PCSK9 Inhibitors in Real-world Practice: Analysis of Data from 314 Patients and 2 Years of Experience in a Center of Preventive Cardiology.

PURPOSE OF REVIEW: PCSK9 inhibitors have been shown to be the most effective class of drugs modifying the levels of LDL-cholesterol as the main risk factor for atherosclerotic cardiovascular disease. The aim of this paper is to assess the effect of monoclonal antibodies on lipid and lipoprotein metabolism in real-world practice. RECENT FINDINGS: The outcome trials showed effective reduction of LDL-C by 56-62%. Landmark studies enrolling over a total of 46,000 patients with CHD in their medical history demonstrated the beneficial effect of both agents on cardiovascular morbidity and mortality. The data from real everyday clinical practice are very limited or missing. Even in real-world practice, PCSK9 inhibitors have been shown to be an effective, safe, and well-tolerated class of drugs with effects comparable with those reported from large randomized controlled trials.

Expert opinion on the cooperation of diabetologists and internists with nephrologists in the care of patients with chronic kidney diseases.

Chronic kidney disease (CKD) affects 10% of the population of developed countries and significantly affects the population health. In addition to the well-known renoprotection tools slowing down the progression of CKD, SGLT2 inhibitors have been newly introduced into clinical practice based on the results of extensive studies, both in diabetics and non-diabetics. This expert opinion discusses the classification of CKD, current renoprotection options, and the recent role of SGLT2 inhibitors in the care of patients with CKD.

Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk.

BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS: The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. CONCLUSIONS: Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

Notes on the new “Recommendations for the treatment of dyslipidemia. Influencing of lipids to reduce cardiovascular risk”.

New guidelines on dyslipidemia (DLP) related problems appear earlier than planned. Primarily in view of the results of science and large clinical studies, but also with regard to the advent of biological therapy (PCSK9-i) in many Euro-pean countries. Also, the “conventional” hypolipidemic therapy is generified and therefore cheaper, more af-fordable. The recommendations are based, as the preceding ones, on the principle of estimating the overall cardiovascular risk. The innovated SCORE tables are used for this, but more emphasis is placed on non-invasive dia-gnostics using imaging methods, be it carotid ultrasound or, in particular, non-contrast CT coronarography. Perhaps the most significant outcome is the reduction of LDL-cholesterol (LDL-C) target values to 1.4 mmol/l and a 50% reduction of baseline LDL-C in patients belonging to the highest risk groups, and in secondary prevention. Moreover, in the case of “extreme” risk the goal is to reduce LDL-C below 1 mmol/l. Essential to DLP therapy is statin treatment. Especially in patients with acute coronary syndrome and those in the highest risk categories, the maximum tolerated doses of statin should be used, if necessary in combination with ezetimibe. Where this maximum “routine” treatment is insufficient to achieve the target values, PCSK9-i therapy is indicated. However the recommendations do not by any means omit non-pharmacological therapy, quite the opposite, it is always emphasized as the first step of DLP therapy. Worthy of notice is the introduction of the term “atherosclerotic cardiovascular disease” - ASCVD, which replaces the older and less accurate CVD.

Vascular age.

Age can be evaluated according to many criteria. Of course the objective measure is the calendar age which may differ from the biological age. The biological age more or less correlates with the vascular age. The concept of vascular age is based on the statement that “An individual is as old as his blood vessels”. The process of vascular aging already starts in childhood. Arterial aging may essentially be viewed from two standpoints. First, it involves stiffening of arteries and loss of their elasticity; second, degenerative changes and formation of atherosclerotic plaques occur, being the cause of ischemia, especially in case of the development of atherothrombosis. Both these processes can be monitored: The change of elasticity (arteriosclerosis) mainly by examination of pulse wave velocity (PWV), atherosclerosis then primarily with non-invasive methods, ultrasound or CT angiography examination. From the clinical point of view it is particularly important whether we can influence vascular age in some way. Evidence is available now that atherosclerosis can be affected by hypolipidemic treatment, arteriosclerosis then in particular by ACE inhibitors. The aforementioned possibility of influencing vascular age brings us to another problem, which is compliance of patients. With regard to that it is good that in a situation where we have two drugs affecting vascular age, we can use their fixed combination. It is available as a combination of atorvastatin and perindopril.

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

The Impact of the International Cooperation On Familial Hypercholesterolemia Screening and Treatment: Results from the ScreenPro FH Project.

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH) is often perceived and described as underdiagnosed and undertreated, though effective treatment of FH is available. Owing to the mentioned facts, it is ever more imperative to screen and treat FH patients. Subsequent to the identification of patients, the project focuses on the improvement of their prognoses. The ScreenPro FH project was established as a functional international network for the diagnosis, screening, and treatment of FH. Individual countries were assigned goals, e.g., to define the actual situation and available treatment. With "central support," more centers and countries participated in the project. Subsequently, individual countries reported the results at the beginning and end of the project. Collected data were statistically evaluated. RECENT FINDINGS: The increasing number of patients in databases, from 7500 in 2014 to 25,347 in 2018, demonstrates the improvement in overall effectiveness, as well as an increase in the number of centers from 70 to 252. Before all, LDL-C decreased by 41.5% and total cholesterol by 32.3%. As data from all countries and patients were not available at the time of the analysis, only those results from 10 countries and 5585 patients at the beginning of the project and at the time of writing are included. Our data are quite positive. However, our results have only limited validity. Our patients are far from the target levels of LDL-C. The situation can be improved with the introduction of new therapy, PCSK9-i, evolocumab, and alirocumab. International cooperation improved the screening of FH and finally led to an improvement in cardiovascular risk.

Comments on the most important and recent studies involving PCSK9i.

The paper provides a brief overview of the key studies focused on PCSK9 inhibitors. It mainly examines positive results of the FOURIER studies on evolocumab, the SPIRE study on boccocizumab and the ODYSSEY Outcomes study on alirocumab. All these studies have not only shown a significant decrease in LDL-cholesterol levels, but also the reduction of cardiovascular events just correlating with these levels. The treatment leading to a dramatic drop in LDL-cholesterol levels was safe and well tolerated by patients. All the studies provided with comments demonstrate a positive impact of biological treatment of hypercholesterolemia on cardiovascular disease and confirm validity of the hypothesis saying “the lower the better”, at least for LDL-cholesterol. In conclusion, Professor Braunwalds hypothesis is mentioned saying that this treatment might eventually lead to as much as eradication of atherothrombotic cardiovascular diseases. Key words: alirocumab - bococizumab - evolocumab - FOURIER - cardiovascular disease - LDL-cholesterol - ODYSSEY Outcomes - SPIRE.

Consensus statement of professional associations on prescribing of PCSK9-inhibitors.

A new class of drugs known as PCSK9 inhibitors (PCSK9i) provide biological treatment for hypercholesterolemia. These drugs are administered using a subcutaneous injection once in two or four weeks. PCSK9i are not a replacement of the existing hypolipidemics, they just expand the therapeutic spectrum for the critically ill and those who cannot use the standard therapy and do not reach satisfactory target values. There are essentially two indications: (1) hypercholesterolemie and mixed dyslipidemia and (2) secondary prevention of cardiovascular diseases (CVD). Statin intolerance is not the only indication for treatment. However as its presence sometimes plays an essential role as to choosing the treatment, it will be also discussed in the paragraph on reimbursement conditions. Reimbursement conditions (very simplified): the treatment will be provided at selected centres. A list of the centres is included in an annexe to this article. You will find it also on www.interna-cz.eu, on www.kardio-cz.cz and www.athero.cz. The indicative concentration of LDL-cholesterol (LDL-C) from which on PCSK9i can be prescribed as covered from the public health insurance, is the following: (1) familial hypercholesterolemia 4.0 mmol/l, (2) for secondary prevention CVD 3.0 mmol/l - Please note: the presented LDL-C level is one reached under maximum (tolerated) high intensity hypo-lipidemic therapy. High intensity hypolipidemic therapy is defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg + ezetimibe. In the case of demonstrated intolerance of both the mentioned statins the patient has to be treated with a maximum tolerated dose of statins, in combination with another hypolipidemic drug (ezetimibe). Statin intolerance is defined as intolerance of at least two successive statins, which results in their discontinuation. Statin intolerance alone is not the indication for PCSK9i treatment! The payment criteria must always be complied with. A medical officer can of course be asked to approve such treatment in exceptional cases. Key words: alirocumab - PCSK9 inhibitors centers - center therapy - evolocumab - familial hypercholesterolemia - proprotein konvertase subtilisin kexin 9 inhibitors (PCSK9i) - secondary prevention - statins intolerance.

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.

BACKGROUND: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). METHODS: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. FINDINGS: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. INTERPRETATION: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. FUNDING: Amgen.

Body Adiposity Changes After Lifestyle Interventions in Children/Adolescents and the NYD-SP18 and TMEM18 Variants.

BACKGROUND This study was carried out to determine the relationship between the common TMEM-18 (rs4854344, G>T) and NYD-SP18 (rs6971091, G>A) gene variants and weight loss after lifestyle interventions (increased physical activity in conjunction with optimal dietary intake) in overweight/obese children/adolescents. MATERIAL AND METHODS We genotyped 684 unrelated, white, non-diabetic children (age 12.7±2.1 years, average BMI at baseline 30.66±4.80 kg/m²). Anthropometric and biochemical examinations were performed before and after 4 weeks of an intensive lifestyle intervention. RESULTS The mean weight loss achieved was 5.20±2.02 kg (P<0.001). NYDSP-18 AA homozygotes had significantly higher abdominal skinfold value before and after the intervention (both, P=0.001). No significant associations between BMI decrease and the NYD-SP18 and TMEM18 variants were found. Associations between all anthropometrical and biochemical changes and genes remained non-significant after data were adjusted for sex, age, and baseline values. CONCLUSIONS Decreased body weight in overweight/obese children is not significantly influenced by the NYD-SP18 rs6971091 or TMEM18 rs4854344 polymorphisms.

[MedPed - the reality of familial hypercholesterolemia care at the biggest center]. / MedPed - realita péce o familiární hypercholesterolemie v nejvetsím centru.

The MedPed project (Make Early Diagnosis to Prevent Early Deaths) aiming at screening, diagnosis and treatment of patients with familial hypercholesterolemia (FH) was initiated more than 19 years ago. More than 60 cooperating centers and a large number of health care professionals have been involved. Till November 15, 2017 the nationwide database has comprised 7 567 entries of individual FH patients, 439 of these being children up to 19 years of age. Given the recently corrected estimated population frequency of FH of 1 to 250 this number represents 18.9 % of the predicted number of 40 000 FH individuals in the Czech Republic. Although the number of patients captured by the database seems to be relatively low, it is the third highest number in the world. This review describes working procedures of one of the national leading centers for FH in the Czech Republic. Additionally, a comparison of the up-to-date data set of 558 FH individuals being actively followed in the center to the original FH cohort (n = 190) as described by prof. Sobra in the late 1960 s. is being discussed.Key words: familial hypercholesterolemia - heterozygous - homozygous - project Medped.

A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.

BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. METHODS: We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. RESULTS: Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. CONCLUSIONS: At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).

[Hyperlipoprotienemias and (not only) atherosclerosis: fragments from history and present]. / Hyperlipoproteinemie a (nejen) ateroskleróza: strípky z historie i soucasnosti.

The examples from the history, as well as the recent view, clearly demonstrate a great change in the perception of hyperlipoprotienemias and dyslipidemias (HLP and DLP) at the end of 20th and at the beginning of 21st century. Our aim is not a complex overview about HLP and DLP. We just want to describe the changing position and importance of these diseases in clinical medicine. We will touch cardiology, angiology, but also diabetology, hepatology and gastroenterology (pancreas). HLP and DLP, which started as a research topic in laboratory became clinically interesting as risk factors of atherosclerosis. They are understood as epidemic occurrence diseases, also in connection with metabolic syndrome. However, some of them, e.g. familial chylomicronemia or homozygous familial hypercholesterolemia fulfill criteria of rare diseases.

ScreenPro FH - Screening Project for Familial Hypercholesterolemia in Central, Southern and Eastern Europe: Rationale and Design.

Familial hypercholesterolemia (FH) is a genetic disorder with well-known genetic transmission and clinical course. Despite great recent progress, FH is still underestimated, under-diagnosed and thus undertreated. Furthermore it represents a significant healthcare challenge as a common risk factor for the premature development of coronary heart disease. The ScreenPro FH Project is an international network project aiming at improving complex care - from timely screening, through diagnosis to up-to-date treatment of familial hypercholesterolemia in Central, Eastern and Southern Europe. An important task for the project is to harmonise and unify diagnostic and therapeutic approaches in participating countries, where the situation differs from country to country. Countries with more experience should serve as a model for countries developing the FH network.Key words: diagnosis - familial hypercholesterolemia - screening - treatment optimization.

ScreenPro FH - Screening Project for Familial Hypercholesterolemia in Central, Southern and Eastern Europe: Basic Epidemiology.

INTRODUCTION: Despite great recent progress, familial hypercholesterolemia (FH) is still underestimated, under-diagnosed and thus undertreated worldwide. We have very little information on exact prevalence of patients with FH in the Central, Eastern and Southern Europe (CESE) region. The aim of the study was to describe the epidemiological situation in the CESE region from data available. METHODS: All local leaders of the ScreenPro FH project were asked to provide local data on (a) expert guess of FH prevalence (b) the medical facilities focused on FH already in place (c) the diagnostic criteria used (d) the number of patients already evidenced in local database and (e) the availability of therapeutic options (especially plasma apheresis). RESULTS: With the guess prevalence of FH around 1 : 500, we estimate the overall population of 588 363 FH heterozygotes in the CESE region. Only 14 108 persons (2.4 %) were depicted in local databases; but the depiction rate varied between 0.1 % and 31.6 %. Only four out of 17 participating countries reported the the LDL apheresis availability. CONCLUSION: Our data point to the large population of heterozygous FH patients in the CESE region but low diagnostic rate. However structures through the ScreenPro FH project are being created and we can hope that the results will appear soon.Key words: diagnosis - epidemiology - familial hypercholesterolemia - screening.

ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.

AIMS: To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT). METHODS AND RESULTS: In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2 : 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L (70 mg/dL). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; -57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; -51.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78. LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo). CONCLUSION: In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin ± other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated. CLINICAL TRIAL REGISTRATION: Cinicaltrials.gov (identifiers: NCT01623115; NCT01709500).

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.

IMPORTANCE: Muscle-related statin intolerance is reported by 5% to 20% of patients. OBJECTIVE: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. DESIGN, SETTING, AND PARTICIPANTS: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. INTERVENTIONS: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. RESULTS: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). CONCLUSIONS AND RELEVANCE: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01984424.

[Estimating the prevalence of potential drug interactions in patients treated with 5 and more drugs in the Czech Republic and Slovac Repuplic]. / Urcení prevalence potenciálních lékových interakcí u pacientu lécených 5 a více lécivými prípravky v Ceské a Slovenské republice.

UNLABELLED: Polypragmasy is currently a growing phenomenon, leading to an increased risk of drug interactions. Empirical data to document this trend can only be obtained through a field survey, which, however, is missing in both Czechia and Slovakia. Therefore an international, multicentre, observational, non-interventional study "Estimating the prevalence of potential drug interactions in patients treated with 5 and more drugs in the Czech Republic and Slovakia" was conducted, with the primary aim to identify the prevalence of potential drug-drug interactions in the conditions of routine clinical practice. The patients aged 18 years or more and treated with 5 and more drugs simultaneously were recruited from 21 September 2013 onward in 4 consecutive quarters, each patient maximally once in a single quarter. The participating sites consisted of general practitioners and outpatient specialist clinics (1 040 physicians altogether), chosen to match the structure of medical specialties as well as to cover the entire territory of the respective country. The data was evaluated with descriptive statistical methods. The level of health risk associated with drug-drug interactions has been expressed by an Interaction Index, a measure developed to estimate the probability of critical risk of drug-drug interaction The prevalence of prescriptions with Interaction index 12, i.e. exposing patients to adverse effects, was significantly influenced mainly by the amount of drugs prescribed and their profile in relation to the risk of interactions; on the other hand, age or gender did not play an important role. The identified seasonal variations in the prevalence of interactions can be explained by additional medication associated with seasonal illnesses. KEY WORDS: drug interactions - interaction index - polypharmacy.

[Severe familial hypercholesterolemia treatment]. / Lécba tezké familiární hypercholesterolemie.

Familial hypercholesterolemia (FH) represents the most frequent of inborn errors of metabolism. It is a group of disorders with a codominant mode of inheritance characterized by marked elevations of LDL-cholesterol as well as atherosclerotic cardiovascular disease risk. Clinical (phenotypic) picture of FH varies widely depending on genotype and concomitant risk factors. Identification of most seriously affected FH individuals is necessary for proper clinical management. The therapeutic approach must be complex and comprehensive. The corner stone of pharmacotherapy is high-intensity statin therapy usually combined with ezetimibe (possibly complemented with bile acid sequestrant). Even this multi-drug combination do not lead majority of patients to their treatment goals. Thus, combinations with other pharmacological (PCSK9 inhibitors, apoB-100 anti-sense therapy, MTP inhibition) and non-pharmacological (LDL-apheresis, liver transplantation) approaches is being used.Key words: ezetimibe - LDL-apheresis - lomitapide - mipomersen - PCSK9 inhibitors - severe familial hypercholesterolemia - statins.