UvA-DARE (Digital Academic Repository) Familial hypercholesterolemia: the Dutch approach Huijgen, R. Link to publication

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1 UvA-DARE (Digital Academic Repository) Familial hypercholesterolemia: the Dutch approach Huijgen, R. Link to publication Citation for published version (APA): Huijgen, R. (2012). Familial hypercholesterolemia: the Dutch approach General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 17 Aug 2018

2 Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: A large crosssectional study in the Netherlands Annemarie H. Pijlman, Roeland Huijgen, Sandra Verhagen, Anton F.H. Stalenhoef, Ben P.M. Imholz, An Ho Liem, John J.P. Kastelein, Frank L.J. Visseren Atherosclerosis 2010;209(1):

3 Abstract Background: Heterozygous Familial Hypercholesterolemia (hefh) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated Low Density Lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-C is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-C to plasma levels <2.5 mmol/l. In the present study we evaluated the treatment of hefh-patients in the Netherlands. Methods: A cross-sectional study was conducted in outpatient lipid clinics of three Academic Centers and two regional hospitals. Patient records of known hefh patients were retrieved and data were reviewed on use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results and reasons for not achieving treatment goals. Results: The data of 1249 patients with hefh were available. Nearly all patients (96%) were on statin treatment. The treatment goal for LDL-C <2.5 mmol/l was achieved in 261 (21%) patients. Among those who did not reach LDL-C goals, 261 (27%) were on combination therapy of maximum statin dose and ezetimibe. Main reasons (32%) why patients did not use maximum therapy despite an LDL-C 2.5 mmol/l was acceptance of a higher target LDL-C level by the treating physician. An alternative treatment goal of >50% LDL-C reduction, as recommended by the NICE guidelines, was achieved in 47% of patients with an LDL-C 2.5 mmol/l and not using maximum therapy. Conclusion: Only a small proportion of patients with hefh reaches the LDL-C treatment target of <2.5 mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options in hefh to further decrease LDL-C levels. 306

4 Achievement of LDLc target levels in outpatient clinics Introduction Familial hypercholesterolemia (FH) is an autosomal dominant hereditary disorder caused by mutations in the LDL-receptor or Apolipoprotein B genes leading to elevated low-density lipoprotein -cholesterol (LDL-c). The prevalence of heterozygous FH (hefh) in the general population is estimated to be 1: Patients with hefh express high levels of plasma LDL-C already at young age. This results in premature atherosclerosis and an increased risk of cardiovascular disease. 2-4 In a 15-year followup study, the cumulative risk of a coronary event without effective treatment was at least 50% in men and 30% in women. 5 Therefore, diagnosis and treatment in early life of patients with hefh is important for cardiovascular risk reduction. 6 International guidelines on treatment of FH consider a treatment target for LDL-C of <100 mg/dl as the optimal level. 7-9 This goal is based on large clinical trials with 10, 11 lipid lowering drugs in patients with clinical cardiovascular disease or diabetes. Although there are no intervention trials in hefh-patients with cardiovascular disease as hard endpoints, there are studies in which surrogate endpoints (coronary lesions, myocardial ischemia, carotid intima-media thickness (cimt), endothelial (dys)function) showed beneficial effect of aggressive LDL-C reduction The Simon Broome registry reported a reduction in relative risk in coronary mortality of 8.0 (95% CI ) to 3.7 (95% CI ) after 1992 which correspondents with the introduction of HMGCoA reductase inhibitors. 5 An alternative treatment goal in hefh is achievement of >50% reduction in LDL-C levels as advocated by NICE. 16 In February 2006, the National Guideline Diagnosis and treatment of familial hypercholesterolemia was published in the Netherlands. 17 In this guideline internists, cardiologists and general practitioners are recommended to start medical treatment in patients with hefh when LDL-C levels are >2.5 mmol/l, in line with the European Guidelines with treatment targets for (other) patients at high cardiovascular risk. 9 In the present study we investigated the adherence to this guideline for treatment of hefh patients treated in three academic and two non-academic lipid clinics in the Netherlands. Methods Patients Participants were patients diagnosed with hefh and 18 years of age. Diagnosis of hefh was defined as a known mutation in the LDL-receptor gene or APOB gene. In the absence of a genetic diagnosis, a patient had to have a clinical diagnosis of hefh

5 based on: a documented untreated total cholesterol (TC) >9.1 mmol/l or untreated LDL-C >5.2 mmol/l in combination with at least one of the following: - a history or presence in the patient or a first degree relative, of tendinous or cutaneous xanthomas, - a history or presence, in an adult first degree relative of a documented mutation in the LDL-receptor gene or APOB gene, - the presence of a first degree adult relative with documentation of untreated TC >9.1 mmol/l or untreated LDL-C >4.9 mmol/l, - a documented history, in a first degree relative, of premature coronary artery disease or sudden death from natural causes prior to age of 55 years in males, or prior to age 60 years of age in females. 18 There had to be at least one outpatient visit in one of the participating outpatient Lipid Clinics after February 2006, which was the date of publication of the FH Guideline in the Netherlands. Patients who were pregnant, had a pregnancy wish or gave breastfeeding were excluded from participation. Study design A cross-sectional study was conducted in the outpatient lipid clinics of three Academic Centers (University Medical Centre Utrecht (UMCU), Academical Medical Centre Amsterdam (AMC) and Radboud University Nijmegen Medical Centre (UMCN)) and two Regional Centers (TweeStedenziekenhuis Tilburg and Oosterscheldeziekenhuis Goes). The analyses of the collected data were performed at the UMCU. Patients were identified by using the diagnosis registries of the participating hospitals. Patient records were retrieved and reviewed. Data were collected on age, gender, diagnosis (hefh / FDB), genetic evidence of hefh/fdb, history of cardiovascular disease, smoking, diabetes mellitus, family history of cardiovascular disease (first degree relative with cardiovascular disease prior to age of 55 years in male, or prior to age 60 years of age in female), Body Mass Index (BMI), hypertension (systolic blood pressure >140mmHg or use of anti-hypertensive medication) and use of lipid lowering medication. Laboratory results were retrieved including most recent total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), LDL-C as calculated with the Friedewald formula, 19 apolipoprotein B (APOB), alanine aminotransferase (ALT), creatine kinase (CK), baseline TC and baseline LDL-C. TC, TG, ALT and CK were measured by enzymatic assays and HDL-C by colorimetry. APOB was determined by nepholometry. The upper limit of normal for ALT was 35 U/l and for CK this was 170 U/l. Maximum statin dose was defined as: simvastatin 80 mg/day, pravastatin 40 mg/day, fluvastatin 80 mg/day, atorvastatin 80 mg/day or rosuvastatin 20 or 40 mg/day, Maximum therapy was considered maximum statin dose combined with ezetimibe 10 mg/day. The following treatment was considered 308

6 Achievement of LDLc target levels in outpatient clinics giving at least a 50% reduction in LDL-C baseline-levels: simvastatin 20 or 40 or 80 mg/day in combination with ezetimibe 10 mg/day, pravastatine 40 mg/day in combination with ezetimibe 10 mg/day, fluvastatin 80 mg/day in combination with ezetimibe 10 mg/day, atorvastatin 40 or 80 mg/day, atorvastatin 10 or 20 mg/ day in combination with ezetimibe 10 mg/day, rosuvastatin 20 or 40 mg/day and rosuvastatin 10 mg/day in combination with ezetimibe 10 mg/day. Data analysis All descriptive and statistical analyses were carried out using SPSS (version 15.0). Characteristics are outlined for the whole sample and subgroups. To create subgroups the study cohort was stratified by attainment of LDL-C target (yes/no) and maximum therapy (yes/no). Categorical variable values are given as number of patients and percentages. Continuous variables with equal distribution are reported as mean with standard deviation. Continuous variables with no equal distribution are given as median with interquartile range. Multivariable logistic regression analyses were performed using attainment of LDL-C target as binary dependent variable (LDL-C < 2.5 mmol/l or LDL-C 2.5 mmol/l). P < <0.05 was considered to be statistically significant. Results A total of 1249 patients met the inclusion criteria: 184 patients (15%) in UMCU, 317 patients (25%) in AMC, 261 patients (21%) in UMCN, 337patients (27%) in Waalwijk and 150 patients (12%) in Goes. At baseline mean age of patients was 49 years of whom 47% were male. Of these patients 54% had a genetic diagnosis; 88% with hefh and 12% with FDB, respectively. A history of cardiovascular disease was found in 17% of our study population. More than half of the patients (56%) had a positive family history of early-onset cardiovascular disease. Hypertension was present in 20% of the patients. Only 2% were known to have diabetes mellitus. Baseline TC was 8.9 ± 2.3 mmol/l and baseline LDL-C was 6.5 ± 2.0 mmol/l. Nearly all patients (96%) were on statin treatment. The most widely prescribed statin was atorvastatin (56%). Ezetimibe was used in 676 patients (54%) of whom 12 (2%) as monotherapy. Fibrates, nicotinic acid and bile sequestrating agents were only prescribed to a few patients. Maximum statin dose was applied in 424 (34%) of patients using statins. Maximum therapy (maximum statin dose in combination with ezetimibe) was used in 310 patients (25%). The mean LDL-C for all patients was 3.2 ± 1.1 mmol/l

7 Characteristics of subgroups stratified according to attainment of treatment goal and maximum therapy are outlined in Table 1. The treatment goal for LDL-C <2.5 mmol/l was only achieved in 261 (21%) patients. Of those patients not on target (n=956), 261 (27%) used maximum lipid-lowering therapy (Table 2). The proportion of patients achieving LDL-C treatment targets in the different participating clinics ranged from 10% to 32%. There was no difference between the three Academic Centers and the two regional hospitals (21% vs. 22%). In the presence of a medical history of cardiovascular disease (OR 1.54 (95% CI )) and hypertension (OR 1.49 (95% CI )) it was more likely to achieve the LDL-C target of <2.5 mmol/l (Table 3). Table 1: Characteristics of patients stratified according to attainment of LDL-c treatment goal and use of maximum lipid-lowering therapy LDL <2.5 mmol/l LDL 2.5 mmol/l 261 (21) a 957 (79) a Maximum No Maximum Maximum No Maximum 43 (16) a 218 (84) a 261 (27) a 696 (73) a Age (years) 55 ± ± ± ± 16 Male gender (%) Diagnosis (%) LDL-receptor mutation FDB Clinical profile History of CVD (%) Smoking (%) Diabetes Mellitus (%) Family history of CVD (%) Body mass index (kg/m 2 ) 26 ± 5 25 ± 4 26 ± 4 25 ± 4 Hypertension (%) Lipids (mmol/l) Total cholesterol 4.0 ± ± ± ± 1.2 Triglycerides 1.2 ± ± ± ± 0.6 HDL-cholesterol 1.3 ± ± ± ± 0.4 LDL-cholesterol 2.2 ± ± ± ± 1.1 Baseline total cholesterol 9.0 ± ± ± ± 2.0 Baseline LDL-cholesterol 6.5 ± ± ± ± 1.7 LDL-cholesterol difference 4.4 ± ± ± ± 0.3 > 50% LDL-c reduction (%) ApoB mean (g/l) 0.9 ± ± ± ± 0.3 ALAT (U/l) 34 ± ± ± ± 17 CK (U/l) 132 ± ± ± ± 105 ALAT >35 U/l (%) ALAT >70 U/l (%) CK >170 U/l (%) CK >240 U/l (%) a n(%) Maximum lipid-lowering therapy is defined as maximum statin dose in combination with ezetimibe. 310

8 Achievement of LDLc target levels in outpatient clinics Table 2: Use of lipid-lowering therapy stratified according to attainment if LDL-c goal and use of maximum lipid-lowering therapy LDL <2.5 mmol/l LDL 2.5 mmol/l 261 (21) a 957 (79) a Maximum No Maximum Maximum No Maximum 43 (16) a 218 (84) a 261 (27) a 696 (73) a Statin (%) Rosuvastatin Atorvastatin Simvastatin Pravastatin Fluvastatin No statin (%) Ezetimibe (%) Fibrate (%) Nicotinic acid (%) Bile acid sequestrant (%) Combination statin and (%) Ezeteimibe Fibrate Nicotinic acid Bile acid sequestrant Maximum statin dosage (%) a n(%) Maximum lipid-lowering therapy is defined as maximum statin dose in combination with ezetimibe. Table 3: Association between clinical variables and attainment of LDL-c target (<2.5 mmol/l) Odds ratio (95% CI) unadjusted Odds ratio (95% CI) adjusted for age and gender Age (per 10 years) 1.01 ( ) 1.00 ( ) a Gender (male) 0.97 ( ) 0.97 ( ) b Genetic confirmed diagnosis (yes) 0.93 ( ) 0.93 ( ) History of CVD (yes) 1.47 ( ) 1.54 ( ) Diabetes mellitus (yes) 2.09 ( ) 2.00 ( ) Smoking (yes) 0.82 ( ) 0.82 ( ) Hypertension (yes) 1.47 ( ) 1.49 ( ) Family history of CVD (yes) 0.80 ( ) 0.80 ( ) BMI (per kg/m 2 ) 1.03 ( ) 1.02 ( ) Baseline total cholesterol (per mmol/l) 0.72 ( ) 0.70 ( ) Baseline LDL-cholesterol (per mmol/l) 0.67 ( ) 0.66 ( ) CK >170 U/L (yes) 1.18 ( ) 1.19 ( ) CK >240 U/L (yes) 0.83 ( ) 0.82 ( ) ALT >35 U/L (yes) 0.70 ( ) 0.71 ( ) ALT >70 U/L (yes) 1.40 ( ) 1.43 ( ) 19 a Adjusted for gender b Adjusted for age. 311

9 In patients not at LDL-C goal, it appeared that males more often used maximum lipid-lowering therapy (OR 1.65 (95% CI )) as well as patients with a history of cardiovascular disease (OR 2.88 (95% CI )) and patients with a genetic confirmed diagnosis (OR 1.35 (95% CI )) (Table 4). Table 4: Determinants of using maximum lipid-lowering therapy in patients not on LDL-C target ( 2.5 mmol/l) Odds ratio (95% CI) unadjusted Odds ratio (95% CI) adjusted for age and gender Age (per 10 years) 1.25 ( ) 1.30 ( ) a Gender (male) 1.56 ( ) 1.65 ( ) b Genetic confirmed diagnosis (yes) 1.19 ( ) 1.35 ( ) History of CVD (yes) 3.37 ( ) 2.88 ( ) Diabetes mellitus (yes) 2.87 ( ) 2.74 ( ) Smoking (yes) 1.07 ( ) 1.12 ( ) Hypertension (yes) 1.58 ( ) 1.32 ( ) Family history of CVD (yes) 1.38 ( ) 1.35 ( ) BMI (per kg/m 2 ) 1.04 ( ) 1.02 ( ) Baseline total cholesterol (per mmol/l) 1.47 ( ) 1.44 ( ) Baseline LDL-cholesterol (per mmol/l) 1.59 ( ) 1.57 ( ) CK >170 U/L (yes) 1.00 ( ) 0.79 ( ) CK >240 U/L (yes) 1.28 ( ) 1.03 ( ) ALT >35 U/L (yes) 1.55 ( ) 1.23 ( ) ALT >70 U/L (yes) 1.45 ( ) 1.35 ( ) LDL-cholesterol (per mmol/l) 1.01 ( ) 1.05 ( ) a Adjusted for gender b Adjusted for age. In the 330 patients with an LDL-C 2.5 mmol/l and not using maximum statin dose and/or no ezetimibe the reasons for not using higher doses or combination therapy were most often acceptance by the treating physician (32%) of not just reaching the treatment goal (Figure 1). In the majority of these cases (68%), LDL-C was below 3.0 mmol/l. Also, a sizeable part of patients were in the up-titration phase of lipidlowering therapy (30%). Of the study population 904 patients (71%) used lipidlowering medication that is expected to reduce LDL-C levels by at least 50%. Within patients not on maximum therapy despite an LDL-C 2.5 mmol/l, 440 patients (61%) used lipid-lowering therapy that is expected to reduce LDL-C levels by at least 50%. In 472 patients baseline values of LDL-C were available. In these patients 222 (47%) achieved an LDL-C reduction of 50%. 312

10 Achievement of LDLc target levels in outpatient clinics Figure 1: Proportion of patients on LDL-C target for different treatment goals Most common side effects reported were myalgia and elevation of ALT or CK levels. To evaluate the practical feasibility of LDL-C treatment goals, the proportion of patients at goal was calculated for different cut off values of LDL-C, ranging from <1.0 to <10.0 mmol/l (Fig. 2). An alternative treatment target of LDL-C <3.0 mmol/l was achieved in 49% of the patients. Figure 2: Reasons for not using maximum lipid-lowering therapy in patients not on LDL-C target ( 2.5 mmol/l) (n=292)

11 Discussion In this study it is shown that only 21% of hefh patients meets the LDL-C treatment goal of <2.5 mmol/l, as published in the Dutch FH treatment guidelines. 17 Of the patients not at target, 73% did not use maximum statin treatment or combination therapy with ezetimibe. Several large studies in patients with a high cardiovascular risk and/or established cardiovascular disease have proven the benefit of reducing LDL-C below <2.5 mmol/l or even lower Although there are no randomized intervention trials with clinical endpoints in patients with FH, these subjects are known to have high plasma LDL-C concentrations and are at high cardiovascular risk. 2-4 There are several studies in hefh patients that used surrogate endpoints of cardiovascular disease showing the effect of lipid-lowering therapy The Simon Broome registry group compared coronary mortality in FH patients before and after the introduction of statins and suggested that coronary mortality may be a 30%% higher when patients are untreated. 2, 5 Therefore it seems reasonable to use the same LDL-C goal for FH patients as is used for other high-risk patients. Compared to other high-risk patients, such as those with clinical manifest vascular diseases or patients with diabetes, the proportion FH patients at LDL-C treatment target is in the similar range. In a survey in patients with coronary heart disease (CHD) 56% reached the target TC <5.5 mmol/l. 24 In the second EUROASPIRE survey 41% of the patients showed an LDL-C <3.0 mmol/l. 25 In a 2003 Survey, performed in the UK, it was revealed that one third of the FH patients achieved an LDL-C target of 3 mmol/l. 26 The authors argued that the advent of ezetimibe may have improved the LDL-C reductions achieved since Compared to these figures the proportion of FH patients in our survey that are at a more stringent LDL-C treatment target is still disappointingly low. Although a lower mean LDL-C level was achieved than reported in the UK audit, the more stringent target levels and possibility to add of ezetimibe did not lead to a larger proportion of FH patients that were optimally treated. In the present study it became apparent that 73% of the patients did not use maximum lipid-lowering therapy, despite LDL-C levels above target. Out of patients not using maximum statin dose and no ezetimibe despite an LDL-C 2.5 mmol/l, 30% were still in the uptitrating phase. Of particular interest are those patients that were not below the LDL-C treatment goal and the treating physician was satisfied with the achieved LDL-C concentration. Reported reasons for accepting LDL-C concentrations 2.5 mmol/l by physicians may include that LDL-C fluctuates around 2.5 mmol/l and is sometimes just above this level. In the present study we analyzed 314

12 Achievement of LDLc target levels in outpatient clinics what the proportion of patients on target would be when the treatment target was set at a higher level. For example, when the treatment target would be 3.0 mmol/l than 49% of patients would meet the treatment goal. Nevertheless, this is not in line with the adagium the lower the better in the treatment of LDL-C, which is likely to be also applicable to FH patients. Another reported reason was that the physician was satisfied because LDL-C was already reduced by more than 50%. This argument is in line with the recently published NICE guidelines for the treatment of FH patients in the UK. 16 Data from a recently published cohort-study showed that patients with FH achieving an LDL-C reduction between 44% and 49% were at a similar CVD risk as subjects above the age of 55 years without FH. 16 This raises the question whether the current treatment target of LDL-C <2.5 mmol/l, advocated in guidelines, is reasonable. Guidelines with unrealistic treatment targets run the risk of discouragement and are often not adopted by physicians in clinical practice. Another reason for not achieving LDL-C treatment goals may also be found in the available pharmacologic interventions. In the present study it is shown that 261 (27%) patients used maximum lipid-lowering therapy but nonetheless had an LDL-C 2.5 mmol/l. Statins are effective and safe but lower LDL-C by a maximum of around 50%. 27 By adding a cholesterol absorption inhibitor, ezetimibe, an additional 14-20% LDL-C reduction can be achieved. 28, 29 In our study only 54% of the patients not reaching the LDL-C goal used ezetimibe. Acceptance among physicians of non-statin add-on therapies may be low. Adding ezetimibe to a high statin dose in FH patients did not affect progression of cimt, 29 although this is in contradiction with results of the earlier ASAP study. 15 Furthermore, the older generation bile acid sequestrants were not well tolerated, which might withhold physicians to even prescribe the new generation bile acid sequestrants. 30 Therefore, it can be concluded that there is room for improvement by better use of currently available lipid-lowering medication. But even among patients using maximal dose of statin in combination with ezetimibe there was a large proportion (86%) not at LDL-C target. Switching to a more potent statin could be a first step. Furthermore, one should consider additional therapy, yet available or to be developed. The addition of new bile acid sequestrants such as colesevalam to statin/ezetimibe combination therapy may lead to an additional LDL-C lowering of around 12%. 31 We acknowledge some strengths and weaknesses of our study. To our knowledge this study is the largest study of its kind in hefh patients. Moreover, a good reflection of daily clinical practice in hefh patients was secured by the participation of both academic and non-academic clinics. However, these clinics are specialized centers for

13 FH and therefore it can be questioned whether these results can be generalized to non-specialized clinics usually treating a smaller number of hefh patients which may be more easy to treat and do not have to be referred to larger centers. We could only retrieve baseline values of LDL-C in 472 patients, which may have induced bias. In conclusion, 79% of hefh patients did not reach the LDL-C treatment target of <2.5 mmol/l as advocated in (inter)national guidelines and 53% of patients not on maximum therapy despite an LDL-C 2.5 mmol/l did not receive lipid-lowering therapy reducing LDL-C by at least 50%. This result emphasizes the need for more robust lipid lowering in hefh patients. There is a medical need for new treatment options, in combination with current therapy, to further lower LDL-C in hefh patients. 316

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