Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies.

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1ß monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.

Effect of medications after cardiac surgery on long-term outcomes in patients with cirrhosis.

ABSTRACT: The aim of this study was to evaluate the effect of beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) after cardiac surgery in the liver cirrhosis (LC) patients. We conducted a population-based cohort study using data from the Taiwanese National Health Insurance Research Database (NHIRD) from 2001 to 2013. The outcomes of interest included all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE) and liver and renal outcomes. Among 1470 LC patients, 35.6% (n = 524) received beta-blockers and 33.4% (n = 491) were prescribed ACEIs and/or ARBs after cardiac surgery. The risk of negative liver outcomes was significantly lower in the ARB group compared with the ACEI group (9.6% vs 22.7%, hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.31-0.83). Furthermore, the risk of MACCE (44.2% vs 54.7%, HR 0.79, 95% CI 0.65-0.96), all-cause mortality (35.3% vs 46.4%, HR 0.74, 95% CI 0.60-0.92), composite liver outcomes (9.6% vs 16.5%, HR 0.56, 95% CI 0.38-0.85) and hepatic encephalopathy (2.7% vs 5.7%, HR 0.45, 95% CI 0.21-0.94) were lower in the ARB group than the control group. Our study demonstrated that ARBs provide a greater protective effect than ACEIs in regard to long-term outcomes following cardiac surgery in patients with LC.

Gaps in Evidence-Based Therapy Use in Insured Patients in the United States With Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease.

Background Evidence-based therapies are generally underused for cardiovascular risk reduction; however, less is known about contemporary patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Methods and Results Pharmacy and medical claims data from within Anthem were queried for patients with established atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Using an index date of April 18, 2018, we evaluated the proportion of patients with a prescription claim for any of the 3 evidence-based therapies on, or covering, the index date ±30 days: high-intensity statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and sodium glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonist. The potential benefit of achieving 100% adoption of all 3 evidence-based therapies was simulated using pooled treatment estimates from clinical trials. Of the 155 958 patients in the sample, 24.7% were using a high-intensity statin, 53.1% were using an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and 9.9% were using either an sodium glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonists. Overall, only 2.7% of the population were covered by prescriptions for all 3 evidence-based therapies, and 37.4% were on none of them. Over a 12-month period, 70.6% of patients saw a cardiologist, while only 18% saw an endocrinologist. Increasing the use of evidence-based therapies to 100% over 3 years of treatment could be expected to reduce 4546 major atherosclerotic cardiovascular events (myocardial infarction, stroke, or cardiovascular death) in eligible but untreated patients. Conclusions Alarming gaps exist in the contemporary use of evidence-based therapies in this large population of insured patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. These data provide a call to action for patients, providers, industry, regulators, professional societies, and payers to close these gaps in care.

A Comparison of Rate Control Agents for the Treatment of Atrial Fibrillation: Follow-Up Investigation of the AFFIRM Study.

There are limited data from randomized controlled trials comparing rate control agents in atrial fibrillation. Patient-level data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was used to compare outcomes in patients randomized to the rate control arm who were treated with a single rate control agent at baseline. The rate control agents used were beta-blockers, non-dihydropyridine calcium channel blockers, and digoxin. The independent variable for this analysis was the initial study drug used and the dependent variables were time to first hospitalization and time to death from any cause. We analyzed 1,144 out of 2,027 participants assigned to the rate control group who were on a single rate control agent at the start of the trial. There were 485 (42.5%) participants in the beta-blocker group, 344 (30%) in the calcium channel blocker group, and 315 (27.5%) in the digoxin group. All hospitalization and all-cause mortality occurred in 55.9% and 12.5% of those in the beta-blocker group, 58.4% and 16.7% in the calcium channel blocker group, and 55.2% and 21.1% in the digoxin group, respectively. After adjustment for differences in baseline characteristics, there were no significant differences in time to hospitalization or death for any group. In the AFFIRM trial, the initial rate control drug used was not associated with statistically significant differences in time to hospitalization or death after controlling for differences in baseline characteristics. There is limited data at present to guide the selection of rate control agents in patients with atrial fibrillation.

Plant Terpenes on Treating Cardiovascular and Metabolic Disease: A Review.

The use of medicinal plants as a therapy alternative is old as human existence itself. Nowadays, the search for effective molecules for chronic diseases treatments has increased. The cardiometabolic disorders still the main cause of death worldwide and plants may offer potential pharmacological innovative approaches to treat and prevent diseases. In the range of plant molecules are inserted the terpenes, which constituent essential elements with several pharmacological characteristics and applications, including cardiovascular and metabolic properties. Thus, the aim of the present review is to update the terpenes use on chronic disorders such as obesity, diabetes, hypertension and vascular conditions. The review includes a brief terpenes description based on the scientific literature in addition to data collected from secondary sources such as books and conference proceedings. We concluded that terpenes could act as adjuvant or main alternative treatment (when started earlier) to improve cardiometabolic diseases, contributing to reduce side effects of conventional drugs, in addition to preserving ethnopharmacological knowledge.

Treatment With Cardiovascular Medications: Prognosis in Patients With Myocardial Injury.

Background There is no clinical guidance on treatment in patients with non-ischemic myocardial injury and type 2 myocardial infarction (T2MI). Methods and Results In a cohort of 22 589 patients in the emergency department at Karolinska University Hospital in Sweden during 2011 to 2014 we identified 3853 patients who were categorized into either type 1 myocardial infarction, T2MI, non-ischemic acute and chronic myocardial injury. Data from all dispensed prescriptions within 180 days of the visit to the emergency department were obtained concerning ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, statins, and platelet inhibitors. We estimated adjusted hazard ratios (HR) with 95% CI for all-cause mortality in relationship to the number of medications (categorized into 0-1 [referent], 2-3 and 4 medications) in the groups of myocardial injury. In patients with T2MI, treatment with 2 to 3 and 4 medications was associated with a 50% and 56% lower mortality, respectively (adjusted HR [95% CI], 0.50 [0.25-1.01], and 0.43 [0.19-0.96]), while corresponding associations in patients with acute myocardial injury were 24% and 29%, respectively (adjusted HR [95% CI], 0.76 [0.59-0.99] and 0.71 [0.5-1.02]), and in patients with chronic myocardial injury 27% and 37%, respectively (adjusted HR [95% CI], 0.73 [0.58-0.92] and 0.63 [0.46-0.87]). Conclusions Patients with T2MI and non-ischemic acute or chronic myocardial injury are infrequently prescribed common cardiovascular medications compared with patients with type 1 myocardial infarction. However, treatment with guideline recommended drugs in patients with T2MI and acute or chronic myocardial injury is associated with a lower risk of death after adjustment for confounders.

Preventing cancer therapy-related heart failure: the need for novel studies.

AIMS: After enhancing the survivorship of cancers, the impact of cardiovascular diseases on mortality is increasing among cancer patients. However, anticancer therapies pose a higher cardiovascular risk to patients. As prevention against cancer therapy-induced cardiomyopathy has yet to be explored, the preventive ability of concomitant cardiovascular medications against incident heart failure was assessed. METHODS: A retrospective, population-based study was run using anonymized integration of healthcare databases. All the Hungarian patients diagnosed with breast or colorectal carcinoma and undergoing chemotherapy or biological therapy were analysed. Participants were not treated with any anticancer therapy nor suffered from heart failure/dilated cardiomyopathy during the preceding observational period (≥6.5 years). The heart failure endpoint was established by I50 International Classification of Diseases codes upon discharge from hospital or issuance of an autopsy report. RESULTS: Among the 9575 patients who were enrolled, the cumulative incidence of heart failure over 4 years was 6.9%. The time until the first heart failure event in the propensity score-matched treated and untreated groups was compared using Cox proportional-hazards models. A significant association between lower heart failure risk and concomitant statin therapy was observed (hazard ratio: 0.748, P = 0.038); the preventive ability was more pronounced in the anthracycline/capecitabine/platinum-treated subgroup (hazard ratio: 0.660, P = 0.032). For angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy, a significantly lower heart failure risk was also observed (hazard ratio: 0.809, P = 0.032). Among beta blockers, nebivolol administered to anthracycline/capecitabine-treated patients was associated with a nonsignificant trend to lower heart failure risk (hazard ratio: 0.584, P = 0.069). CONCLUSION: Only concomitant statin and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapies were associated with significantly lower risk of anticancer therapy-related heart failure.

Medical Treatment in Coronary Patients: Is there Still a Gender Gap? Results from European Society of Cardiology EUROASPIRE V Registry.

PURPOSE: This study is aimed at investigating gender differences in the medical management of patients with coronary heart disease (CHD). METHODS: Analyses were based on the ESC EORP EUROASPIRE V (European Survey Of Cardiovascular Disease Prevention And Diabetes) survey. Consecutive patients between 18 and 80 years, hospitalized for a coronary event, were included in the study. Information on cardiovascular medication intake at hospital discharge and at follow-up (≥ 6 months to < 2 years after hospitalization) was collected. RESULTS: Data was available for 8261 patients (25.8% women). Overall, no gender differences were observed in the prescription and use of cardioprotective medication like aspirin, beta-blockers, and ACE-I/ARBs (P > 0.01) at discharge and follow-up respectively. However, a statistically significant difference was found in the use of statins at follow-up, in disfavor of women (82.8% vs. 77.7%; P < 0.001). In contrast, at follow-up, women were more likely to use diuretics (31.5% vs. 39.5%; P < 0.001) and calcium channel blockers (21.2% vs. 28.8%; P < 0.001), whereas men were more likely to use anticoagulants (8.8% vs. 7.0%; P < 0.001). Overall, no gender differences were found in total daily dose intake (P > 0.01). Furthermore, women were less likely than men to have received a CABG (20.4% vs. 13.2%; P < 0.001) or PCI (82.1% vs. 74.9%; P < 0.001) at follow-up. No gender differences were observed in prescribed (P = 0.10) and attended (P = 0.63) cardiac rehabilitation programs. CONCLUSION: The EUROASPIRE V results show only limited gender differences in the medical management of CHD patients. Current findings suggest growing awareness about risk in female CHD patients.

Cardiovascular drug use among people with cognitive impairment living in nursing homes in northern Sweden.

PURPOSE: The aim of this study was to describe changes in the pattern of cardiovascular agents used in elderly people living in nursing homes between 2007 and 2013. Further, the aim was to analyse the use of cardiovascular drugs in relation to cognitive impairment and associated factors within the same population, where prescription of loop diuretics was used as a proxy for heart failure. METHODS: Two questionnaire surveys were performed including 2494 people in 2007 and 1654 people in 2013 living in nursing homes in northern Sweden. Data were collected concerning drug use, functioning in activities of daily living (ADL) and cognition, using the Multi-Dimensional Dementia Assessment Scale (MDDAS). The use of different drugs and drug classes among people at four different levels of cognitive function in 2007 and 2013 were compared. RESULTS: The proportion of people prescribed ASA and diuretics was significantly lower at all four levels of cognitive function in 2013 compared to 2007. Among people prescribed loop diuretics, the use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARBs) increased from 37.8 to 45.6%, ß-blockers from 36.0 to 41.8% and warfarin from 4.4 to 11.4%. The use of warfarin, ACEI/ARBs, ß-blockers and mineralocorticoid receptor antagonists (MRAs) were less common among individuals with more severe cognitive impairment. CONCLUSION: The results indicate that cardiovascular drug treatment has improved between 2007 and 2013, but there is room for further improvement, especially regarding adherence to guidelines for heart failure. Increasing cognitive impairment had an effect on treatment patterns for heart failure and atrial fibrillation.

Physicians' guideline adherence is associated with long-term heart failure mortality in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry.

BACKGROUND: Physicians' adherence to guideline-recommended therapy is associated with short-term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer-term outcomes is poorly documented. Here, we present results from the 18-month follow-up of the QUALIFY registry. METHODS AND RESULTS: Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF-related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF-related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87-0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94-0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all-cause, CV or HF hospitalizations were not (all-cause: SHR 0.99, 95% CI 0.9-1.02; CV: SHR 0.98, 95% CI 0.96-1.01; and HF: SHR 0.99, 95% CI 0.96-1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). CONCLUSION: These results suggest that physicians' adherence to guideline-recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians' adherence to guidelines.

Three Generations of ß-blockers: History, Class Differences and Clinical Applicability.

BACKGROUND: Beta-adrenergic receptors are expressed in cardiomyocytes and activated by either noradrenaline released from sympathetic synapses or circulating catecholamines. Their corresponding receptors have three subtypes, namely, ß1, ß2 and ß3, which are members of the G protein-coupled receptors (GPCRs) family. Activation of ß1-adrenergic receptors causes various physiological reactions including cardiac contraction and renin secretion from juxtaglomerular cells of the kidney. Antagonists of ß-adrenergic receptors, known as ß-blockers, have been used effectively for over four decades and have beneficial effects in the treatment of cardiovascular diseases. There are three generations of ß-blockers according to their pharmacological properties. Firstgeneration ß-blockers are non-selective, blocking both ß1- and ß2-receptors; second-generation ß- blockers are more cardioselective in that they are more selective for ß1-receptors; and thirdgeneration ß-blockers are highly selective drugs for ß1-receptors. The latter also display vasodilator actions by blocking α1-adrenoreceptors and activating ß3-adrenergic receptors. In addition, thirdgeneration ß-blockers exhibit angiogenic, antioxidant, anti-proliferative, anti-hypertrophic and antiapoptotic activities among other effects that are still under investigation. CONCLUSION: The objective of this review is to describe the evolution observed during the development of the three distinctive generations, thereby highlighting the advantages of third-generation ß- blockers over the other two drug classes.

Performance of current claims-based approaches to identify aortic dissection hospitalizations.

OBJECTIVE: To describe index visits for acute aortic dissection (AD) to an academic center and validate the prevailing claims-based methodology to identify and stratify them. METHODS: Inpatient hospitalizations at a single center assigned an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for AD from January 2005 to September 2015 were identified. Diagnoses were verified by review of medical records and imaging studies. All visits were secondarily stratified with the algorithm based on ICD-9 codes. Sensitivity and specificity analyses were conducted to evaluate the ability of the algorithm to correctly identify acute AD by Stanford class and treatment modality (type A open repair [TAOR], type B open repair [TBOR], thoracic endovascular repair [TEVAR], medical management [MM]). RESULTS: In the study interval, there were 1245 visits coded for AD attributed to 968 unique patients. Chart review verification demonstrated that the majority of visits were for AD (79%; n = 981), of which 32% (n = 310) were for an index acute AD event. The true distribution of acute AD visit classifications was TAOR (46.1%; n = 143), TBOR (5.2%; n = 16), TEVAR (7.7%; n = 24), and MM (39.4%; n = 122). The algorithm, which used ICD-9 codes, identified 631 acute visits and stratified them as TAOR (27.1%; n = 171), TBOR (4.1%; n = 26), TEVAR (4.9%; n = 31), and MM (63.9%; n = 403). Analyses demonstrated high specificities, but generally low sensitivities of the algorithm (TAOR: sensitivity, 58%, specificity, 92%; TBOR: sensitivity, 13%, specificity, 98%; TEVAR: sensitivity, 17%, specificity, 98%; MM: sensitivity, 73%, specificity, 72%). CONCLUSIONS: The prevalent claims-based strategy to identify hospitalizations with acute AD is specific, but lacks sensitivity. Caution should be exercised when studying AD with ICD-9 codes and improvements to existing claims-based methodologies are necessary to support future study of acute AD.

How Heart Rate Should Be Controlled in Patients with Atherosclerosis and Heart Failure.

PURPOSE OF REVIEW: Resting heart rate is an independent risk factor for all-cause and cardiovascular mortality in patients with heart failure. The main objectives are to discuss the prognosis of heart rate, its association with coronary atherosclerosis, and the modalities of control of the heart rate in sinus rhythm and in the rhythm of atrial fibrillation in patients with chronic heart failure. RECENT FINDINGS: As a therapeutic option for control heart rate, medications such as beta-blockers, digoxin, and finally ivabradine have been studied. Non-dihydropyridine calcium channel blockers are contraindicated in patients with heart failure and reduced ejection fraction. The influence of the magnitude of heart rate reduction and beta-blocker dose on morbidity and mortality will be discussed. Regarding the patients with heart failure and atrial fibrillation, there are different findings in heart rate control with the use of a beta-blocker. Patients eligible for ivabradine have clinical benefits and increased ejection fraction. Vagal nerve stimulation has low efficacy for the control of heart rate. Complementary therapies such as tai chi and yoga showed no effect on heart rate. In this review, we discuss the main therapeutic options for the control of heart rate in patients with atherosclerosis and heart failure. More research is needed to examine the effects of therapeutic options for heart rate control in different population types, as well as their effects on clinical outcomes and impact on morbidity and mortality.

[Optimizing medical treatment of abdominal aortic aneurysm: Interest of vascular centers]. / Optimiser le traitement médical de l'anévrysme de l'aorte abdominale : intérêt des centres vasculaires.

Diagnosis of abdominal aortic aneurysm (AAA) at preoperative stage is increasingly frequent. It carries both a local risk of rupture and an increased global cardiovascular risk. Patients with AAA have indeed a 20 times higher risk of dying from myocardial infarction or stroke than from a ruptured aneurysm. Cardiovascular risk factors control is therefore essential, particularly smoking cessation. Treatment in cardiovascular prevention is also warranted. Seeking for atheromatous sites is needed as they determine prognosis. Evidence of the benefit of medical treatment to slow AAA growth is still lacking. In practice, it is recommended to prescribe statins and angiotensin converting enzyme inhibitor to prevent cardiovascular events. These preventive measures are as well necessary to improve postoperative prognosis and must be continued after surgical repair. A vascular medical and surgical cooperation is primordial to enhance comprehensive management of patients with AAA.

Management, characteristics and outcomes of patients with acute coronary syndrome in Sri Lanka.

BACKGROUND: Ischaemic heart disease is the leading cause of in-hospital mortality in Sri Lanka. Acute Coronary Syndrome Sri Lanka Audit Project (ACSSLAP) is the first national clinical-audit project that evaluated patient characteristics, clinical outcomes and care provided by state-sector hospitals. METHODS: ACSSLAP prospectively evaluated acute care, in-hospital care and discharge plans provided by all state-sector hospitals managing patients with ACS. Data were collected from 30 consecutive patients from each hospital during 2-4 weeks window. Local and international recommendations were used as audit standards. RESULTS: Data from 87/98 (88.7%) hospitals recruited 2177 patients, with 2116 confirmed as having ACS. Mean age was 61.4±11.8 years (range 20-95) and 58.7% (n=1242) were males. There were 813 (38.4%) patients with unstable angina, 695 (32.8%) with non-ST-elevation myocardial infarction (NSTEMI) and 608 (28.7%) with ST-elevation myocardial infarction (STEMI). Both STEMI (69.9%) and NSTEMI (61.4%) were more in males (P<0.001). Aspirin, clopidogrel and statins were given to over 90% in acute setting and on discharge. In STEMI, 407 (66.9%) were reperfused; 384 (63.2%) were given fibrinolytics and only 23 (3.8%) underwent primary percutaneous coronary intervention (PCI). Only 42.3 % had thrombolysis in <30 min and 62.5% had PCI in <90 min. On discharge, beta-blockers and ACE inhibitors/angiotensin II receptor blockers were given to only 50.7% and 69.2%, respectively and only 17.6% had coronary interventions planned. CONCLUSIONS: In patients with ACS, aspirin, clopidogrel and statin use met audit standards in acute setting and on discharge. Vast majority of patients with STEMI underwent fibrinolyisis than PCI, due to limited resources. Primary PCI, planned coronary interventions and timely thrombolysis need improvement in Sri Lanka.

Effect of a health literacy intervention trial on knowledge about cardiovascular disease medications among Indigenous peoples in Australia, Canada and New Zealand.

OBJECTIVES: To assess the effect of a customised, structured cardiovascular disease (CVD) medication health literacy programme on medication knowledge among Indigenous people with, or at high risk of, CVD. DESIGN: Intervention trial with premeasures and postmeasures at multiple time points. SETTING: Indigenous primary care services in Australia, Canada and New Zealand. PARTICIPANTS: 171 Indigenous people aged ≥20 years of age who had at least one clinical diagnosis of a CVD event, or in Canada and Australia had a 5-year CVD risk ≥15%, and were prescribed at least two of the following CVD medication classes: statin, aspirin, ACE inhibitors and beta blockers. INTERVENTION: An education session delivered on three occasions over 1 month by registered nurses or health educators who had received training in health literacy and principles of adult education. An interactive tablet application was used during each session and an information booklet and pill card provided to participants. PRIMARY OUTCOME MEASURES: Knowledge about the CVD medications assessed before and after each session. RESULTS: Knowledge at baseline (presession 1) was low, with the mean per cent correct answers highest for statins (34.0% correct answers), 29.4% for aspirin, 26.0% for beta blockers and 22.7% for ACE inhibitors. Adjusted analyses showed highly significant (P<0.001) increases in knowledge scores between preassessments and postassessments at all three time points for all medication classes. For the four medications, the absolute increases in adjusted per cent correct items from presession 1 to postsession 3 assessments were 60.1% for statins, 76.8% for aspirin, 71.4% for ACE inhibitor and 69.5% for beta blocker. CONCLUSIONS: The intervention was highly effective in contextually diverse Indigenous primary healthcare services in Australia, Canada and New Zealand. The findings from this study have important implications for health services working with populations with low health literacy more generally. TRIAL REGISTRATION NUMBER: ACTRN12612001309875.