Aggressive lipid lowering in patients with familial hypercholesterolaemia van Wissen, S.

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1 UvA-DARE (Digital Academic Repository) Aggressive lipid lowering in patients with familial hypercholesterolaemia van Wissen, S. Link to publication Citation for published version (APA): van Wissen, S. (2003). Aggressive lipid lowering in patients with familial hypercholesterolaemia 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: 07 Jun 2018

2 Thee significance of femoral intima-media thicknesss and plaque scoring in the Atorvastatinn versus Simvastatin Atherosclerosiss Progression (ASAP) study Sannee van Wissen 1, Tineke Smilde 3, Eric de Groot 1, Barbaraa Hutten 2, John Kastelein 1 and Anton Stalenhoef 'Departmentt of Vascular Medicine and department of Clinical Epidemiology and Biostatistics, Academicc Medical Center, University of Amsterdam, Amsterdam and 'Departmentt of Medicine, Division of General Internal Medicine, University Medical Center Nijmegen,, Nijmegen, The Netherlands JournalJournal of Cardiovascular Risk; in press

3 Chapterr 10 Abstract t Background d Measurementt of intima-media thickness (IMT) is a well established surrogate marker for cardiovascularr endpoints. We studied the long-term effects of statins on femoral IMT and plaquee scoring in the effects of Atorvastatin versus Simvastatin on Atherosclerosis Progressionn (ASAP) study. Materiall and methods Threee hundred and twenty-five patients with familial hypercholesterolaemia were randomisedd to either atorvastatin 80 mg/day or simvastatin 40 mg/day. Patients were treated forr 2 years. IMT was measured at baseline and after 2 years. Results s Att baseline, femoral IMT was 1.69 mm in the atorvastatin group and 1.61 mm in the simvastatinn group; at 2 years, IMT increased 0.06 mm (p=0.24) and 0.15 mm(p=0.012), respectively.. No significant differences were obvious between these two treatment arms (p=0.26).. Femoral plaques were present in 64.7% in the atorvastatin group and 56.1% in thee simvastatin group at baseline; after 2 years, these proportions rose to 66.0% (p=0.47) andd 67.3% (p=0.02), respectively (p=0.87 between treatment arms). Carotid plaques were presentt in 6.3% versus 4.9%; after 2 years, these percentages were 5.0% (p=0.48) versus 5.5%% (p=0.71), respectively (p=0.90 between treatment arms). Conclusions s Ourr study indicates increased efficacy of atorvastatin 80 mg in retarding progression of atherosclerosiss in the femoral artery compared to simvastatin 40 mg. Interestingly, in the carotidd arteries these statins influenced IMT to a greater extent, whereas in the femora! arteryy the effects were more pronounced on plaque frequency. These findings underscore thee generalized effects of lipid lowering on atherosclerosis

4 Femorall IMT and plaque scoring Introduction n Thee measurement of intima-media thickness (IMT) of superficial arteries has been validated as a surrogatee marker for atherosclerotic changes. Prospective studies have shown that increased IMT cann predict myocardial infarction (MI) and cerebral vascular events. 1 "' An increase of IMT of mm/year is considered clinically significant, since this is associated with a relative risk of 2.22 for nonfatal MI or coronary death. 4 Recently,, we have reported on the ASAP (effects of Atorvastatin versus Simvastatin on Atherosclerosis Progression)) study cohort. 5 In this trial we studied patients with heterozygous familial hypercholesterolaemiaa (FH). FH is an autosomal dominant disease characterized by a 2- to 3-fold increasee in low density lipoprotein cholesterol (LDL-c) caused by mutations in the LDL-receptor gene.. FH patients have a sharply increased risk for early cardiovascular disease (CVD) due to rapidlyy progressive and extensive atherosclerosis. Thee ASAP study was a 2-year, double-blind, randomised clinical trial, where patients were treated withh either atorvastatin 80 mg/day or simvastatin 40 mg/day. Ultrasound scans of carotid and femorall arterial walls were performed. Carotid IMT defined the primary ultrasound endpoint and thesee data have been previously reported. 5 Subsequently, we reassessed the dataset of the ASAP studyy to include the femoral artery IMT, a secondary outcome parameter in this trial, as well as thee plaque scoring of both carotid and femoral arteries. 6 Our primary objective was to determine whetherr changes in femoral IMT would parallel those in the carotid arteries. Second, we wanted too assess whether plaque frequency, as a marker for advanced atherosclerosis, would also respond favourablyy to intensive or moderate lipid lowering therapy. In particular, it has been suggested thatt plaque measurements are better correlated with atherosclerotic events than IMT itself. 7 Materialss and methods Protocol l Designn and main results of the ASAP study have been reported previously.^ In summary; ASAP wass a 2-year, two centre, randomised, double-blind trial in FH patients to assess whether treatment withh atorvastatin 80 mg/day or simvastatin 40 mg/day could retard atherosclerosis progression in FHH patients. Men and women aged between 30 and 70 years with FH were screened for eligibility. Patientss were either previously untreated or treated, but w ith LDL-c remaining above 4.5 mmol/1. Afterr an 8-week placebo run in, in which all lipid lowering medication was discontinued, baseline measurementss of lipoprotein parameters and IMT were performed. These measurements were repeatedd after 2 years. The Institutional Review Boards of both centres approved the protocol and 117 7

5 Chapteii H) writtenn informed consent of all participants was obtained. 5/ ' Laboratory y Lipoproteinn parameters included total cholesterol (TC), (calculated) LDL-c, high density lipoproteinn cholesterol (HDL-c) and triglycerides (TG) and were analysed as described previously. 6 Ultrasoundd imaging IMTT measurement procedures have been reported before. 6 Ultrasound examinations were performed usingg a Biosound Phase-2 real time scanner (BiosoundEsaote, USA). A high resolution scanner withh a 10 MHz transducer was used. The mean carotid IMT represents the average of anterior and posteriorr walls in the common carotid artery (CCA), the carotid bifurcation (BUL) and the posterior walll of the internal carotid artery (ICA), bilaterally. The mean femoral IMT represents the far walll of the common femoral artery (CFA). Inn this study a plaque was predefined as a an IMT > 1.3 mm and/or wall interface displacement. 6 Imagess were analysed off-line with semi-automatic edge detection software (Eurequa; TSA company,, Meudon, France). 8 Ultrasound scans were performed by well-trained ultrasonographers inn the two centers. The images were stored on disk and analysed by independent readers blinded too treatment information of the patients. During the study reproducibility was checked at regular timee points. The intra-observer and inter-observer coefficients of variation were <5%. Statisticall analysis Thee number of participants required to detect a minimal relevant effect over 2 years (change in meann IMT) of 0.05 mm with a power of 80%, a= 0.05 and a within-subject over time standard deviationn estimated as 0.15, equals 141 per treatment group. Allowing for a 10% drop-out rate, the totall number of patients would amount to 313. In effect a total of 325 patients could be included. Thee primary outcome parameter was change in IMT in millimetres after 24 months. Changes fromm baseline within groups were analysed with a paired t-test or a Wilcoxon lest for variables withh a skewed distribution. Differences between groups were compared using the independent t- lest.. McNemar tests were applied for comparing the proportion before and after treatment within groups.. Changes of dichotomous data between groups were tested using conditional logistic regressionn analysis. Spearman correlations coefficients were calculated to assess evidence of associationn between femoral artery IMT and carotid artery IMT and plaques presence in the femorall and carotid artery. Statistical analyses were performed using SAS (version 8.02, SAS Institutee Inc. Cary, NC, USA)

6 Femorall IMT and plaque scoring Results s Lipids s Thee lipid results have been published before/ In short, at baseline there were no significant differencess in lipid levels between both treatment groups. LDL-c was reduced by 50.5% in the atorvastatinn 80 mg group and 41.2 % in the simvastatin 40 mg group. HDL-c increased by 13% in bothh treatment groups. Atorvastatin reduced TG levels by 29.2% and simvastatin reduced these levelss by 17.7%. Atorvastatin was significantly better in lowering LDL-c and TG levels as compared too simvastatin 40 mg (p= and p = , respectively). 5 Femorall artery IMT Baselinee characteristics of patients in the ASAP study are summarized in table 1. The IMT of the commonn femoral arterial walls could be obtained in 156 (98%) of the 160 patients in the atorvastatin 800 mg treated patients and 158 (96%) of the 165 patients in the simvastatin 40 mg treated patients. Baselinee IMT of the CFA was 1.69 mm in the atorvastatin arm versus 1.61 mm in the simvastatin arm.. Femoral artery IMT was significantly correlated with carotid artery IMT (r=0.29; po.001). Tablee 1. Baseline characteristics of the patients in the ASAP study Atorvastatinn 80 mg (n=160) ) Simvastatinn 40 mg (n=65) ) Agee (years) Genderr (female/male) Smoking g CVDD (%) BM11 (kg/m 2 ) BP(mmllg) ) 488 (11) 94/ (33%) 433 (27%) 25.9(3) ) 1311 (16)/ 79(8) 49(11) ) 103/ (30%) 422 (26%) (4) 1311 (16)/79 (8) TCC (mmol/l) HDL-cc (mmol/l) LDL-cc (mmol/l) TGG (mmol/l) ApoBB (mg/1) 9.99(1.87) ) 1.18(0.32) ) 8.00(1.83) ) 1.57( ) ) 1954(417) ) 10.27(2.07) ) 1.16(0.28) ) 8.33(2.03) ) 1.85( ) ) 1992(420) ) Valuess are means (SD), except for triglycerides, which is given in medians (interquartile ranges), ASAP= Atorvastatinn versus Simvastatin on Atherosclerosis Progression, CVD= cardiovascular disease, BMI= body masss index. BP= blood pressure, TC= total cholesterol, HDL-c= high density lipoprotein cholesterol, LDLc== low density lipoprotein cholesterol, TG= triglycerides, ApoB= apolipoprotein B

7 Chapterr 10 Afterr 2 years of statin treatment these values were l.74 mm and l.75 mm, respectively (Table 2). Thee 1MT increase of 0.05 mm in the atorvastatin group did not reach significance (p=0.24). In contrast,, the 0.14 mm increase of IMT in the simvastatin group was significant (p=0.0l2). No significantt difference (p=0.26) was obvious between these two treatment arms. Tablee 2. Mean IMT at baseline and at 2 years in the atorvastatin and simvastatin treated patients Baseline e 22 years Femorall artery Atorvastatinn (n=!56) Simvastatinn (n=158) 1.69(0.70) ) (0.78) 1.74(0.77) ) 1.75(0.76)* * Carotidd artery Atorvastatinn (n=160) Simvastatinn (n=163) (0.22) 0.92(0.21) ) (0.21) *t (0.20) * Valuess are means (SD), 1MT= intima-media thickness, *= p<0.05 within one treatment arm, t= p<0.05 betweenn the 2 treatment arms. Carotidd artery IMT Thee findings with regards to mean carotid IMT were published previously. 5 In short, atorvastatin 800 mg lead to a decrease of mm (p<0.002), while in contrast simvastatin 40 mg was associated withh an increase of mm (p<0.005) of mean carotid IMT after 2 years of treatment (difference betweenn treatments p<0.001 ). s Plaquee scoring Plaquess were present in the femoral arteries in 65.0% of the patients in the atorvastatin 80 mg groupp and in 57.0% in the simvastatin 40 mg group. The plaque frequency at baseline was not significantlyy different between the two treatment arms (p=0.19). After 2 years of statin treatment thesee percentages increased to 67.5% and 68.5%, respectively (Table 3). The rise in the atorvastatin armm was not significant (p=0.48), but again in the simvastatin arm the increment did reach statistical significancee (p=0.004). The difference between both treatment arms was not significant (p=0.87). Inn the carotid arteries plaques were present in 6.3% of the patients in the atorvastatin 80 mg group andd 4.9% in the simvastatin 40 mg group. After 2 years of treatment these percentages were 5.0% andd 5.5%. respectively (Table 3). The change within the treatment groups was neither significant in thee atorvastatin arm (p=0.48), nor in the simvastatin arm (p=0.71). In addition, the difference between thee two treatment arms after 2 years was also not significant (p=0.90). No significant correlation 120 0

8 Femorall IMT and plaque scoring wass observed between plaques present in the femoral artery and in the carotid artery (r=0.073; p=0.48),, which is most likely due to the small number of plaques present in the carotid arteries. Tablee 3. Plaques score (%) at baseline and at 2 years in the atorvastatin and simvastatin treated patients s Baseline e 22 years Femorall artery Atorvastatinn (n=156) Simvastatinn (n=158) % % % % * Carotidd artery Atorvastatinn (n= 160) Simvastatinn (n=163) 6.33 % 4.99 % 5.00 % 5.55 % Valuess are means (SD), IMT= intima-media thickness, *= p<0.05 within one treatment arm. Discussion n Thesee analyses of the femoral and carotid arteries of FH patients show that the increase of femoral IMTT seen over the course of 2 years of simvastatin 40 mg treatment was attenuated in the atorvastatinn 80 mg treated patients. In support of these findings, the percentage of plaques in the femorall artery increased significantly in the simvastatin arm, but not in the atorvastatin arm. Lastly,, and perhaps most importantly, the percentage of plaques in the carotid artery increased in thee simvastatin arm, but decreased in the atorvastatin arm. Although this change did not reach statisticall significance the latter results point to a trend comparable with the IMT data. These differencess in terms of IMT and plaque development in the two treatment regimens seem likely duee to the stronger LDL-c and TG reductions in the atorvastatin 80 mg arm. 5 Nevertheless,, these results raise several questions. First, is there a fundamental difference between thee atherosclerotic process in the carotid compared to the femoral artery? In support of this hypothesis,, is that the atorvastatin treated patients did not demonstrate a clear decrease of femoral IMT,, such as previously reported for the carotid IMT.' The direction of these changes, however, wass similar in thee femoral and carotid artery for both atorvastatin 80 mg and simvastatin 40 mg treatedd patients. This may indicate that even stronger reductions of LDL-c levels are necessary to inducee regression of the arterial wall thickening in the femoral versus the carotid artery. Or, conversely,, that LDL modification does not have a similar impact on atherosclerotic changes in 121 1

9 Chapterr 10 thee vasculature of lower extremities. The latter is highly unlikely, since the Heart Protection Studyy (HPS) shows similar percentage event reductions in event rates for coronary, cerebrovascular andd peripheral arterial disease. 4 Another possible explanation is that organised andfibroticplaques, whichh are present at a higher frequency in the femoral artery, show smaller therapeutic response. Furthermore,, the size of the effect of statin intervention depends to a significant extent on variability off 1MT per se and since variability is greater in the femoral artery, this could mask the effect of statinn intervention on change in femoral IMT. Second,, are our findings compatible with the results of other lipid lowering trials using IMT as a surrogatee marker? Recently, an expert panel concluded that the far wall of the CCA is the preferred segmentt to use in lipid lowering trials. 1 " Indeed, the Atherosclerosis Risk in Communities (ARIC) studyy showed that the CCA correlated well with all major cardiovascular risk factors and supported thee results of the Cholesterol Lowering Atherosclerosis Study (CLAS). : J Moreover, the Pravastatin, Lipidss and Atherosclerosis in the Carotid Arteries (PLAC-ÏI) study demonstrated that the far wall off the CCA was significantly correlated with both progression and regression of atherosclerotic disease."" Furthermore, in CLAS the therapy effect observed in the femoral arteries was less markedd than the strong and consistent benefit reported for both native coronary arteries and aortocoronaryy bypass grafts. 12 Inn contrast, in the Regression Growth Evaluation Statin Study (REGRESS) IMT measurements weree performed in a subgroup of 255 patients with CVD. In this study pravastatin retarded the increasee in IMT compared to placebo, seen over a 2-year period. This effect was predominantly observedd in the far wall of the common femoral artery. l > Recently, a study in which the association betweenn carotid and femoral IMT and coronary artery disease was investigated, indicated that the femorall IMT was also a strong and independent predictor of the extent and severity of coronary atherosclerosiss as assessed by coronary angiography. 14 However, another study did not find a significantt relationship between femoral artery IMT and coronary atherosclerosis. 15 Thee question now before us is whether the femoral artery should be used in IMT scanning protocols. Dataa on femoral IMT alone are scarce and conflicting, in contrast to the reproducible and vast amountt of data on carotid IMT. Therefore, we feel that measurement of the carotid IMT provides sufficientt information to assess the efficacy of different drug regimes in lipid lowering intervention trials.. Recently, Iglesias del Sol et al, lf ' discussed that all the different IMT measurement sites in thee carotid artery have the same ability to predict future MI. Inn conclusion, our study indicates that atorvastatin 80 mg inhibits atherosclerosis progression to aa greater extent than simvastatin 40 mg in both carotid and femoral vascular beds. Specifical ly, in 122 2

10 Femorall IMT and plaque scoring thee carotid arteries statins had greater effects on IMT, whereas in the femoral artery plaque modificationn by statins was more obvious. These findings in the carotid and femoral arteries illustratee the systemic effects of statins on the arterial wall, irrespective of localisation. Acknowledgements s Wee thank P. Netten, P. Bouter, P. Lestrade, W. Bogers and B. Imholz for assistance with recruitement;; A. Theloose, M. Brok, J. Visser, J. den Arend, G van der Biezen for the ultrasound investigations.. T. Terburg and H. van Langen for technical assistance. This study was financially supportedd by Parke-Davis B.V., The Netherlands. John Kastelein is an established investigator of thee Netherlands Heart Foundation (2000D039). References s 1.. Bots ML, Hoes AW, Koudstaal PJ et al. Common carotid intima-media thickness and risk of stroke andd myocardial infarction: the Rotterdam Study. Circulation 1997;96: Chambless LE, Heiss G, Folsom AR et al. Association of coronary heart disease incidence with carotidd arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC)) Study, Am J Epidemiol 1997;146: O'Leary DH, Polak JF, Kronmal RAet al. Carotid-artery intima and media thickness as a risk factor forr myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Researchh Group. N Engl J Med 1999;340: Hodis HN, Mack WJ, LaBree L et al. The role of carotid arterial intima-media thickness in predicting clinicall coronary events. Ann Intern Med 1998;128: Smilde TJ, van Wissen S, Wollersheim H et al. Effect of aggressive versus conventional lipid loweringg on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised,, double-blind trial. The Lancet 2001;357: Smilde TJ, Trip MD, Wollersheim H et al. Rationale, design and baseline characteristics of a clinical triall comparing the effects of robust vs conventional cholesterol lowering and intima media thickness inn patients with familial hypercholesterolaemia. The atorvastatin versus simvastatin on atherosclerosis progressionn (ASAP) study. Clinical Drug Investigation 2001;20: Homma S, Hirose N, Ishida H et al. Carotid plaque and intima-media thickness assessed by b-mode ultrasonographyy in subjects ranging from young adults to centenarians. Stroke 2001 ;32: Touboul PJ, Prati P, Scarabin PY et al. Use of monitoring software to improve the measurement of carotidd wall thickness by B-mode imaging. J Hypertens Suppl 1992;10:S37-S MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in high-risk individuals:: a randomised placebo-controlled trial. The Lancet 2002;360: Barth JD. An update on carotid ultrasound measurement of intima-media thickness. The American Journall of Cardiology 2002;89: Byington RP, Furberg CD, Crouse JR, III et al. Pravastatin, Lipids, and Atherosclerosis in the Carotidd Arteries (PLAC- II). Am J Cardiol 1995;76:54C-9C Blankenhorn DH, Azen SP, Crawford DW et al. Effects of colestipol-niacin therapy on human femorall atherosclerosis. Circulation 1991;83:

11 Chapterr de Groot E, Jukema JW, Montauban van Swijndregt AD et al. B-mode ultrasound assessment of pravastatinn treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographicc findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Amm Coll Cardiol 1998;31: Lekakis JP, Papamichael CM, Cimponeriu AT et al. Atherosclerotic changes of extracoronary arteries aree associated with the extent of coronary atherosclerosis. Am J Cardiol 2000;85: Hulthe J, Wikstrand J, Emanuelsson H et al. Atherosclerotic changes in the carotid artery bulb as measuredd by B-mode ultrasound are associated with the extent of coronary atherosclerosis Stroke 1997;28: Iglesias del Sol A, Bots ML, Grobbee DE et al. Carotid intima-media thickness at different sites: relationn to incident myocardial infarction. The Rotterdam Study. Eur Heart J 2002;23: