Access to Nonstatin Lipid-Lowering Therapies in Patients at High Risk of Atherosclerotic Cardiovascular Disease.

DA VINCI study: Change in approach to cholesterol management will be needed to reduce the implementation gap between guidelines and clinical practice in Europe

Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a foundation for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publication of clinical practice guidelines without commercial support, and members volunteer their time to the writing and review efforts. Clinical practice guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease (CVD). The focus is on medical practice in the United States, but these guidelines are relevant to patients throughout the world. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients’ interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment. Recommendations for guideline-directed management and therapy, which encompasses clinical evaluation, diagnostic testing, and both pharmacological and procedural treatments, are effective only when followed by both practitioners and patients. Adherence to recommendations can be enhanced by shared decision-making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated conditions and comorbidities. The ACC/AHA Task Force on Clinical Practice Guidelines strives to ensure that the guideline writing committee both contains requisite expertise and is representative of the broader medical community by selecting experts from a broad array of backgrounds, representing different geographic regions, sexes, races, ethnicities, intellectual perspectives/biases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators. The ACC and AHA have rigorous policies and methods to ensure that documents are developed without bias or improper influence. The complete policy on relationships with industry and other entities (RWI) can be found online. Beginning in 2017, numerous modifications to the guidelines have been and continue to be implemented to make guidelines shorter and enhance “user friendliness.” Guidelines are written and presented in a modular knowledge chunk format, in which each chunk includes a table of recommendations, a brief synopsis, recommendation-specific supportive text and, when appropriate, flow diagrams or additional tables. Hyperlinked references are provided for each modular knowledge chunk to facilitate quick access and review. More structured guidelines–including word limits (“targets”) and a web guideline supplement for useful but noncritical tables and figures–are 2 such changes. This Preamble is an abbreviated version, with the detailed version available online. The reader is encouraged to consult the full-text guideline(P-1) for additional guidance and details, since the executive summary contains mainly the recommendations.

Familial hypercholesterolemia (FH) is one of the most common genetic disorders characterized by a predominant elevation in plasma low-density lipoprotein (LDL) cholesterol (LDL-C) concentration and higher incidence of premature atherosclerotic cardiovascular disease (ASCVD). It has been reported that the long-term coronary artery disease (CAD) and ASCVD risk in the US adults with the FH phenotype are up to approximately five-fold higher than that in the general population.[1] It has also been estimated that there is an important long-term burden of ASCVD in phenotypic but undiagnosed FH patients in the US, with the acceleration of CAD risk by 20–30 years.[1] In recent years, the features of under-diagnosis and under-treatment of FH patients has attained an intensive attention worldwide.[2] This increased risk is age dependent, with the highest relative risk in younger index ages. Notably, several atherosclerosis-related international academic organizations or societies have issued statements or guidelines consequently, which call for the actions to improve the diagnosis and treatment of this unique, treatable disease globally.[3–6] In the Asia Pacific region, FH is estimated to affect at least 15 million people.[7] Among them, China alone may account for more than half of the FH patients as it is the world's most populous country. The general knowledge regarding FH is not very unfamiliar for medical professionals. Premature ASCVD is a great concern in FH patients due to the extremely high plasma LDL-C concentration. If homozygous FH (HoFH) is left untreated, tendon xanthomas may usually be detected.[2] Since the 1950s, FH patients have been divided into heterozygous FH (HeFH) and HoFH, and diagnosing HeFH and HoFH based on the phenotypic features of ASCVD or xanthomas has frequently been difficult without the DNA analysis of FH genes.[3] With the development of genetic testing technology, multiple studies revealed that a severe defect in the ability to bind and internalize LDL particles was caused by mutations in both alleles of the gene encoding the LDL receptor (LDLR).[8] Recent genetic insights indicate that besides LDLR (approximately 75%–95%), mutations in alleles of other genes including apolipoprotein B (ApoB), proprotein convertase subtilin/kexin9 (PCSK9), and LDLR adapter protein 1 (LDLRAP1) may also be a cause in few FH patients, which can result in impaired LDL metabolism, leading to life-long elevations in LDL-C and increased risk for premature ASCVD.[8–10] Currently, it is estimated that this unique disease of abnormal cholesterol metabolism presents in all racial and ethnic groups affecting 1 of 200–500 individuals worldwide and is now increasingly recognized as a global health issue.[5,6] From the perspectives of theory and clinical practice, FH as a major global public health challenge is even more serious in China. First, China is the largest country in the world and accounts for nearly one-fifth (18.84%) of the total 6.7 billion of the world's population. A commonly cited estimation of the frequency of HeFH is 1/500 (0.2%), which was calculated from the FH frequency in survivors of myocardial infarction (MI), of <60 years of age in a single study with some assumptive frequencies, including the prevalence of CAD in the population of the US.[4] However, contemporary data have suggested a higher frequency, highlighting that the burden of the disease is increasing including in the Chinese population.[9,10] According to the recently published 2016 Chinese guidelines for the management of dyslipidemia in adults (2016 revised version), the prevalence of dyslipidemia in Chinese adults reaches as high as 40.4% and covered approximately 160 million individuals.[11] This implies that at least seven millions of Chinese individuals may be classified as HeFH according to the commonly cited overall frequency estimation. Furthermore, a Chinese FH patients’ study with a large sample size from Beijing Fuwai hospital has recently reported that 3.5% of the patients were identified with definite/probable FH phenotype (definite, 1.0% and probable, 2.5%).[9] This study enrolled 8,050 consecutive patients undergoing coronary angiography (CAG) due to angina-like chest pain, and FH was diagnosed made using Dutch Lipid Clinic Network (DLCN) criteria and target exome sequencing in LDLR, ApoB, and PCSK9 genes. Simultaneously, another study by the same researchers showed that in 1843 consecutive patients with myocardial infraction (MI), the prevalence of definite/probable FH was 3.9% (7.1% in patients with premature MI and 0.9% in those with non-premature MI).[10] The authors concluded that the prevalence of FH among Chinese patients with MI or undergoing CAG appeared to be common, particularly among those with premature MI. These data strongly emphasize that FH is not uncommon in China. Therefore, FH should be considered as a condition of high concern, and more efforts are needed for its management. Another challenge is the change in the pattern of lipids during the past several years in China. Although the serum LDL-C concentration and the frequency of CAD may be slightly lower in the Chinese population than those before. With rapid economic growth and lifestyle changes, Chinese populations are experiencing increased cardiovascular risk and cardiovascular disease has become the leading cause of death.[11] A national prospective cohort study performed between 1991 and 2000 reported that 43.8% of deaths in Chinese adults of ≥ 40 years of age were attributable to CAD and stroke.[12] A report from the China National Diabetes and Metabolic Disorders Study (CNDMDS) comprising 46,232 Chinese adults suggests an alarm that levels of total cholesterol (TC) and LDL-C are considerably higher than those previously reported in the general Chinese population.[13] Accordingly, the increasing cholesterol levels have changed the FH phenotype in China, which may be another challenge in its diagnosis. Moreover, early diagnosis as well as effective treatment strategies in affected children with FH are challenges among experts, especially in China due to the single-child policy.[14] Single-child policy which lasted for more than half of a century, resulted in many single-child families. This phenomenon has a high impact on the family in terms of economics burden, psychological stress, healthcare issues, and domestic happiness. Hence, earlier screening of FH individuals including parent-mediated early diagnosis and intervention is important for single-child families.[15] Hence, parent-mediated early diagnosis and treatment for young children are the best strategies for prevention of premature ASCVD and improvement of survival in FH, especially in HoFH patients in the single-child society setting. Furthermore, improving public and healthcare professionals’ awareness of FH is another way for early diagnosis of FH. It is worth emphasizing that Chinese medical professionals should be obliged to actively take part in a global call for FH management.[16] In China, many people are unaware of FH, even among medical professionals who are working in well-known hospitals located in the first line cities. To improve the awareness, knowledge, and perception of FH among practitioners and hospitalized patients, a FH survey was recently performed in multiple cardiovascular centers including Beijing, Shanghai, Guangzhou, Wuhan, and Changchun (unpublished data). Surprisingly, among 345 cardiologists and 1,083 hospitalized patients with CAD, <10% of doctors recognized that an individual with plasma LDL-C >6.5 mmol/L might be considered as a diagnosis of FH (probable), and 3% of them answered that a person whose plasma LDL-C levels are > 8.5 mmol/L should be diagnosed as FH. Although as high as 82% of hospitalized patients vaguely considered that lipid disorders could be genetically inherited, only 0.7% of them learned about FH through consultation of a health website before hospitalization. More importantly, <50% of the investigated patients did not recognize that consistent elevated plasma LDL-C level was a risk factor of CAD. Therefore, a program of FH course for professionals and more propaganda for the population are urgently needed to improve the management of FH in China. Besides early diagnosis, early intervention of FH is crucial for the prevention of CAD. FH represents a major gap in preventive medicine and is clearly a public health problem. Considering the public health challenges that FH poses, gaps in care are currently being addressed by clinicians and researchers worldwide. Treatment of elevated LDL-C concentration in FH involves dietary and lifestyle management and pharmacotherapy. Statins are the mainstay pharmacotherapy and are supported by new evidence. A proportion of patients may need additional therapy with ezetimibe or bile-acid sequestrants. Furthermore, PCSK9 inhibitors are also recommended to treat FH. Without treatment, approximately 50% of men and 30% of women experience an ASCVD-related event by age 50 and 60 years, respectively. Evidence has shown that young adults with 20 years of statin therapy started in childhood had lower rates of both ASCVD-related events (1%) and death (0%) than their affected parent at a comparable age (26% and 7%, respectively), who started statin therapy later in life. According to previous studies,[17,18] 750,000 cases of CAD onset and 10,500 CAD deaths could be prevented if early intervention be employed based on the estimated seven million HeFH patients in China. Hence, early and appropriate intervention is of high importance. In addition, although China has already developed its own diagnostic criteria for FH, which is simpler and more convenient for clinically early diagnosis, more efforts are needed for its popularization and application. During the past several decades, there were scarce studies focusing on FH in China, which were mainly presented as case reports.[19] More recently, a novel modified system of simplified Chinese criteria for FH has been developed.[20] In this criteria, definite FH could be diagnosed in patients who meet any two out of the three items: LDL-C > 4.8 mmol/L, tendon xanthomas, and DNA mutation, which has similar sensitivity and specificity with the Simon Broome (SB) criteria and the Dutch Lipid Clinic Network (DLCN) criteria demonstrated by a large Chinese cohort.[20] However, these novel criteria need to be generalized in Chinese population. Studies in Chinese general population are required to test and confirm these novel FH criteria. Finally, China needs more joint efforts to respond to FH-related global call to arms due to the basic features of developing countries and imbalance in economics. As well-known, there is a great difference of health insurance system and economic growth between urban and rural areas in China, which may influence the early-diagnosis of FH in children and adolescents.[16] Early detection of FH is difficult due to lack of conventional physical examination, especially in vast rural areas of rural China. Universal lipid screening is not conventionally used in some parts of rural area. More efforts are needed for FH screening, early diagnosis, and early treatment, such as establishing a special network and foundation, performing a registry study, and strengthening the publicity.[21] The professionals, society, and even government should pay attention to this issue. Universal lipid screening FH in children between the ages of 9 and 11 years and common genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies to improve the efficacy of early identification and management of FH in China.[1,2] China may bear a heavy health burden as the most populous country in the world.[22,23] Conclusion FH is a common genetic disease characterized by premature ASCVD, which is associated with higher cardiovascular events but is preventable and treatable. With one-sixth of the world's population of individuals who are living with FH residing in China, the time has come to action for FH individuals. The phenotype of FH in China and other Chinese populations is now comparable to that in Western countries and the prevalence of FH in the general population is also similar. However, only a very small proportion of cases has been identified and treated. Although intensive statin treatment or statin plus ezetimibe or PCSK9 inhibitor is recommended for Chinese FH patients, the LDL-C target is often not achieved. Despite a high progress in FH management in China during the last decade, more efforts are needed to improve the current situation of our patients with FH, including engaging healthcare professionals, developing public awareness campaigns, and establishing national FH alliances. Universal lipid screening in children and common or expanded genetic cascade screening for FH in patients with premature CAD or LDL-C > 4.9 mg/dL may be the most effective strategies. Finally, optimization of patient care pathways is critical to improve both the rate of diagnosis and the management of FH patients. In summary, although the progress in FH management has been made in China during the past years, greater efforts are still needed in the future. Funding This work was partially supported by the Capital Health Development Fund (201614035), and CAMS Major Collaborative Innovation Project (2016-I2M-1-011) awarded to Dr Jianjun Li, MD, PhD. Conflict of interest statement The author has no conflict of interest with regard to the content of this manuscript.

SEX DISPARITIES IN TREATMENT AND CLINICAL OUTCOMES OF FAMILIAL HYPERCHOLESTEROLEMIA

In this retrospective study, we analyzed data from patients with hypercholesterolemia to describe treatment patterns, adherence, low-density lipoprotein cholesterol (LDL-C) control, cardiovascular outcomes, and healthcare resource utilization among treated patients in a real-world setting in Israel. Deidentified data from the medical records of patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalent (ASCVD-RE), and familial hypercholesterolemia (FH) treated with lipid-lowering therapy (LLT) between 2013 and 2019 were analyzed. LDL-C values were based on routine laboratory reporting in Maccabi Healthcare Services and were calculated using the Friedewald equation during the study period. Controlled LDL-C was defined as LDL-C < 70 mg/dL for ASCVD patients and <100 mg/dL for ASCVD-RE and FH patients. Adherence to LLTs was assessed using the proportion of days covered (PDC), and associations with cardiovascular outcomes and healthcare resource utilization were evaluated. A total of 15,258 patients with hypercholesterolemia (FH [7.0%], ASCVD [33.3%], and ASCVD-RE [59.7%]) were identified. Most of them (>90%) received statin monotherapy, while 2.9% received a combination of a statin and other LLTs. High adherence to LLTs (PDC ≥ 80%) was achieved by 54.1% of ASCVD patients, followed by 35.3% of ASCVD-RE patients and 17.7% of FH patients. Combination therapy with high-intensity statins (HIS) plus ezetimibe was associated with lower first postinitiation LDL-C levels in the ASCVD and ASCVD-RE groups, with 47.6% and 52.0% of patients, respectively, achieving LDL-C < 55 mg/dL; Among FH patients, 30.8% achieved LDL-C levels of 70-100 mg/dL with HIS monotherapy. A PDC ≥ 80% was significantly associated with a longer time to percutaneous coronary intervention and CABG procedures and a longer time to death in both the ASCVD and ASCVD-RE groups. During the study period, LDL-C targets were achieved by 61.1% of ASCVD patients. LDL-C < 100 mg/dL was reached by 79.9% of ASCVD-RE patients and 33.5% of FH patients. In this large, treated real-world cohort, substantial gaps in LDL-C control and treatment adherence were observed across high-risk populations. Higher adherence to lipid-lowering therapy was associated with better LDL-C control and longer time to selected clinical outcomes; however, these findings should be interpreted as associations rather than evidence of causality, given the observational study design. In this real-world cohort, higher adherence to lipid-lowering therapy (PDC ≥ 80%) was associated with better LDL-C control and more favorable cardiovascular outcome patterns. These findings highlight the potential importance of sustained treatment adherence as a key determinant of lipid control in routine clinical practice and suggest that strategies supporting long-term adherence may contribute to improved cardiovascular risk management in high-risk populations.

Secondary Prevention for Atherosclerotic Cardiovascular Disease: Comparing Recent US and European Guidelines on Dyslipidemia.

The effects of 3-year statin therapy and the achievement of LDL cholesterol target values in familial hypercholesterolemia patients: An experience from Serbia

Backgrounds Familial hypercholesterolemia (FH) patients have higher serum lipoprotein(a) (Lp(a)) levels than non-FH patients, and high Lp(a) levels raise atherosclerotic cardiovascular disease (ASCVD) risk 1). We previously reported that decreased cholesterol efflux capacity (CEC) is a risk marker for ASCVD in patients with statin-treated FH 2). Others have reported that Lp(a) interferes with the enhancement of ABCA1-mediated cholesterol efflux by plasminogen and that ABCA1-mediated CEC is lower in patients with Lp(a) &amp;gt;50 mg/dL. However, the association of CEC, not necessarily ABCA1-mediated, with Lp(a) is not clear and has not been studied in patients with FH. It is also unclear whether high Lp(a) and low CEC in patients with FH are associated with the severity of atherosclerosis. Purpose We examined whether Lp(a) levels are negatively associated with ABCA1-independent CEC in patients with FH receiving lipid-lowering therapy. We also examined the impact of the combination of high Lp(a) and low CEC on the presence of corneal arcus, Achilles tendon thickness, carotid intima-media thickness (IMT), and pre-existing ASCVD. Methods This cross-sectional study included 371 patients clinically diagnosed with FH receiving lipid-lowering therapy. CEC was measured in apolipoprotein B-depleted plasma and 3H-cholesterol-labeled J774.1 cells without cAMP-stimulated ABCA1 overexpression. Lp(a) was measured by enzymatic methods (Sekisui Medical, Tokyo, Japan) using an automated analyser. Achilles tendon thickness was measured by X-ray and carotid IMT by ultrasound. Results Mean age was 55±16 years, and 191 (51%) were women. The median serum Lp(a) level was 18.7 mg/dL, higher than the previously reported median level (13 mg/dL) in a Japanese population. One hundred nineteen patients (32%) had serum Lp(a) levels of 30 mg/dL or higher, and they had significantly lower CEC (P=0.0015). This negative association persisted after adjusting for age, sex, BMI, smoking status, serum LDL-cholesterol, serum triglycerides, and eGFR in a multiple linear regression model (beta-coefficient: -0.047, 95% CI: -0.075 - -0.019, P=0.0011). In addition, patients with both Lp(a) &amp;gt; 30 mg/dL and CEC lower than the median had a higher percentage of corneal arcus, thicker Achilles tendons, greater carotid IMT, and a higher prevalence of pre-existing ASCVD compared to patients with either or neither. Conclusions We found an inverse relationship between Lp(a) levels and CEC in FH patients receiving lipid-lowering therapy. Our results suggest that Lp(a) may also inhibit ABCA1-independent CEC, including passive cholesterol diffusion from peripheral cells. Furthermore, the combination of high Lp(a) and low CEC may be a residual risk for patients with FH receiving lipid-lowering therapy. Future studies are needed to determine whether agents that decrease Lp(a) levels will increase CEC and thereby resolve part of the residual ASCVD risk in FH.

Comparing Primary Prevention Recommendations: A Focused Look at United States and European Guidelines on Dyslipidemia.

Cardiovascular risk factor profiles in familial hypercholesterolemia patients with and without genetic mutation compared to a nationally representative sample of adults in a high-risk European country

Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction

Statin Intolerance and Noncompliance: An Empiric Approach

Equivalent Impact of Elevated Lipoprotein(a) and Familial Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease

SEX DISPARITIES IN THE TREATMENT AND OUTCOMES OF FAMILIAL HYPERCHOLESTEROLEMIA

Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics.