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ABSTRACT: Unhealthy lifestyles have placed a significant burden on individuals' cardiovascular health. Anthocyanins are water-soluble flavonoid pigments found in a wide array of common foods and fruits. Anthocyanins have the potential to contribute to the prevention and treatment of cardiovascular disease by improving lipid profiles and vascular function, reducing blood glucose levels and blood pressure, and inhibiting inflammation. These actions have been demonstrated in numerous clinical and preclinical studies. At the cellular and molecular level, anthocyanins and their metabolites could protect endothelial cells from senescence, apoptosis, and inflammation by activating the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthases, silent information regulator 1 (SIRT1), or nuclear factor erythroid2-related factor 2 pathways and inhibiting the nuclear factor kappa B, Bax, or P38 mitogen-activated protein kinase pathways. Furthermore, anthocyanins prevent vascular smooth muscle cell from platelet-derived growth factor -induced or tumor necrosis factor-α-induced proliferation and migration by inhibiting the focal adhesion kinase and extracellular regulated protein kinases signaling pathways. Anthocyanins could also attenuate vascular inflammation by reducing the formation of oxidized lipids, preventing leukocyte adhesion and infiltration of the vessel wall, and macrophage phagocytosis of deposited lipids through reducing the expression of cluster of differentiation 36 and increasing the expression of ATP-binding cassette subfamily A member 1 and ATP-binding cassette subfamily G member 1. At the same time, anthocyanins could lower the risk of thrombosis by inhibiting platelet activation and aggregation through down-regulating P-selectin, transforming growth factor-1, and CD40L. Thus, the development of anthocyanin-based supplements or derivative drugs could provide new therapeutic approaches to the prevention and treatment of vascular diseases.

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PURPOSE OF REVIEW: Heart failure is a clinical syndrome with signs and symptoms from underlying cardiac abnormality and evidence of pulmonary or systemic congestion on laboratory testing or other objective findings (Bozkurt et al. in Eur J Heart Fail 23:352-380, 2021). Heart failure with reduced ejection fraction (HFrEF), when heart failure is due to underlying reduction in ejection fraction to ≤ 40. The goal of this review is to briefly describe the mechanisms and benefits of the various pharmacological interventions described in the 2022 AHA/ACC/HFSA Guidelines focusing on Stage C: Symptomatic Heart Failure HFrEF, while providing basic guidance on safe use of these medications. RECENT FINDINGS: Use of medications from each class as recommended in the 2022 Guidelines can provide significant morbidity and mortality benefits for our patients. Despite advances in therapeutics for patients with HFrEF, patients are frequently under treated and more research is needed to help optimize management of these complicated patients.

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Background: Management strategies for stable angina include pharmacotherapy, revascularization, and exercise-based cardiac rehabilitation (CR). The optimal treatment for stable angina patients with severe coronary artery stenosis remains unclear. This study aimed to compare interventional therapy with exercise rehabilitation in this population. Methods: Fifty stable angina patients with severe coronary stenosis who underwent stent implantation were included in the optimal medical therapy (OMT) plus percutaneous coronary intervention (PCI) group, and 50 patients who did not undergo interventional treatment were included in OMT plus CR group receiving exercise rehabilitation guidance for one year. Cardiovascular composite endpoint events, cardiopulmonary fitness, and quality of life scale scores were assessed after one year. Results: No significant difference in incidence of cardiovascular composite endpoint events was observed between OMT plus PCI group with OMT plus CR group (20.0% vs 14.6%) after one year. Cardiopulmonary fitness represented as peak VO2 (19.2±3.5 vs 17.6±3.2 mL/kg/min), peak load (120±19 vs 108±20 W), and AT (13.5±1.5 vs 12.1±1.3 mL/kg/min) were significantly higher in the rehabilitation group than the intervention group after one year. Both groups showed improvement in their quality of life, but the rehabilitation group improved in more scales. Conclusion: Interventional therapy did not reduce cardiovascular events compared to exercise-based rehabilitation in stable angina patients with severe coronary artery stenosis, but the rehabilitation can improve cardiovascular fitness and quality of life more.

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Phase 3 randomized controlled trials (RCTs), while the gold standard for treatment efficacy and safety, are not always feasible, are expensive, can be prolonged and can be limited in generalizability. Other under-recognized sources of evidence can also help advance drug development. Basic science, proof-of-concept studies and early-phase RCTs can provide evidence regarding the potential for clinical benefit. Real-world evidence generated from registries or observational datasets can provide insights into the treatment of rare diseases that often pose a challenge for trial recruitment. Pragmatic trials embedded in healthcare systems can assess the treatment effects in clinical settings among patient populations sometimes excluded from trials. This Perspective discusses potential sources of evidence that may be used to complement explanatory phase 3 RCTs and to speed the development of new cardiovascular medications. Content is derived from the 19th Global Cardiovascular Clinical Trialists meeting (December 2022), involving clinical trialists, patients, clinicians, regulators, funders and industry representatives.

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PURPOSE: The aim of this study was to describe a population of very old people with heart failure (HF), to analyse the use of cardiovascular drugs over time, and to explore factors influencing cardiovascular drug treatment for this group. METHODS: All participants with information regarding HF diagnosis were selected from the Umeå 85+/Gerontological Regional Database (GERDA). The people in GERDA are all ≥85 years old. Trained investigators performed structured interviews and assessments. Information regarding medications and diagnoses was obtained from the participants and from medical records. Medical diagnoses were reviewed and confirmed by an experienced geriatrician. RESULTS: In this very old population, the prevalence of HF was 29.6% among women and 30.7% among men. Between 2000 and 2017, there was an increase in the use of renin-angiotensin (RAS) inhibitors (odds ratio [OR] 1.107, 95% confidence interval [CI] 1.072-1.144) and beta-blockers (BBs) (OR 1.123, 95% CI 1.086-1.161) among persons with HF, whereas the prevalence of loop diuretics (OR 0.899, 95% CI 0.868-0.931) and digitalis (OR 0.864, 95% CI 0.828-0.901) decreased (p < 0.001 for all drug classes). Higher age was associated with lower use of RAS inhibitors and BBs. CONCLUSION: In this HF population, the use of evidence-based medications for HF increased over time. This may be a sign of better awareness among prescribers regarding the under-prescribing of guidelines-recommended treatment to old people. Higher age associated with a lower prevalence of RAS inhibitors and BBs. This might indicate that further improvement is possible but could also represent a more cautious prescribing among frail very old individuals.

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INTRODUCTION: Clinical trials, essential for medical advancement, vary significantly in methodology and regulatory pathways depending on the type of therapeutic intervention (i.e., drugs or devices). This study aimed to determine whether the drug or device intervention types influence the impact of randomized trials in cardiovascular medicine. METHODS: We analyzed late-breaking randomized controlled trials presented at major cardiology conferences from 2015 to 2021. The primary endpoint was the total number of citations obtained. Secondary endpoints included the number of citations at 1 and 2 years, number of total and 1-year mentions, and several metrics of study conduct and publication. Statistical analysis included tests for comparisons of continuous or categorical variables, based on their distribution, as appropriate. To adjust the results for potential confounders, univariable and multivariable regression models were utilized. Additionally, sensitivity analyses were conducted to explore both the effect of neutral or positive study outcomes on the comparative impact of drug versus device trials and the impact of the coronavirus disease 2019 (COVID-19) pandemic on the primary endpoint. RESULTS: Of 382 eligible randomized trials, 227 (59.4%) were trials of drugs and 155 (40.6%) were trials of devices. Drug trials had a higher median number of total citations compared to device studies (93 [interquartile range {IQR} 48-137] vs. 82 [IQR 39-192]; p = 0.025). This difference was consistent at 1 and 2 years and was also observed in the number of total mentions and mentions at 1 year. All the metrics of study conduct and publication were similar, except for drug studies being more often stopped prematurely (8.8 vs. 1.9%; p = 0.006). After adjusting for multiple potential confounders, the difference in citations and mentions was no longer statistically significant. However, drug trials remained more likely to be stopped prematurely (adjusted odds ratio = 1.15; 95% confidence interval 1.03-1.28; p = 0.009). Positive study outcomes significantly influenced the number of citations and the likelihood of a trial being stopped prematurely. CONCLUSIONS: Drug trials are often stopped early and receive more citations and mentions than device trials. However, these differences are mainly due to factors other than the treatment itself. Studies published simultaneously tend to get more attention, and drug trials with positive results are cited more often than those with neutral results.

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BACKGROUND: Physician underprescribing and patient nonadherence are major barriers to the benefits of guideline-directed medical therapy. An important contributor to both underprescribing and patient nonadherence is concern about medication-related side effects. Yet, there are few to no data on approaches used by physicians to: (1) elicit medication-related side effects, (2) attribute these side effects to specific medications, and (3) take appropriate action. METHODS AND RESULTS: The authors conducted semistructured interviews with physicians to identify facilitators and barriers to each critical step of heart failure medication management: elicitation of side effects, attribution of side effects to a medication, and action in response to attributed side effects. Interviews were transcribed and coded using directed content analysis. For elicitation of potential side effects, limited patient communication and family discordance in reporting were key barriers, whereas guiding questions, measurement, and open channels of communication were key facilitators. For attribution of side effects, confounding from other medications, limited time for clinical encounters, and nonspecific symptoms were key barriers, whereas time-limited medication discontinuation trials and medication rechallenges were key facilitators. For taking action, challenges with weighing risks and benefits and physician fear about causing harm or interfering with other clinicians were barriers, whereas patient-physician communication and the results of a medication discontinuation trials and medication rechallenge were facilitators. CONCLUSIONS: This study generated key facilitators and barriers to 3 key aspects of heart failure medication management related to side effects that should drive future work to improve heart failure medication management.

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Partial or complete imaging resolution of left ventricular (LV) systolic dysfunction in patients with heart failure with reduced ejection fraction (HFrEF) has gone by many names in the past few decades, including LV recovery, remission, reverse remodeling, and, most recently, improvement. This phenomenon has been described in a variety of clinical scenarios, including removal of an acute myocardial insult, unloading with durable LV assist devices, and treatment with various devices as well as pharmacotherapies, termed guideline-directed medical therapy (GDMT). Irrespective of definition, systolic improvement is associated with improved clinical outcomes compared to persistent systolic dysfunction. In the past few years, systolic improvement has been distinguished from HFrEF as a new clinical entity referred to as HF with improved EF (HFimpEF). Given the relative novelty of this condition, there is a paucity of data with regard to the clinical trajectory and management of this population. In this review, we describe the history of myocardial improvement terminology and explore notable findings that have led to the delineation of HFimpEF. Additionally, we highlight the importance of understanding LV trajectory and the potential opportunity for new GDMT management for clinicians when treating patients with HFimpEF.

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BACKGROUND: Chronic heart failure affects approximately 26 million people globally. World Health Organization data show that only approximately half of chronically ill patients in developed countries adhere to recommended medication, with even lower rates in developing countries. Medication adherence is critical for managing chronic heart failure symptoms, delaying disease progression, and preventing hospitalizations. However, poor adherence increases rehospitalization, morbidity, mortality, and healthcare costs. OBJECTIVE: To assess medication adherence and associated factors among chronic heart failure patients on follow-up at North Shewa Public Hospitals, Oromia Region, Ethiopia, in 2023. METHODS: This institutional-based cross-sectional study was conducted from March 1 to April 30, 2023, G.C. A total of 603 individuals were selected consecutively among those who underwent chronic OPD after being proportionally allocated to five hospitals in the zone. The data were collected using an interviewer-administered questionnaire and a medical chart review. The data were entered into Epi-data version 3.1 and then exported to SPSS version 26 for analysis. The multivariable logistic regression model included variables with a P value < 0.25 in the bivariate analysis. The degree of association was expressed using an adjusted odds ratio (AOR) with a 95% confidence interval (CI) at a P value < 0.05. RESULTS: Among the 603 patients, 56% had optimal medication adherence, with a 95% CI of 52.1 to 60. Being able to read and write (AOR: 2.20; 95% CI: 1.34, 3.61), having a secondary education (AOR: 1.97; 95% CI: 1.06, 3.67), having community-based health insurance (AOR: 1.82; 95% CI: 1.22, 2.71), not having comorbidities (AOR: 1.82; 95% CI: 1.18, 2.52), taking several drugs < 2 (AOR: 2.11; 95% CI: 1.20, 2.45), not adding salt when cooking (AOR: 1.72; 95% CI: 1.20, 2.45), and asking a doctor or nurse without fear (AOR: 1.87; 95% CI: 1.03, 3.40) were factors associated with medication adherence among CHF patients. CONCLUSION: This study revealed that 56% of chronic heart failure patients had optimal medication adherence. Factors associated with higher adherence included higher education, community health insurance, lack of comorbidities, fewer medications, avoiding added salt, and comfortable communication with providers. Health professionals should provide education to strengthen medication adherence.

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AIM: Cardiovascular diseases are the leading cause of death globally. Ensuring ongoing use of medicines-medication persistence-is crucial, yet no prior studies have examined this in residential aged care facilities (RACFs). We aimed to identify long-term trajectories of persistence with cardiovascular medicines and determine predictors of persistence trajectories. METHOD: A longitudinal cohort study of 2837 newly admitted permanent residents from 30 RACFs in New South Wales, Australia. We monitored weekly exposure to six cardiovascular medicine classes-lipid modifiers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs), beta-blockers, diuretics, calcium channel blockers (CCB), and cardiac therapy-over 3 years. Group-based trajectory modeling was employed to determine persistence trajectories for each class. RESULTS: At baseline, 76.6% (n = 2172) received at least one cardiovascular medicine with 41.2% receiving lipid modifiers, 31.4% ACEI/ARBs, 30.2% beta-blockers, 24.4% diuretics, 18.7% CCBs, and 14.8% cardiac therapy. The model identified two persistence trajectories for CCBs and three trajectories for all other classes. Sustained high persistence rates ranged from 68.4% (ACEI/ARBs) to 79.8% (beta-blockers) while early decline in persistence and subsequent discontinuation rates ranged from 7.6% (cardiac therapy) to 25.3% (CCBs). Logistic regressions identified 11 predictors of a declining persistence across the six medicine classes. CONCLUSION: Our study revealed varied patterns of cardiovascular medicine use in RACFs, with 2-3 distinctive medicine use trajectories across different classes, each exhibiting a unique clinical profile, and up to a quarter of residents discontinuing a medicine class. Future studies should explore the underlying reasons and appropriateness of nonpersistence to aid in identifying areas for improvement.

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Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies that investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies and the individual load of actionable PGx variants. Given the high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond. SIGNIFICANCE STATEMENT: Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting PGx testing in the cardiovascular area is limited to a few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond.

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KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS-driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.).

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ABSTRACT: Heart rate (HR) stands as a prognostic indicator of cardiovascular disease and a modifiable risk factor in heart failure (HF). Medication intolerance can curtail the application of conventional HR-lowering ß-blockers to the optimum target dose. Ivabradine (IVA), a specific negative-chronotropic agent, selectively inhibits I f current in pacemaker cells of the sinoatrial node without depressing myocardial contractility or comprising hemodynamics. This review summarized ivabradine's clinical labeled and off-label uses and mechanism of action focusing on the clinical outcomes. PubMed was searched up to January 2024 using the main keywords of IVA, coronary artery disease (CAD), HF, postural tachycardia syndrome (POTS), and tachyarrhythmia. To comprehensively review IVA's clinical indications, mechanisms, and therapeutic effects, all studies investigating treatment with IVA in humans were included, comprising different types of studies such as randomized controlled trials and longitudinal prospective observational studies. After screening, 141 studies were included in our review. A large number of reviewed articles were allocated to heart failure with reduced ejection fraction and CAD, suggesting IVA as an alternative to ß-blockers in case of contraindications or intolerance. The beneficial effects of IVA as premedication for coronary computed tomography angiography, HR lowering in POTS, and inappropriate sinus tachycardia constituted most studies among off-label uses. The promising results have been reported on the efficacy of IVA in controlling HR, especially in patients with inappropriate sinus tachycardia or POTS. Owing to the unique mechanism of action, IVA has the potential to be used more frequently in future clinical practice.

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The aim of this network meta-analysis was to compare the efficacy of various commonly used drugs in treating patients with hypertrophic cardiomyopathy (HCM). Randomized controlled trials on drugs for HCM treatment were retrieved from PubMed, Embase, Cochrane Library, and Web of Science (search cutoff: January 10, 2024). Quality assessment was performed using the risk of bias tool, and data analysis used R software. Seventeen studies (1,133 patients with HCM) were included. The network meta-analysis indicated that mavacamten and perhexiline improved peak oxygen consumption compared with placebo. Mavacamten reduced N-terminal pro-B-type natriuretic peptide, left ventricular mass index, left atrial volume index, and septal E/e' ratio. Losartan decreased systolic blood pressure, whereas candesartan, mavacamten, and valsartan reduced maximum wall thickness. Perhexiline had better efficacy in increasing peak oxygen consumption, and candesartan in reducing maximum wall thickness. No drug significantly improved left ventricular ejection fraction compared with placebo. In conclusion, on the basis of current studies, commonly used drugs may effectively improve some of the outcome measures in patients with HCM, whereas the novel drug mavacamten showed significant therapeutic effects in most of the remaining outcome measures except for left ventricular ejection fraction.

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Cardiovascular disease exacts a heavy toll on health and quality of life and is the leading cause of death among people ≥65 years of age. Although medical, surgical, and device therapies can certainly prolong a life span, disease progression from chronic to advanced to end stage is temporally unpredictable, uncertain, and marked by worsening symptoms that result in recurrent hospitalizations and excessive health care use. Compared with other serious illnesses, medication management that incorporates a palliative approach is underused among individuals with cardiovascular disease. This scientific statement describes palliative pharmacotherapy inclusive of cardiovascular drugs and essential palliative medicines that work synergistically to control symptoms and enhance quality of life. We also summarize and clarify available evidence on the utility of guideline-directed and evidence-based medical therapies in individuals with end-stage heart failure, pulmonary arterial hypertension, coronary heart disease, and other cardiomyopathies while providing clinical considerations for de-escalating or deprescribing. Shared decision-making and goal-oriented care are emphasized and considered quintessential to the iterative process of patient-centered medication management across the spectrum of cardiovascular disease.

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BACKGROUND: The efficacy of optimal medical therapy (OMT) with or without revascularization therapy in patients with stable coronary artery disease (SCAD) remains controversial. We performed a meta-analysis of randomized controlled trials (RCTs) that compared OMT with or without revascularization therapy for SCAD patients. METHODS: Studies were searched in PubMed, EMBASE, and the Cochrane Central Register of Clinical Trials from January 1, 2005, to December 30, 2023. The main efficacy outcome was a composite of all-cause death, myocadiac infarction, revascularization, and cerebrovascular accident. Results were pooled using random effects model and fixed effects model and are presented as odd ratios (ORs) with 95% confidence intervals (CI). RESULTS: Ten studies involving 12,790 participants were included. The arm of OMT with revascularization compared with OMT alone was associated with decreased risks for MACCE (OR 0.55 [95% CI 0.38-0.80], I²=93%, P = 0.002), CV death (OR 0.84 [95% CI 0.73-0.97], I²=36%, P = 0.02), revascularization (OR 0.32 [95% CI 0.20-0.50], I²=92%, P < 0.001), and MI (OR 0.85 [95% CI 0.76-0.96], I²=45%, P = 0.007). While there was no significant difference between OMT with revascularization and OMT alone in the odds of all-cause death (OR 0.94 [95% CI 0.84-1.05], I²=0%, P = 0.30). CONCLUSIONS: The current updated meta-analysis of 10 RCTs shows that in patients with SCAD, OMT with revascularization would reduce the risk for MACCE, cardiovascular death, and MI. However, the invasive strategy does not decrease the risks for all-cause mortality when comparing with OMT alone.

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BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and at present, India has the highest burden of acute coronary syndrome and ST-elevation myocardial infarction (MI). A key reason for poor outcomes is non-adherence to medication. METHODS: The intervention is a 2 × 2 factorial design trial applying two interventions individually and in combination with 1:1 allocation ratio: (i) ASHA-led medication adherence initiative comprising of home visits and (ii) m-health intervention using reminders and self-reporting of medication use. This design will lead to four potential experimental conditions: (i) ASHA-led intervention, (ii) m-health intervention, (iii) ASHA and m-health intervention combination, (iv) standard of care. The cluster randomized trial has been chosen as it randomizes communities instead of individuals, avoiding contamination between participants. Subcenters are a natural subset of the health system, and they will be considered as the cluster/unit. The factorial cluster randomized controlled trial (cRCT) will also incorporate a nested health economic evaluation to assess the cost-effectiveness and return on investment (ROI) of the interventions on medication adherence among patients with CVDs. The sample size has been calculated to be 393 individuals per arm with 4-5 subcenters in each arm. A process evaluation to understand the effect of the intervention in terms of acceptability, adoption (uptake), appropriateness, costs, feasibility, fidelity, penetration (integration of a practice within a specific setting), and sustainability will be done. DISCUSSION: The effect of different types of intervention alone and in combination will be assessed using a cluster randomized design involving 18 subcenter areas. The trial will explore local knowledge and perceptions and empower people by shifting the onus onto themselves for their medication adherence. The proposal is aligned to the WHO-NCD aims of improving the availability of the affordable basic technologies and essential medicines, training the health workforce and strengthening the capacity of at the primary care level, to address the control of NCDs. The proposal also helps expand the use of digital technologies to increase health service access and efficacy for NCD treatment and may help reduce cost of treatment. TRIAL REGISTRATION: The trial has been registered with the Clinical Trial Registry of India (CTRI), reference number CTRI/2023/10/059095.

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