How can we further improve the LDL-cholesterol target level achievement rate based on the Hungarian MULTI GAP 2011 study results and considering the new Europea dyslipidemia guidelines?

How can we u he imp o e he LDL-choles e ol a ge le el achie emen a e based on he Hunga ian MULTI GAP 2011 s udy esul s and conside ing he new Eu opean dyslipidemia guidelines? Laszlo Ma k1, Gyö gy Pa agh2, Is an Ka adi3, Is an Reibe 4, Gyula Pados5, Zol an Kiss6 Abs ac In oduc ion: Despi e he con inuous imp o emen o he quali y o lipid low- e ing he apy he achie emen o a ge alues is s ill no sa is ac o y, mainly in he e y high ca dio ascula isk ca ego y pa ien s, whe e he goal o low densi y lipop o ein choles e ol (LDL-C) is 1.80 mmol/l. Ma e ial and me hods: The ends in lipid lowe ing ea men o 17420 pa ien s om di e en s udies conduc ed be ween 2004 and 2010 we e compa ed o ha o 1626 pa ien s o MULTI GAP (MULTI Goal A ainmen P oblem) 2011 ea - ed by gene al p ac i ione s (GPs) and specialis s. Resul s: In MULTI GAP 2011 he mean LDL-C le el ± SD) o pa ien s ea ed by GPs was ound o be 2.87 ±1.01 mmol/l, he a ge alue o 2.50 was achie ed by 40% o hem, in he specialis s’ pa ien s he mean LDL-C le el p o ed o be 2.77 ±1.10 mmol/l and he achie emen a e was 45%. In he 2.50 mmol/l achie emen a e o GPs’ pa ien s a sa is ac o y imp o emen was obse ed in he s udied yea s, bu he 1.80 mmol/l LDL-C goal in 2011 was a ained only in 11% o e y high isk cases. The e was a linea co ela ion be ween he pa ien compliance es ima ed by he physicians and he LDL-C achie emen a e. Conclusions: As he numbe o e y high isk ca ego y pa ien s has been inc eased acco ding o he new Eu opean dyslipidemia guidelines, g owing a en- ion needs o be placed on a ainmen o he 1.80 mmol/l LDL-C le el. Based on he esul s o he MULTI GAP s udies, imp o ing pa ien s’ adhe ence and he con inuous aining o physicians a e necessa y. Key wo ds: p e en ion, isk ac o s, hype choles e olemia, LDL choles e ol. In oduc ion Lipid-lowe ing he apy, he basic d ugs o which a e s a ins, became ca dio ascula p e en ion’s mos impo an elemen in ecen yea s. A se ies o s udies showed ha he adminis a ion o s a ins can educe ca dio ascula e en s and mo ali y as well [1-3]. Recen ly he issue came Co esponding au ho : Laszlo Ma k MD, PhD 2nd Depa men o In e nal Medicine – Ca diology Pandy Kalman Bekes Coun y Hospi al Semmelweis u. 1 P.O. Box 46 5701 Gyula, Hunga y Phone: +36-209288053 Fax: +36-66526543 E-mail: ma [email protected] Clinical esea ch 12nd Depa men o Medicine – Ca diology, Pandy Kalman Bekes Coun y Hospi al, Gyula, Hunga y 21s Depa men o Medicine, Medical and Heal h Science Cen e, Uni e si y o Deb ecen, Hunga y 33 d Depa men o Medicine, Semmelweis Uni e si y, Budapes , Hunga y 44 h Depa men o Medicine, S . Geo ge Feje Coun y Hospi al, Szekes ehe a , Hunga y 5S . Im e Hospi al, Independen Depa men o Lipidology, Budapes , Hunga y 6MSD Hunga y K , Budapes , Hunga y Submi ed: 29 Feb ua y 2012 Accep ed: 15 May 2012 A ch Med Sci 2012; 8, 4: 608-613 DOI: 10.5114/aoms.2012.30283 Copy igh © 2012 Te media & Banach A ch Med Sci 4, Augus / 2012 609 up ha his g oup o medicines could inc ease he occu ence o new onse diabe es; howe e , he bene i o s a in applica ion is no compa able o he ha m o his possible side e ec , especially in pa ien s wi h known ascula disease [4-6]. The goal o lipid-lowe ing he apy is always o educe he equency o ca dio ascula e en s. How- e e , wi hin his he e is a well-de ined su oga e endpoin o s opping he p og ession o causing he eg ession o a he oscle osis ha is conside ed he cause he clinical e en s. A se ies o s udies has p o ed ha lowe ing he LDL-C le el by 50% could esul in eg ession o a he oscle o ic plaques [7-9]. All his makes unde s andable he ac ha in he new Eu opean dyslipidemia guidelines he numbe o diseases belonging o he e y high isk ca ego- y has been enla ged [10]. I ascula s enosis is de ec ed, an e o should be made o s op he p ocess and s a i s eg ession, aiming o each he 1.80 mmol/l a ge le el and exceed he 50% educ- ion o LDL-choles e ol le el. Mos o he p e ious s udies demons a ed ha he a ainmen a e o he 2.50 mmol/l LDL-C le el is insu icien . How can we each his a ge when mos o ou pa ien s should achie e he 1.80 mmol/l LDL-C le el al eady? Wha conclusions can be d awn om he su ey conduc ed since 2004 and he MULTI GAP 2011 esul s in o de o ea ou pa ien s mo e e ec i ely? Al hough his su ey was conduc ed in Hunga y, he compa ison made wi h he ea lie in e na ional s udies showed ha he p oblems a e simila in all Eu opean coun ies [11-16]; he e o e we belie e ha he lessons lea ned om his in es iga ion may be alid o o h- e coun ies as well. Ma e ial and me hods The ends in lipid lowe ing ea men we e s ud- ied using he da a o 17 420 pa ien s in o al om di e en su eys (CEL P og am 2004 and 2005, KONSZENZUS-CEL P og am 2006, REALITY 2004 and 2007 s udies, MULTI GAP 2008, 2009 and 2010) pe - o med on high ca dio ascula isk pa ien s o GPs and specialis s in Hunga y [17, 18]. In he MULTI-GAP 2011 s udy we analyzed da a and ea men s a egies o 1626 pa ien s om 149 andomly selec ed specialis s (73 specialis s o in e nal medicine, 40 ca diologis s, 16 diabe olo- gis s, 20 neu ologis s) and 53 GPs (app oxima ely 10 pa ien s pe physician we e en olled) using a s uc u ed ques ionnai e in Augus and Sep em- be 2011. The pa ien s ga e hei consen o pa icipa ion; he s udy was conduc ed in acco dance wi h he Dec- la a ion o Helsinki and ICH-GCP (In e na ional Con- e ence on Ha monisa ion – Good Clinical P ac ice). The MULTI GAP 2011 pa ien s in ol ed 383 cas- es o uns able angina, 560 cases o p e ious myoca dial in a c ion, 283 wi h known pe iphe al a e y disease (PAD) o ascula ope a ion due o PAD, 481 wi h s oke and 279 wi h ansi o y ischemic a ack; 766 pa ien s we e diabe ic and 1430 had hype ension. The exis ence and ex en o smoking, as well as he sex, age, body mass index and wais ci cum e ence we e eco ded. The physicians also es ima ed pa ien s’ compli- ance based on equency o s a in p esc ip ion and ques ioning he pa ien . All pa ien s belonged a leas o he high ca - dio ascula isk ca ego y acco ding o he 4 h Hun- ga ian Ca dio ascula Consensus Con e ence ec- ommenda ions [19], and hey had LDL-C a ge s a leas o ≤2.50 mmol/l. S a i ying he pa ien s acco ding he new dyslipidemia guidelines o he ESC/EAS (Eu opean Socie y o Ca diology and Eu o- pean A he oscle osis Socie y), 83% o hem belonged o he e y high isk ca ego y wi h an LDL-C a ge alue o 1.80 mmol/l [10]. S a is ical analysis In he case o ca ego ical a iables we used e- quencies o alid cases. In he case o con inuous a iables means and medians a e p esen ed. Sig- ni icance es s we e pe o med by χ2 o ca ego i- cal, by ANOVA o con inuous a iables (wi h Fish- e ’s leas signi ican di e ence [LSD] es me hod o mul iple compa isons). Asymme ic 2-sided sco es we e conside ed. Values o p( wo- ailed) < 0.05 we e accep ed as signi ican . All s a is ical analyses we e pe o med by SPSS. Resul s In he MULTI GAP 2011 s udy 1626 pa ien s pa - icipa ed, 683 women and 943 men; hei mean age was 66.0 ±10 yea s, body mass index 29.0 ±10 kg/m2, eGFR 61 ±13 ml/min/1.73 m2, 28% o he pa ien s we e smoke s (among he smoke s 28% smoked 10 o less ciga e es/day, 48% be ween 10 and 20, and 24% 20 o mo e) (Table I). The mean LDL-C le el (± SD) o he o al popu- la ion was 2.82 ±1.0 mmol/l, he a ainmen a e o 2.50 mmol/l was 43.3%. The mean LDL-C al- ues o GPs’ and specialis s’ pa ien s we e 2.87 ±1.00 mmol/l and 2.77 ±1.10 mmol/l, espec i ely (Table I). Figu e 1 p esen s changes in LDL-C le el be ween 2004 and 2011; i shows a dec ease o almos 1.0 mmol/l o pa ien s ea ed by GPs. In Figu e 2 he a e o GPs’ pa ien s achie ing he 2.50 mmol/l LDL-C a ge alue is p esen ed; his was 40% in 2011, while ha o specialis s’ pa ien s p o ed o be 45% (p= 0.137). The change in goal achie emen a e o GPs be ween 2010 and 2011 p o ed o be s a is ically signi ican (p= 0.035), while ha o specialis s (39% in 2010 [18] and 45% in 2011) was no signi ican (p= 0.064). How can we u he imp o e he LDL-choles e ol a ge le el achie emen a e based on he Hunga ian MULTI GAP 2011 s udy esul s and conside ing he new Eu opean dyslipidemia guidelines? 610 A ch Med Sci 4, Augus / 2012 Among specialis s he plan o he physician ega ding he ea men o pa ien s whose LDL-cho- les e ol le el was no on goal was e alua ed. In 68% o he cases he physician did no go u he , and he pa ien s we e le unde ea ed. In 32% o he pa ien s wi h LDL le el o e 2.50 mmol/l he ol- lowing plans we e decla ed o he change o cu - en ea men : in 34% doubling he dose o s a in, in 43% swi ching o a s onge s a in and in 21% in oduc ion o combina ion he apy (in 2% o cas- es he plan o he apy modi ica ion was no p op- e ly decla ed). Figu e 3 shows he dis ibu ion o LDL-C alues in he GPs’ pa ien s o he MULTI GAP 2011 s udy. The achie emen a e o 2.50 mmol/l LDL-C was 40%, bu ha o 1.80 mmol/l was only 11%. The 2011 MULTI GAP s udy also e alua ed he pa ien s’ compliance wi h he lipid-lowe ing med- ical ea men . This was es ima ed by he physician based on ques ioning he pa ien and he equency o d ug p esc ip ions. The esul was gi en in pe - cen age. Fi e g oups we e o med based on com- pliance: 60% o below, 61-70%, 71-80%, 81-90% and o e 90% o pa ien s we e conside ed coope a i e in each g oup, espec i ely. The 2.50 mmol/l LDL-C a ge achie emen a e was 20%, 25%, 28%, 36% and 42%, espec i ely (Figu e 4). Physician Pa ien To al LDL HDL T iglyce ide numbe choles e ol choles e ol choles e ol [mmol/l] (n)[mmol/l][mmol/l][mmol/l] Mean ± SD Mean ± SD Mean ± SD) Mean ± SD GPs 474 5.12 ±1.30 2.87 ±1.01 1.26 ±0.34 1.99 ±1.67 Specialis s 1152 4.97 ±1.25 2.77 ±1.10 1.29 ±0.43 2.05 ±1.23 Gende 943 males/683 emales Age [yea s] 66 ±10 BMI (body mass index) 29.0 ±10 kg/m2 Wais ci cum e ence: Males > 102 cm 39% Females > 88 cm 71% eGFR 61 ±13 ml/min/1.73 m2 Smoke s 27% Uns able angina 383 (23%) P e ious myoca dial in a c ion 560 (34%) Known pe iphe al a e y disease: • (PAD) o ascula ope a ion due o PAD 283 (17%) • T ansi o y ischemic a ack 279 (17%) • Diabe es 766 (46%) • Hype ension 1430 (88%) Lipid lowe ing he apy (s a in, pa ien s’ %,/mean daily dose) • Sim as a in 18%/29 mg • A o as a in 46%/32 mg • Rosu as a in 29%/20 mg • Flu as a in 3%/72 mg • Eze imibe 16%/10 mg • Fib a es 7%/201 mg Table I.Cha ac e is ics and mean lipid alues o he pa ien s o GPs and specialis s in he Hunga ian MULTI GAP 2011 s udy 4.0 3.5 3 2.5 2 2004 2005 2006 2007 2008 2009 2010 2011 Figu e 1. Change in mean LDL-choles e ol le els o high ca dio ascula isk pa ien s ea ed by GPs and specialis s, o e he yea s T ea men goal GPs Specialis s 3.78 3.34 3.01 2.85 2.74 3.71 3.38 3.14 3.05 3.10 2.84 2.77 3.01 2.87 Laszlo Ma k, Gyö gy Pa agh, Is an Ka adi, Is an Reibe , Gyula Pados, Zol an Kiss A ch Med Sci 4, Augus / 2012 611 Discussion The clinical bene i o lipid-lowe ing he apy is indispu able and has inc easing impo ance in ca - dio ascula p e en ion. Acco ding o he new dys- lipidemia guidelines o he ESC/EAS 1.80 mmol/l LDL-choles e ol is ecommended o mo e pa ien s han be o e [10]. This means ha mo e e o should be made, since e en he achie emen a e o he 2.50 mmol/l le el could no mee ou sa is- ac ion. The medica ion possibili ies a e limi ed (s a ins and eze imibe) and in he nex ew yea s in oduc ion o a new g ound-b eaking LDL choles- e ol-lowe ing agen is no expec ed. Also a ew mo e yea s mus elapse un il he p omising PCSK9 inhibi o he apy [20] comes in o p ac ice. The imp o emen o lipid pa ame e s beyond LDL-C can happen mo e equen ly wi h he adminis a ion o niacin and ib a es. Also he in oduc ion o CETP inhibi o s may occu . These may dec ease LDL-C le - els as well, bu subs an ial imp o emen can be expec ed only om a mo e e ec i e use o he s a in + eze imibe combina ion [21]. We ha e been analyzing he changes in lipid le - els and he achie emen o he a ge s in Hunga y since 2004 [17, 18]. A e he signi ican all o lipid le els expe ienced in he ea ly yea s, ecen ly s ag- na ion has been obse ed. We could no be sa is- ied wi h a ainmen o he 2.50 mmol/l LDL-C le - el ei he , and ega ding he signi ican ly inc eased and p obably u he inc easing demands o each he le el o 1.80 mmol/l, we ha e o look o addi- ional ways o imp o e. The Hunga ian CORVUS (COn olled TaRge s o High Vascula Risk Pa ien s Using E ec i e S a ins) s udy in es iga ed he e ec o swi ching o osu- as a in on he success o lipid lowe ing he apy in 1385 high isk pa ien s. In his 3-mon h, mul icen- e , p ospec i e, obse a ional, non-in e en ional, open-label s udy du ing he ea men pe iod he le el o o al choles e ol dec eased by 25.2% and LDL choles e ol by 35.0%; a he end o he s udy he a e o achie ing he 2.50 mmol/l LDL-C a ge le el was 58%. One housand and se en y-se en ou o 1385 pa ien s belonged o he e y high isk ca ego y, and in his g oup o pa ien s he 1.80 mmol/L LDL-C achie emen a e p o ed o be only 19% [22, 23]. This esul sugges s ha s a in mono he apy, e en in he case o he mos po en osu as a in, in he majo i y o e y high isk pa ien s is ine ec i e and he adminis a ion o eze- imibe is ine i able. In he MULTI GAP 2010 s udy, compa ing s a in mono he apy s. combina ion he apy, a 19% di - e ence was shown in he 2.50 mmol/l LDL-choles- e ol achie emen a e in a ou o he la e , i.e. eze imibe adminis a ion [18]. A u he ool o achie ing be e lipid lowe ing esul s could be he imp o emen o he apeu ic 45 40 35 30 25 20 15 10 5 02004 2005 2006 2007 2008 2009 2010 2011 Yea 14 19 24 32 31 30 32 40 Pa ien s [%] Figu e 2. Changes in he a io o pa ien s eaching he a ge 2.50 mmol/l o LDL-choles e ol le el ea - ed by GPs be ween 2004 and 2011 12 10 8 6 4 2 0 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 Concen a ions [mmol/l] Figu e 3. The dis ibu ion o LDL-C alues in he pa ien s o GPs in he MULTI GAP 2011 s udy Pa ien s [%] 1.80 mmol/l a ge alue 2.50 mmol/l a ge alue 11 % 40% Figu e 4. The ela ionship be ween he a ainmen o 2.50 mmol/l LDL-choles e ol le el and he pa ien s’ compliance in he MULTI GAP 2011 s udy 45 40 35 30 25 20 15 10 5 0 42 36 22% di e ence 28 25 20 > 90% 81-90% 71-80% 61-70% < 61% How can we u he imp o e he LDL-choles e ol a ge le el achie emen a e based on he Hunga ian MULTI GAP 2011 s udy esul s and conside ing he new Eu opean dyslipidemia guidelines? coope a ion o he pa ien s. A se ies o s udies has p o en a linea co ela ion be ween pa ien s’ adhe - ence o lipid lowe ing he apy and long- e m su - i al o a e o clinical e en s [24-26]. In ou 2010 s udy he e was a 17% di e ence in a ge le el a ainmen a e be ween he good and bad com- 612 A ch Med Sci 4, Augus / 2012 pliance g oup [18]. The MULTI GAP 2011 s udy p o ed again he linea co ela ion be ween he pa ien s’ coope a ion in d ug aking and achie e- men o he LDL-C a ge alue (Figu e 4); he e was no a s a is ically signi ican di e ence compa ed wi h he esul s o 2010. The pa ien s’ willingness o coope a e is c ucial. In a ecen s udy, acco ding o he da abase o he Hunga ian Na ional Heal h Insu ance Fund, he dis- pensa ion a e o p esc ibed s a ins in pa ien s’ newly placed on s a in he apy was analyzed and i showed ha in he second and hi d mon hs o he ea men abou hal o he pa ien s did no go o he pha macy o he p esc ibed d ugs and a yea la e his p opo ion became only 26.3% [27]. The mos ob ious possibili y o imp o emen is ha a e e y d ug p esc ip ion he pa ien ’s a en ion should be d awn o he long- e m commi men as he ea men needs app op ia e coope a ion in o de o maximize he bene i s and educe he e- quency o clinical e en s. In he MULTI GAP 2010 s udy he physicians ecei ing special educa ion and access o so wa e which called a en ion o he pa ien s’ weaknesses in achie ing hei lipid goals had 10-11% be e esul s in eaching he 2.5 mmol/l LDL-C a ge le - el han doc o s wi hou he special educa ion [18]. This suppo s he ideas o u he educa ion and use o compu e so wa e applica ion which acili a es hei wo k while bo h enhance a ge achie emen a es. Acco ding o he MULTI GAP 2011 su ey 68% o he physicians do no modi y he he apy when he pa ien s’ lipid esul s do no mee he a ge s. This high numbe con i ms he ac ha he con- inuing educa ion o physicians is essen ial. Fo his Table II may se e as guidance showing which he - apeu ic op ions (dose doubling, swi ching o a s onge s a in o combina ion wi h eze imibe) o choose depending on he app op ia e a ge alue (2.50 mmol/lo 1.80 mmol/l) and he cu en LDL-C le el. Expe ience shows ha physicians need and a e willing o ecei e help om such ma e ials. In conclusion, we can summa ize ha a ge le - el achie emen s indica ing he quali y o ea men in lipid-lowe ing he apy ha e signi ican ly imp o ed in ecen yea s; howe e , he momen um o imp o emen came o a hal . To achie e u he imp o emen s possibili ies a e a ailable bo h a he pa ien s’ and doc o s’ sides. On one side, con inu- ous moni o ing o pa ien s’ co-ope a ion is needed o imp o e hei adhe ence. The physician should in o m he pa ien ha he lipid-lowe ing he apy is a li elong ac i i y which, i success ul, could s op he p ocess o a he oscle osis and eg ession can be achie ed. On he o he side, a e e y doc o - pa ien mee ing he impo ance o managemen should be emphasized and a e each labo a o y con ol he p e ious ea men should be e iewed. This belongs o he imp o emen o medical ac i - i y. The key o imp o ing he quali y o lipid-lowe - ing is based on he doc o ’s knowledge and his/he a i ude o he lipid-lowe ing he apy and hese can be assis ed by MULTI GAP o o he simila su eys. Acknowledgmen s The a ious s udies analyzed in his pape we e conduc ed by Dend i e L d, Hunga y. All au ho s had ull access o all he da a in he s udy, ake LDL-C % Reduc ion P ac ical app oach LDL-C % Reduc ion P ac ical app oach le el [mmol/] needed o each a ge le el [mmol/] needed o each a ge on s a in 1.80 mmol/l LDL-C on s a in 2.50 mmol/l LDL-C he apy a he in e y high isk he apy a he high isk beginningpa ien s beginningpa ien s 2.0 10% Double he s a in dose 2.2 18% Swi ch o a mo e 2.4 25% po en s a in 2.6 31% 2.8 36% 3.0 40% 3.2 44% 3.4 47% 3.6 50% 3.8 53% 4.0 55% > 4.2 57% Table II. P ac ical guide o each he 1.80 and 2.50 LDL-choles e ol le els as a unc ion o he s a ing le el Conside a ion o combina ion he apy acco ding o he guide- lines (eze imibe/ ib a e/ nico inic acid and s a in) No he apy modi ica ion needed, egula check o LDL-C le el Conside a ion o combina ion he apy acco ding o he guidelines (eze imibe/ ib a e/nico inic acid and s a in) 2.0 2.2 2.4 2.6 4% Double he s a in dose 2.8 11% 3.0 17% 3.2 22% 3.4 26% 3.6 31% 3.8 34% 4.0 38% > 4.2 40% Swi ch o a mo e po en s a in Laszlo Ma k, Gyö gy Pa agh, Is an Ka adi, Is an Reibe , Gyula Pados, Zol an Kiss A ch Med Sci 4, Augus / 2012 613 esponsibili y o he in eg i y o he da a and he accu acy o he da a analyses, and ag eed o he manusc ip as w i en. The au ho s ha e gi en alks, a ended con e ences and pa icipa ed in o he i- als o ad iso y boa ds sponso ed by a ious pha - maceu ical companies. This ma e ial was w i en independen ly, and no company o ins i u ion sup- po ed he au ho s inancially. 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