Health system barriers and facilitators to medication adherence for the secondary prevention of cardiovascular disease: a systematic review

Background: Secondary prevention is cost-effective for cardiovascular disease (CVD), but uptake is suboptimal. Understanding barriers and facilitators to adherence to secondary prevention for CVD at multiple health system levels may inform policy. Objectives: To conduct a systematic review of barriers and facilitators to adherence/persistence to secondary CVD prevention medications at health system level. Methods: Included studies reported effects of health system level factors on adherence/persistence to secondary prevention medications for CVD (coronary artery or cerebrovascular disease). Studies considered at least one of β blockers, statins, angiotensin–renin system blockers and aspirin. Relevant databases were searched from 1 January 1966 until 1 October 2015. Full texts were screened for inclusion by 2 independent reviewers. Results: Of 2246 screened articles, 25 studies were included (12 trials, 11 cohort studies, 1 cross-sectional study and 1 case–control study) with 132 140 individuals overall (smallest n=30, largest n=63 301). 3 studies included upper middle-income countries, 1 included a low middle-income country and 21 (84%) included high-income countries (9 in the USA). Studies concerned established CVD (n=4), cerebrovascular disease (n=7) and coronary heart disease (n=14). Three studies considered persistence and adherence. Quantity and quality of evidence was limited for adherence, persistence and across drug classes. Studies were concerned with governance and delivery (n=19, including 4 trials of fixed-dose combination therapy, FDC), intellectual resources (n=1), human resources (n=1) and health system financing (n=4). Full prescription coverage, reduced copayments, FDC and counselling were facilitators associated with higher adherence. Conclusions: High-quality evidence on health system barriers and facilitators to adherence to secondary prevention medications for CVD is lacking, especially for low-income settings. Full prescription coverage, reduced copayments, FDC and counselling may be effective in improving adherence and are priorities for further research

Tissue factor A-603G genotype associates with carotid intima-media thickness in subjects undergoing cardiovascular risk prevention

Tissue factor (TF), key initiator of coagulation, is also ascribed a non-haemostatic function in inflammation, cell migration and proliferation, suggesting a role of TF not only in thrombosis but also in atherosclerosis development. Polymorphisms in the TF gene promoter have been shown to modulate the expression of TF, and thereby potentially also its involvement in atherosclerosis and individual predisposition to atherosclerotic disease. Hence, this study was aimed at investigating associations between TF promoter polymorphisms and carotid intima-media thickness (IMT), a well-established surrogate marker of atherosclerotic disease. To this end, the TF A-603G polymorphism was analyzed in 316 subjects enrolled in a primary and secondary cardiovascular risk prevention programme, with measurements of carotid IMT by B-mode ultrasound. Also, the TF Ins-1208Del polymorphism was investigated in a limited number of subjects, which confirmed the previously reported complete concordance between the -603A and -1208Del alleles. The subjects were aged 60.2\ub18.4 years, 80% were male, and 78% were undergoing secondary prevention with a history of coronary, cerebrovascular, or peripheral atherosclerotic disease. Both mean and maximum carotid IMT (measured at the common carotid artery, carotid bifurcation, and internal carotid artery) differed significantly according to A-603G genotype, being highest in -603N A (n=93), intermediate in NG (n=161) and lowest in G/G (n=62) (mean IMT: A/A 1.31\ub10.36 mm, NG 1.27\ub10.33 mm, G/G 1.19\ub10.32 mm; max IMT: A/A 2.36\ub10.88 mm, NG 2.26\ub10.85 mm, 2.05\ub10.88 mm; both p<0.05; adjusted for age, gender, and statin treatment). In summary, a significant association between TF promoter genotype and carotid IMT was observed, perhaps mediated via alterations of TF expression levels in the circulation or within the carotid vessel wall. These findings support the hypothesis that TF plays a role in the atherosclerotic process, beyond its well-known role in haemostasis and thrombosis, thus further implicating TF not only in thrombotic complications of atherosclerotic disease, but also in plaque progression

Exploring the Barriers to and Facilitators of Using Evidence-Based Drugs in the Secondary Prevention of Cardiovascular Diseases Findings From a Multistakeholder, Qualitative Analysis

Abstract: Background Health-system barriers and facilitators associated with cardiovascular medication adherence have seldom been studied, particularly in low- and middle-income countries where uptake rates are poorest. Objectives: This study sought to explore the major obstacles and facilitators to the use of evidence-supported medications for secondary prevention of cardiovascular disease using qualitative analysis in 2 diverse countries across multiple levels of their health care systems. Methods: A qualitative descriptive study approach was implemented in Hamilton, Ontario, Canada, and Delhi, India. A purposeful sample (n = 69) of 23 patients, 10 physicians, 2 nurse practitioners, 5 Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homoeopathy physicians, 11 pharmacists, 3 nurses, 4 hospital administrators, 1 social worker, 3 nongovernmental organization workers, 2 pharmaceutical company representatives, and 5 policy makers participated in interviews in Hamilton, Ontario, Canada (n = 21), and Delhi, India (n = 48). All interviews were digitally recorded and transcribed followed by directed content analysis to summarize and categorize the interviews. Results: Themes that emerged across the stakeholder groups included: medication counseling; monitoring adherence; medication availability; medication affordability and drug coverage; time restrictions; and task shifting. The depth of verbal medication counseling provided varied substantially between countries, with prescribers in India unable to convey relevant information about drug treatments due to time constraint and high patient load. Canadian patients reported drug affordability as a common issue and very few patients were familiar with government subsidized drug programs. In India, patients purchased medications out-of-pocket from private, community pharmacies to avoid long commutes, lost wages, and unavailability of medications from hospitals formularies. Task shifting medication-refilling and titration to nonphysician health workers was accepted and supported by physicians in Canada but not in India, where many of the physicians considered a high level of clinical expertise a precondition to carry out these tasks skillfully. Conclusions: Our findings reveal context-specific, health system factors that affect the patient's choice or ability to initiate and/or continue cardiovascular medication. Strategies to optimize cardiovascular drug use should be targeted and relevant to the health care system

Atorvastatin pretreatment diminishes the levels of myocardial ischemia markers early after CABG operation: an observational study

<p>Abstract</p> <p>Background</p> <p>Statin pretreatment has been associated with a decrease in myocardial ischemia markers after various procedures and cardiovascular events. This study examined the potential beneficial effects of preoperative atorvastatin treatment among patients undergoing on-pump CABG operation.</p> <p>Methods</p> <p>Twenty patients that had received atorvastatin treatment for at least 15 days prior to the operation and 20 patients who had not received any antihyperlipidemic agent prior to surgery were included in this study. CK-MB and troponin I levels were measured at baseline and 24 hours after the operation. Perioperative variables were also recorded.</p> <p>Results</p> <p>Twenty-four hours after the operation, troponin I and CK-MB levels were significantly lower in the atorvastatin group: for CK-MB levels, 12.9 ± 4.3 versus 18.7 ± 7.4 ng/ml, p = 0.004; for troponin I levels, 1.7 ± 0.3 versus 2.7 ± 0.7 ng/ml, p < 0.001. In addition, atorvastatin use was associated with a decrease in the duration of ICU stay.</p> <p>Conclusions</p> <p>Preoperative atorvastatin treatment results in significant reductions in the levels of myocardial injury markers early after on-pump CABG operation, suggesting a reduction in perioperative ischemia in this group of patients. Further studies are needed to elucidate the mechanisms of these potential benefits of statin pretreatment.</p

Evaluation of the performance of Dutch Lipid Clinic Network score in an Italian FH population: The LIPIGEN study

Background and aims: Familial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of blood cholesterol from birth and premature coronary heart disease. Thus, the identification of FH patients is crucial to prevent or delay the onset of cardiovascular events, and the availability of a tool helping with the diagnosis in the setting of general medicine is essential to improve FH patient identification.Methods: This study evaluated the performance of the Dutch Lipid Clinic Network (DLCN) score in FH patients enrolled in the LIPIGEN study, an Italian integrated network aimed at improving the identification of patients with genetic dyslipidaemias, including FH.Results: The DLCN score was applied on a sample of 1377 adults (mean age 42.9 +/- 14.2 years) with genetic diagnosis of FH, resulting in 28.5% of the sample classified as probable FH and 37.9% as classified definite FH. Among these subjects, 43.4% had at least one missing data out of 8, and about 10.0% had 4 missing data or more. When analyzed based on the type of missing data, a higher percentage of subjects with at least 1 missing data in the clinical history or physical examination was classified as possible FH (DLCN score 3-5). We also found that using real or estimated pre-treatment LDL-C levels may significantly modify the DLCN score.Conclusions: Although the DLCN score is a useful tool for physicians in the diagnosis of FH, it may be limited by the complexity to retrieve all the essential information, suggesting a crucial role of the clinical judgement in the identification of FH subjects

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Tissue factor A-603G genotype associates with carotid intima-media thickness in subjects undergoing cardiovascular risk prevention

Tissue factor (TF), initiator of coagulation, is also ascribed a non-hemostatic function in atherosclerosis development. Polymorphisms in the TF gene promoter have been shown to modulate the expression of TF, and thus perhaps also its role in atherosclerosis. Hence, this study investigated associations between TF promoter genotype and carotid intima-media thickness (IMT), a well-established marker of atherosclerosis. The TF A-603G polymorphism and carotid IMT was analyzed in 324 patients undergoing primary and secondary cardiovascular risk prevention. Subjects were 60.5\ub18.4 years old, 80% were male, and 77% were undergoing secondary prevention with a history of atherosclerotic disease. Both mean and maximum carotid IMT (measured at the common carotid, bifurcation, and internal carotid) differed significantly according to A-603G genotype, being highest in -603A/A (n=95), intermediate in A/G (n = 164) and lowest in G/G (n = 65) (mean IMT: A/A 1.31\ub10.37 nm, A/G 1.28\ub10.33mm, G/G 1.22\ub10.35 mm; max IMT: A/A 2.35\ub10.91 mm, A/G 2.25\ub10.84mm, G/G 2.15+0.97 mm; both p<0.05; tested for tend; adjusted for age, gender, smoking habits, and anti-hypertensive treatment. In summary, a significant association between TF promoter genotype and carotid IMT was observed, maybe mediated via altered TF expression levels in the circulation or within the carotid vessel wall. These findings support a role of TF in the atherosclerotic process, beyond its role in hemostasis and thrombosis, thus implicating TF not only in thrombotic complications of atherosclerotic disease, but also in plaque progression

Correlation between plasma lipoprotein(a) levels and intimal medial thicness of common carotid arteries

Previous studies by our group have shown that in hypercholesterolemic patients mean intimal-medial complex of common carotid arteries (CC-IMT) as well as the prevalence of small plaques in the carotid arterial tree were increased with respect to normocholesterolemics. Recently, a number of clinical and epidemiological studies have suggested that the prevalence of elevated plasma Lp(a) levels may be considered an independent risk factor for vascular disease in different districts. In this study the association between elevated Lp(a) levels and changes in CC-IMT was investigated. To this end, 40 patients with diagnosis of hyperlipoproteinemia (18 type Ha, 13 type lIb and 9 type IV) were selected in our Lipid Clinic. Plasma lipid and lipoprotein values were determined by standardized techniques. B-mode ultrasound interrogation was performed with a Bio-Sound 2000 II. For each patient, average intimal-medial thickness (CC-IMT) was determined. The results indicate that CC-IMT values significantly correlate with plasma Lp(a) levels (r=0.35 , p30 mg/dl. It is concluded that, Lp(a) may be considered an additional risk factor that affects the thickness of common carotid arteries in hyperlipoproteinemic patients

Different acute phase response to a standardized stimulus in patients with history of stable or unstable coronary heart disease

The basis of the relationship between inflammation and atherosclerosis are not fully understood. We speculated that the characteristics of the innate immune response may influence the development and expression of CHD. Thus, we compared the C-reactive protein (CRP) and serum amyloid A (SAA) responses to a standardized inflammatory stimulus in patients with history of stable or unstable CHD Methods: Adjuvanted influenza subcutaneous vaccination (lnflexal v\uae) was given to 60 adult male non-diabetic and non-current smoker patients with quiescent CHD and well controlled cardiovascular (CV) risk factors who had presented at onset of CHD as silent or inducible ischemia (group 1, n=26) or as acute coronary syndromes (group 2; n=34 ). CRP and SAA were determined by ELISA on plasma samples collected at baseline and 48 hours after vaccination, according to the results of a pilot time-course study performed in 5 healthy subjects. Results: The patients were immunocompetent and free of inflammatory conditions. Both groups were similar at baseline in terms of risk factor control, use of CV drugs including aspirin (1 00%) and statins (90%), and median [25-75th perc] CRP and SAA levels. Vaccination significantly augmented CRP in both groups (group 1: 0.47 [0.21-0.86] to 0.56 [0.32-1.17] \ub5g/ml, p=0.005; group 2: 0.64 [0.21-1.09] to 0.75 [0.33-1.48] \ub5g/ml, p=0.003), without significant differences between groups in terms of absolute or percent changes. Conversely, SAA did not change after vaccination in group 1 (14.4 [8.9-19.5] to 14.8 [10.3- 18.8] \ub5g/ml , p=0.88) whereas it augmented significantly in group 2 (16.9 [1 0.0-21.5] to 19.2 [11.3-29.1] \ub5g/ml , p=0.002), with significant differences between groups in terms of absolute and percent changes (p=0.015 and 0.019, respectively). Use of statins significantly interacted with changes induced by vaccination in CRP levels (p=0.05) but not in SAA levels (p=0.47). Conclusion: CHD patients with a history of stable or unstable disease respond differently to a defined standardized inflammatory stimulus (influenza vaccination) in terms of SAA changes, suggesting that individual features of the innate immune response may influence the clinical expression of CHD, presumably by determining attributes of atherosclerotic lesions. Lack of significant differences in terms of CRP changes may be related to interference by statins