Among the 1307 patients, 625 (47.8%) were prescribed empagliflozin, 447 (34.2%), canagliflozin, 214 (16.4%) dapagliflozin, and 21 (1.6%) ertugliflozin. Eight incidences of eDKA were noted on 8 unique patients; 5 had undergone emergent and 3 had undergone non-emergent procedures. In the 3 non-emergent cases, only 1 patient had received counseling to stop the SGLT2i three days prior to the procedure. In perioperative patients who were prescribed an SGLT2i over a six-year period, the incidence of eDKA was 0.17% for non-emergent procedures and 1.1% for emergent procedures. Conclusions Euglycemic DKA was rare in patients undergoing non-emergent procedures. The implementation of a pre-operative program to instruct patients to stop their SGLT2i three days pre-operatively likely contributes to this low incidence. The incidence of eDKA was notably higher in patients undergoing emergent procedures, likely due to inability to plan for temporary SGLT2i cessation. To decrease such events, recent literature has suggested considering a perioperative intravenous insulin and glucose infusion. At our institution, we are implementing a real-time monitoring system with an automated alert to the endocrinology service for hospitalized patients who have been on SGLT2i and have hyperglycemia, acidosis, or ketosis. With the anticipated increased use of SGLT2i, including in the inpatient setting, we urge hospitals and health systems to increase vigilance and develop protocols to mitigate the risk of eDKA. Presentation: No date and time listed

Renin-Angiotensin System Inhibitors and Major Cardiovascular Events after Sepsis.

Rationale: Adult sepsis survivors have an increased risk of experiencing long-term cardiovascular events. Objectives: To determine whether the cardiovascular risk after sepsis is mitigated by renin-angiotensin system inhibitors (RASi). Methods: We conducted a population-based cohort study of adult sepsis survivors designed to emulate a target randomized trial with an active comparator and new-user design. We excluded patients with a first-line indication for prescription of RASi (e.g., coronary heart disease, heart failure, chronic kidney disease, and hypertension with diabetes mellitus). The main exposure of interest was a new prescription of a RASi within 30 days of hospital discharge. The active comparator was a new prescription of either a calcium channel blocker or a thiazide diuretic, also within 30 days of hospital discharge. The primary outcome of interest was the composite of myocardial infarction, stroke, and all-cause mortality during follow-up to 5 years. We used inverse probability weighting of a Cox proportional hazards model and reported results using hazard ratios with 95% confidence intervals. Results: The cohort included 7,174 adult sepsis survivors, of whom 3,805 were new users of a RASi and 3,369 were new users of a calcium channel blocker or a thiazide diuretic. New users of a RASi experienced a lower hazard of major cardiovascular events than new users of a calcium channel blocker or a thiazide diuretic (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99). This association was consistent across different follow-up intervals and multiple sensitivity analyses. Conclusions: A new RASi prescription is associated with a reduction in major cardiovascular events after sepsis. A randomized controlled trial should be considered to confirm this finding.

The Impact of Successful Percutaneous Coronary Intervention on the Reduction of Major Cardiovascular Events in Patients with Chronic Total Coronary Occlusion In dr. Saiful Anwar's Malang Hospital

Background: Chronic total coronary occlusion (CTOs) is associated with an increased risk of adverse clinical outcomes. The benefits of percutaneous coronary intervention (PCI) in CTO are still being debated due to the limited data available. This study aims to determine the relationship between the success of PCI in CTOs and the reduction of major cardiovascular events compared to those who failed or did not perform revascularization in patients with chronic coronary total occlusion in RSUD by Dr. Saiful Anwar Malang. Methods:This study is an analytic observational study with a retrospective cohort design. Of a total of 2165 patients who underwent angiography at Saiful Anwar Hospital, Malang, for the period August 2017–September 2020, consecutively, 578 patients with lesions of at least one CTO were found. There were 68 patients who were excluded, so 510 patients were analyzed in this study. They were divided into two groups, the CTO group that was successfully revascularized with PCI (n = 141) and the group that was not revascularized (n = 369). The outcome of this study was major cardiovascular events (MACE), which included cardiac mortality , all cause mortality, and rehospitalization events. Result: Patients with CTO who were not revascularized compared to those with revascularized CTO had a higher history of heart failure, involvement of LM disease, multivessel disease, and three vessel disease (41.2% vs 18.4%, p = 0.041; 16.5% vs 1.8%, p &lt; 0.001; 69.4% vs 22.7%, p &lt; 0.001; 56.5% vs 14.1%, p &lt; 0.001) with a lower mean LVEF (0.49 ± 0.06 vs 0.51 ± 0.07, p=0.045) and older age (60±9 vs 57±8 years ; p=0.007).. At a 12-month follow-up, in the CTO group that was successfully revascularized by PCI, there was a better prognosis than the non-revascularized CTO group in terms of major cardiovascular events (19.9% vs 33.1% Plog-rank = 0.002). These results were consistent for all-cause mortality (5.5% vs 20.6%, Plog-rank =0.027), cardiac mortality (3.7% vs 20.6%, Plog-rank &lt; 0.001) and rehospitalization events. (7.5% vs 32.2%, Plog-rank = 0.001). Conclusion: Successful revascularization of CTO by PCI may provide clinical benefits in patients with CTO in association with major cardiovascular events.

Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection

Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.

Compounding Benefits of Cholesterol-Lowering Therapy for the Reduction of Major Cardiovascular Events: Systematic Review and Meta-Analysis.

Mendelian randomization studies use genetic variants as natural experiments to provide evidence about causal relations between modifiable risk factors and disease. Recent Mendelian randomization studies suggest each mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) sustained over a lifetime can reduce the risk of cardiovascular disease by more than half. However, these findings have not been replicated in randomized clinical trials, and the effect of treatment duration on the magnitude of risk reduction remains uncertain. The aim of this article was to evaluate the relationship between lipid-lowering drug exposure time and relative risk reduction of major cardiovascular events in randomized clinical trials. We conducted a systematic review and meta-analysis of randomized clinical trials of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors that report LDL-C levels and effect sizes for each year of follow-up. The primary end point was major vascular events, defined as the composite of cardiovascular death, myocardial infarction, stroke, and coronary revascularization. Hazard ratios during each year of follow-up were meta-analyzed using random-effects models. A total of 21 trials with 184 012 patients and an average mean follow-up of 4.4 years were included. Meta-regression showed there was greater relative risk reduction in major vascular events with increasing duration of treatment (P<0.001). For example, each mmol/L LDL-C lowered was associated with a relative risk reduction in major vascular events of 12% (95% CI, 8%-16%) for year 1, 20% (95% CI, 16%-24%) for year 3, 23% (95% CI, 18%-27%) for year 5, and 29% (95% CI, 14%-42%) for year 7. The benefits of LDL-C lowering do not seem to be fixed but increase steadily with longer durations of treatment. The results from short-term randomized trials are compatible with the very strong associations between LDL-C and cardiovascular events seen in Mendelian randomization studies.