Persistence with statin therapy in Hungary

Pe sis ence wi h s a in he apy in Hunga y Zol an Kiss1, Laszlo Nagy1, Is an Reibe 2, Gyö gy Pa agh3, Ma k Pe e Molna 4, Gyö gy Rokszin5, Zsol Abonyi-To h5, Laszlo Ma k6 Abs ac IInn oodduucc iioonn:: Pe sis ence wi h lipid-lowe ing d ug he apy by ca dio ascula pa ien s in Hunga y has no been s udied p e iously. This s udy was designed o de e mine he a e wi h which Hunga ian pa ien s wi h hype lipidemia pe - sis in aking lipid-lowe ing agen s, and o compa e his wi h a es epo ed om o he coun ies. MMaa ee iiaall aanndd mmee hhooddss:: This was a e ospec i e s udy ha u ilized da a om he Ins i u ional Da abase o he Na ional Heal h Insu ance Fund o analyze pe - sis ence a es wi h s a ins and eze imibe. The s udy included da a o pa ien s who s a ed lipid-lowe ing he apy be ween Janua y 1, 2007, and Ma ch 31, 2009. Va iables included ype o lipid-lowe ing he apy, yea o he apy s a , and pa ien age. Main ou come measu es we e medians o pe sis ence in mon hs, pe cen ages o pa ien s pe sis ing in he apy o 6 and 12 mon hs, and Kaplan- Meie pe sis ence plo s. RReessuull ss:: The pe cen age o pa ien s who pe sis ed wi h o e all s a in he apy was 46% a e 1 mon h, 40.3% a e 2 mon hs, 27% a e 6 mon hs, and 20.1% a e 12 mon hs. Pe sis ence was sligh ly g ea e o s a in he apy s a ed du - ing 2008 han du ing 2007. Olde pa ien s we e mo e pe sis en wi h he apy han younge pa ien s. Pe sis ence wi h he combina ion o eze imibe-s a in he apy was g ea e han wi h s a in o eze imibe mono he apy. CCoonncclluussiioonnss:: Pe sis ence wi h s a in he apy by pa ien s in Hunga y was low compa ed wi h o he coun ies. Low pe sis ence may ha e nega ed po en ial clinical bene i s o long- e m s a in he apy. KKeeyy wwoo ddss:: pe sis ence, adhe ence, s a ins, eze imibe, Hunga y. In oduc ion Hunga ians ha e a highe isk o p ema u e dea h due o ca dio ascu- la disease (CVD) compa ed wi h esiden s o wes e n Eu opean coun ies [1, 2] and he lowes li e expec ancy a bi h (72.4 yea s) among a ea na ions in he O ganiza ion o Economic Coope a ion and De elopmen (OECD) [3]. The impo ance o lipid-lowe ing he apy is well es ablished [4, 5]. Rega ding he Hunga ian lipid goal achie emen a es in ecen yea s he e a e signi ican imp o emen s, bu he esul is s ill a om expec- CCoo eessppoonnddiinngg aauu hhoo :: 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 1MULTI GAP S udy G oup, Budapes , Hunga y 2S . Geo ge Feje Coun y Hospi al, 4 h Depa men o Medicine, Szekes ehe a , Hunga y 3Medical and Heal h Science Cen e, Uni e si y o Deb ecen, 1s Depa men o Medicine, Deb ecen, Hunga y 4Co inus Uni e si y, Budapes , Hunga y 5Rx Ta ge S a is ical Agency, Budapes , Hunga y 6Pandy Kalman Bekes Coun y Hospi al, 2nd Depa men o Medicine – Ca diology, Gyula, Hunga y SSuubbmmii eedd:: 7 Janua y 2013 AAcccceepp eedd:: 13 Ap il 2013 A ch Med Sci 2013; 9, 3: 409-417 DOI: 10.5114/aoms.2013.35327 Copy igh © 2013 Te media & Banach 410 A ch Med Sci 3, June / 2013 Zol an Kiss, Laszlo Nagy, Is an Reibe , Gyö gy Pa agh, Ma k Pe e Molna , Gyö gy Rokszin, Zsol Abonyi-To h, Laszlo Ma k a ions [6-8]. In a 2007 summa y o 14 key clinical ials o lipid lowe ing conduc ed since 2004 and in ol ing 90 056 indi iduals [9]. Ray e al. de e - mined ha s a in he apy was sa e and signi ican ly educed he ca dio ascula endpoin s. Fu he mo e, a ecen me a-analysis o da a om 170 000 pa - icipan s in 26 andomized ials o s a in he apy demons a ed ha mo e in ensi e lowe ing o low- densi y lipop o ein choles e ol (LDL-C) sa ely p o- duced signi ican u he educ ions (15%; 95% con- idence in e al (CI) 11-18; p< 0.0001) in majo ascula e en s, wi h no e idence o a h eshold wi hin he choles e ol ange s udies below which u he educ ions did no esul in inc emen al educ ions in CVD isk [10]. E en among hose a - aining 1.8 mmol/l o lowe wi h a s anda d s a in egimen, u he educ ion yielded bene i ( ela i e isk (RR) 0.63, 99% CI 0.41-0.95; p = 0.004). In e na ional clinical ials ha e shown ha he op imal ca dio ascula ad an ages o s a in he a- py a e achie ed only wi h he pa ien ’s long- e m pe sis ence (i.e., con inuing he ea men o he p esc ibed du a ion) and adhe ence (i.e., ex en o con o mi y wi h he p esc ibed iming, dosage, and equency o a egimen) [11, 12]. The ea lies poin in some ials a which pa ien s who pe sis ed wi h ac i e he apy began o expe ience ca dio ascula ad an ages o s a in compa ed wi h placebo he - apy ( he poin o isual di e gence – PVD) [13] was a 6 [14] o 12 mon hs o he apy [15]. In a s udy ha assessed pa ien adhe ence jus a e hospi- aliza ion, Ho e al. ound ha pa ien s who dis- con inued s a in he apy 1 mon h a e ini ia ion ollowing an acu e myoca dial in a c ion had sig- ni ican ly lowe 1-yea su i al compa ed wi h hose who con inued wi h s a in he apy [16]. Lack o pe sis ence wi h medica ions in gene al, and wi h s a in he apy in pa icula , emains a wide- sp ead p oblem wo ldwide [17-19]. Se e al decades o esea ch indica e ha up o 20% o all pa ien s do no ill a new p esc ip ion, ega dless o diagno- sis, and app oxima ely one hal o hose who do ill a new p esc ip ion discon inue he apy in he i s 6 mon hs [20]. Up o 69% o all medica ion- ela ed hospi al admissions a e due o subop imal medica- ion adhe ence [19]. Lack o pe sis ence wi h s a in he apy in pa icula has been associa ed wi h in - c eased ca dio ascula e en s (odds a io (OR) 1.40, 95% CI 1.35-1.45 in p ima y p e en ion; OR 1.59, 95% CI 1.51-1.68 in seconda y p e en ion) and in - c eased all-cause mo ali y (haza d a io (HR) 1.25, 95% CI 1.09-1.42; p = 0.001) [17, 18, 21-23]. In addi ion, s a in he apy o insu icien pe sis ence is associ- a ed wi h highe hospi aliza ion a es and o al di ec heal hca e cos s compa ed wi h good adhe - ence o he apy o e he i s 2 yea s o use [24]. Po en ial ba ie s o illing and adhe ing o p e- sc ip ion ea men s include he p esence o psy- chological diso de s (e.g. dep ession) o cogni i e impai men ; ad e se e ec s, cos s (and copaymen s a us), and complexi y o medica ion egimens; pa ien s' lack o insigh in o hei illnesses and/o belie in he bene i s o hei ea men s; and poo p o ide -pa ien ela ionships, such as inadequa e ollow-up o ea men planning and/o missed appoin men s; and logis ical issues such as ans- po a ion p oblems/incon enience/long pha macy wai imes, and/o ha ing a su icien supply o medica ions a home [19, 25]. Cu en ly, only a ew s udies add ess pe sis ence wi h s a in he apy, he deg ee o which his he - apy con ibu es o educ ion o ca dio ascula e en s, o e ec s o he Na ional Heal h Insu ance Fund paymen s o s a in he apy on imp o ing he heal h o he gene al popula ion in Hunga y [26]. We unde ook he cu en s udy o de e mine pe sis ence wi h s a in he apy o Hunga ian pa - ien s wi h hype choles e olemia, and o compa e his wi h pe sis ence o he apy in o he coun ies. The s udy examined gene al pe sis ence, as well as pe sis ence wi h ini ial he apy and pe sis ence wi h he apies con aining eze imibe in ce ain g oups. The s udy also e alua ed he in luence o s a in, age, and geog aphic loca ion on pe sis ence. Ma e ial and me hods This was a e ospec i e s udy o da a main ained in he d ug-dispensing da abase o he Hunga ian Na ional Heal h Insu ance Fund, which con ains p e- sc ip ion da a o all pa ien s ecei ing heal h insu - ance subsidies. The s udy included da a o all pa ien s o any age and ei he sex who s a ed lipid- lowe ing he apy wi h a s a in, eze imibe, o a combi - na ion o a s a in and eze imibe be ween Janua y 1, 2007, and Ma ch 31, 2009. To help ensu e ha only pa ien s who began he apy du ing his pe iod we e included, da a o any pa ien who ecei ed such he apy in 2006 we e excluded. Da a we e also excluded o pa ien s who ecei ed a combina ion o a s a in and any lipid-lowe ing d ug o he han eze imibe on he ini ial day o he apy, and o pa - ien s who died du ing he pe iod o he s udy. The ollow-up pe iod was be ween 4 and 31 mon hs depending on he beginning o he he apy. Da a analyses we e conduc ed acco ding o he yea du ing which he apy was s a ed, he ac i e ing edien and s eng h o he p oduc (s) ini ially dispensed, and pa ien age and esidence. Diag- nos ic da a we e limi ed o he In e na ional Clas- si ica ion o Diseases (ICD) code w i en on p e- sc ip ions, limi ing he abili y o de e mine whe he he apy was aimed a p ima y o seconda y p e- en ion. On he basis o na ional he apeu ic guide- lines, howe e , i could be assumed ha a o as- a in 80 mg and eze imibe we e p esc ibed only o seconda y p e en ion. A ch Med Sci 3, June / 2013 411 Pe sis ence wi h s a in he apy in Hunga y In de e mining pe sis ence, he i s dispensing o a p esc ip ion was conside ed he s a o s udy he apy. We conside ed he apy o ha e been dis- con inued i a pa ien did no ob ain a eplenishmen o d ug o a leas 60 days ( he “g ace pe iod”), ac - co ding o he ecommenda ion o he In e na ion- al Socie y o Pha macoeconomics and Ou comes Resea ch (ISPOR) [19]. An addi ional analysis was con- duc ed o all pa ien s ea ed wi h a s a in using a g ace pe iod o 180 days. Da a we e examined and esul s epo ed in 1-mon h uni s; a mon h is he sho es ime span o which he Na ional Heal h Insu ance Fund p o ides da a. We a emp ed o de e mine he end o he he apy as accu a ely as possible by es ima ing he pa ien ’s ac ual use o an agen , assuming ha , om he i s p esc ip ion, a pa ien would ha e aken one able daily. S a ing wi h he second p esc ip ion, we calcula ed how many days o he apy would ha e been possible wi h he numbe o able s pu chased o ha da e. S udy analyses we e pe o med only o hose pa ien s whose consump ion o able s was calcu- la ed o be 0.75 o 1.25 imes he numbe p esc ibed (calcula ed om he numbe o able s dispensed and he ime pe iods o e which he able s we e dispensed). By doing so, small luc ua ions could be excluded, which migh be caused by in e up- ion o he apy o pa ien s ockpiling o d ugs. In calcula ing gene al o o al s a in pe sis ence, all s a in p oduc s we e conside ed oge he , dis e- ga ding swi ches o a di e en d ug o a di e en dosage o he same d ug. Fo ea men g oups o he han he o al s a in g oup, we conside ed ha ini ial he apy was e - mina ed when a pa ien had a 60-day pe iod du - ing which he ini ial he apy was no longe aken exac ly as p esc ibed, e en i he pa ien hen ook a d ug ha was simila o he ini ial d ug (e.g., a o - as a in o sim as a in-eze imibe ixed combina- ion ins ead o sim as a in), used he ini ial d ug subsequen ly, o ook a p oduc wi h he same ac i e ing edien as he ini ial d ug bu wi h a di - e en dosage. Fo hese speci ic g oups, we he e- o e de e mined du a ion o pe sis ence wi h he ini ially p esc ibed d ug egimen, e en hough he p esc ip ion migh ha e changed. The o al s a in g oup consis ed o all pa ien s who con inued wi h any s a in a any dose, while g oups o use s o indi- idual s a ins consis ed o only hose who emained on he ini ially p esc ibed s a in and dosage. The Na ional Heal h Insu ance Fund da abase enabled us o s udy eze imibe he apy, whe he i consis ed o eze imibe mono he apy, eze imibe- s a in ixed combina ion he apy, o he apy wi h eze imibe plus a s a in as sepa a e p oduc s. We calcula ed he leng h o he apy om he i s pu - chase o eze imibe o he comple ion o he eze- imibe he apy, ega dless o when he eze imibe he apy was s a ed. The s a o eze imibe he a- py was no necessa ily simul aneous wi h he s a o s a in he apy. SS aa iiss iiccaall aannaallyyssiiss Su i al analysis me hods we e used o assess pe sis ence; censo ed da a necessa y o analyses we e a ailable. Su i al cu es we e cons uc ed acco ding o Kaplan-Meie analysis (unadjus ed); he a io o pa ien s s ill ecei ing he apy om mon h o mon h was calcula ed. Obse a ions we e censo ed when a pe son died o became ins i u ionalized, o when he end o he s udy pe iod was eached. We de e mined he medians o pe sis ence and hei 95% CIs. The medians o pe sis ence in di e en g oups we e compa ed wi h he Pe o-Wilcoxon es . Resul s A o al o 459 034 pa ien s s a ed on any s a - in he apy: 188 245 in 2007 and 209 716 in 2008 (Table I). The apy was ini ia ed wi h a o as a in in 277 378 pa ien s, sim as a in in 120 921, and osu- as a in in 19 687. The apy was ini ia ed wi h eze- imibe in 8893 pa ien s: eze imibe mono he apy in 2112, eze imibe plus a s a in in 2044, and a ixed- combina ion eze imibe-s a in p oduc in 5145. Age g oupings o pa ien s anged om < 20 (n = 2568) o ≥70 yea s (n = 101 301). In he o al g oup o pa ien s who ecei ed s a in he apy, 54% discon inued du ing he i s mon h, based on a g ace pe iod o 60 days. Du ing he sec- ond mon h, 40.3% o pa ien s we e s ill ecei ing s a in-based lipid-lowe ing ea men (Figu e 1). This pe cen age dec eased o 27% a 6 mon hs and o 20.1% a he end o he i s yea (Table I). Because o he high deg ee o e osion (54%) du ing he i s mon h, an analysis was conduc ed based on a g ace pe iod o 180 days and yielded 27% pe sis ence a e 12 mon hs. F om he o al 459 034 pa ien s in 5590 cases he e we e enough da a abou a o me myoca dial in a c ion o pe cu aneous co ona y in e en ion in he da abase. In hese cases he pe - sis ence a 1 mon h was 76%, a 6 mon hs 61%, and a 12 mon hs 50%. These a e a o able da a, bu no absolu e. The eal seconda y p e en ion popula ion migh be highe . Du ing he i s yea o he apy, pe sis ence o all s a in he apy s a ed in 2008 was sligh ly g ea e han o he apy s a ed in 2007. Du ing no mon h was he di e ence be ween yea s as much as 4%. The e o e, al hough he di e ence be ween he median pe sis ence o he apies s a ed in 2007 and 2008 was s a is ically signi ican (p < 0.001), i was no deemed clinically ele an . The median pe sis ence o a o as a in and sim- as a in was 1 mon h, and o osu as a in i was 2 mon hs (Table I); di e ences we e s a is ically 412 A ch Med Sci 3, June / 2013 Zol an Kiss, Laszlo Nagy, Is an Reibe , Gyö gy Pa agh, Ma k Pe e Molna , Gyö gy Rokszin, Zsol Abonyi-To h, Laszlo Ma k signi ican (p < 0.001). Pe sis ence cu es we e also de e mined sepa a ely o he indi idual s a ins. The g ea es di e ence be ween pe sis ence cu es was only 6% (obse ed in he i s mon h), indica ing ha he di e ences we e no o clinical signi icance. Cu es o pe sis ence wi h di e en doses o sim as - a in a e shown in Figu e 2. Pe sis ence was g ea es wi h he 20-mg dose, lowe wi h he 40-mg dose, and lowes wi h he 10-mg dose. The di e ence be ween he g oups was s a is ically signi ican (p < 0.001) bu no clinically signi ican , wi h he g ea es di - e ence being only 6.3%, seen in he hi d mon h. Cu es o pe sis ence wi h di e en doses o a o as a in a e shown in Figu e 3. A e he i s mon h, pe sis ence dec eased p og essi ely in he ollowing dose o de : 20 mg, 10 mg, 40 mg, and GG oouuppNNuummbbee oo PPee ssiiss eennccee mmeeddiiaann iinn mmoonn hhss PPee cceenn aaggee oo ppaa iieenn ss ppaa iieenn ss((9955%% ccoonn iiddeennccee iinn ee aall))ppee ssiiss iinngg iinn hhee aappyy aa 66 aanndd 1122 mmoonn hhss AAllll ((oo oo aall)) ss aa iinnss** All pa ien s ecei ing s a in he apy 459034 1 (1.1) 27%, 20.1% 2007 s a o s a in he apy 188245 1 (1.1) 25.4%, 20.3% 2008 s a o s a in he apy 209716 1 (1.1) 27.4%, 19.9% IInnddii iidduuaall ss aa iinn hhee aappiieess**** A o as a in, all 277378 1 (1.1) 27.3%, 20.9% A o as a in 10 mg 42037 1 (1.1) 22.7%, 16.1% A o as a in 20 mg 139850 1 (1.1) 24.5%, 17.5% A o as a in 40 mg 94678 1 (1.1) 20.2%, 14.5% A o as a in 80 mg 6409 1 (1.1) 13.2%, 8.2% Rosu as a in, all 19687 2 (1.2) 28.1%, 21.3% Sim as a in, all 120921 1 (1,1) 26%, 20.5% Sim as a in 10 mg 12217 1 (1,1) 15.9%, 10% Sim as a in 20 mg 68778 1 (1.1) 21.6%, 15.3% Sim as a in 40 mg 41919 1 (1.1) 18.3%, 12.6% AAggee gg oouuppss [[yyeeaa ss]]****** < 20 2568 1 (1.1) 1%, no da a ≥20 o < 30 9084 1 (1.1) 6.9%, 3.7% ≥30 o < 40 30229 1 (1.1) 12.1%, 7.9% ≥40 o < 50 65137 1 (1.1) 17.6%, 11.8% ≥50 o < 60 139142 1 (1.1) 22.3%, 15.9% ≥60 o < 70 117096 1 (1.1) 28.6%, 21.5% ≥70 101301 1 (1.1) 30.8%, 23.5% EEzzee iimmiibbee******** All eze imibe g oups n= 8893 2 (2.2) 36.6%, 26.7% Eze imibemono he apy n= 2112 1 (1.1) 24.1%, 16.6% Eze imibe add-on o a s a in n= 2044 3 (3.4) 39.4%, 25.5% Fixed eze imibe-sim as a in combina ion n= 5145 3 (3.3) 38.5%, 27.5% *This able con ains pa ien s wi h s a in he apy only he e o e pa ien s wi h Eze imibemono he apy a e no lis ed he e. 61,073 pa ien s s a ed hei he apy in 2009 Q1 pe iod and hei da a was no compa ed o he pa ien s s a ed in 2007 o 2008 because o he much sho e ollow up ime. **Some ini ial he apies a e no lis ed he e, eg. lu as a in, p a as a in because hei impo ance is qui e low in Hunga y. In he ac i e sub- s ance le el (eg. sim as a in) he numbe o pa ien s migh be less han in he s eng h le el (eg. sim as a in 10 mg, 20 mg, 40 mg). I is possible ha a pa ien daily dosage is 1 pill du ing he ini ial sim as a in 10 mg he apy so he/she is isible in he able. He/she may swi ch o sim as a in 20 mg and du ing he he apy may ha e less o mo e han one pill dosage. In his case he/she is excluded om he examina ion in he ac i e sub- s ance le el. ***The Na ional Heal h Insu ance Found doesn' p o ide da a o g oups whe e he numbe o pa ien s is less han 10. In he able o age g oups 15 pa ien s ha e been dele ed o ha eason because he o iginal da a was mo e de ailed (age + agen ). ****Eze imibe add-on and ixed Eze imibe he apy is possible o he same pa ien i he/she swi ches om add-on he apy o ixed combina ion he apy. TTaabbllee II..G oupings o pa ien s by he apy, age, and geog aphic loca ion, wi h numbe s, median mon hs o pe sis - ence, and pe sis ence pe cen ages a 6 and 12 mon hs A ch Med Sci 3, June / 2013 413 Pe sis ence wi h s a in he apy in Hunga y inally 80 mg, which had a pe sis ence conside ably lowe han ha o he lowe doses. The pe sis ence o ini ial he apies inc eased as he age o pa ien s inc eased (Table I, Figu e 4). A 6 mon hs, pe sis ence was 1% o he < 20-yea age g oup and 30.8% o he ≥70-yea age g oup, an app oxima e 30% di e ence be ween he younges and oldes age g oups. The median pe sis ence o all age g oups was 1 mon h; he di e ences we e s a is ically signi ican (p < 0.001). Pe sis ence da a o di e en eze imibe egimens a e shown in Table I and Figu e 5. The median pe - sis ence wi h eze imibe mono he apy was 1 mon h and ha o eze imibe added o s a in o o ixed eze imibe-s a in combina ion he apy was 3 mon hs. The e was no s a is ically signi ican di e ence be ween he add-on and ixed combina ion egimens (p = 0.94). Pe sis ence wi h all eze imibe he apies (median 2 mon hs) was g ea e han o sim as a in and a o as a in he apies (Table I and Figu e 6). Discussion This is he i s s udy, o ou knowledge, o de - ailed pe sis ence pa e ns wi h s a in he apy 100 90 80 70 60 50 40 30 20 10 0 FFiigguu ee 11..Kaplan-Meie plo o o al s a in pe sis ence TToo aall ss aa iinn ppee ssiiss eennccee [[%%]] 012345678910 11 12 13 14 15 16 17 18 19 TTiimmee [[mmoonn hh]] 100 90 80 70 60 50 40 30 20 10 0 FFiigguu ee 22..Kaplan-Meie plo o pe sis ence o di e - en sim as a in doses PPee ssiiss eennccee [[%%]] 012345678910 11 12 13 14 15 16 17 18 19 20 TTiimmee [[mmoonn hh]] Sim as a in 10 mg Sim as a in 20 mg Sim as a in 40 mg 100 90 80 70 60 50 40 30 20 10 0 FFiigguu ee 33.. Kaplan-Meie plo o pe sis ence o di e - en a o as a in doses PPee ssiiss eennccee [[%%]] 012345678910 11 12 13 14 15 16 17 18 19 20 TTiimmee [[mmoonn hh]] A o as a in 10 mg A o as a in 20 mg A o as a in 40 mg A o as a in 80 mg 100 90 80 70 60 50 40 30 20 10 0 FFiigguu ee 44..Kaplan-Meie plo o pe sis ence o di - e en age coho s PPee ssiiss eennccee [[%%]] 012345678910 11 12 13 14 15 16 17 18 19 20 TTiimmee [[mmoonn hh]] Age < 20 20 ≤Age < 30 30 ≤Age < 40 40 ≤Age < 50 50 ≤Age < 60 60 ≤Age < 70 70 ≤Age 100 90 80 70 60 50 40 30 20 10 0 FFiigguu ee 55..Kaplan-Meie plo o pe sis ence o eze- imibe as mono he apy, add-on o a s a in, and eze- imibe-s a in ixed combina ion PPee ssiiss eennccee [[%%]] 012345678910 11 12 13 14 15 16 17 18 19 20 TTiimmee [[mmoonn hh]] Mono EZT Add-on EZT Inegy 100 90 80 70 60 50 40 30 20 10 0 FFiigguu ee 66..Kaplan-Meie plo o o al eze imibe and o al s a in pe sis ence PPee ssiiss eennccee [[%%]] 0123456789 11 13 15 17 19 21 23 25 27 TTiimmee [[mmoonn hh]] Eze imib S a in 414 A ch Med Sci 3, June / 2013 Zol an Kiss, Laszlo Nagy, Is an Reibe , Gyö gy Pa agh, Ma k Pe e Molna , Gyö gy Rokszin, Zsol Abonyi-To h, Laszlo Ma k among Hunga ian pa ien s. We de e mined ha , when pe sis ence was based on a 60-day g ace pe i- od, he pe cen age o pa ien s who pe sis ed wi h he apy was only 46% a e 1 mon h, 40.3% a e 2 mon hs, 27% a e 6 mon hs, and 20.1% a e 12 mon hs. Almos 80% o pa ien s had discon inued he apy du ing he i s yea . When pe sis ence was based on a mo e lenien g ace pe iod o 180 days, pe sis ence a e 12 mon hs was inc eased only om 20.1% o 27%. These esul s indica e ha , because o ea ly discon inua ion, a conside able p opo ion o Hunga ian pa ien s do no expe ience ad an ages o s a in he apy. Se e al s udies ha e shown ha he du a ion o s a in he apy can be a majo ac o in de e mining he apeu ic bene i ; he apy ha is no su icien ly pe sis en may p o ide no signi i- can ca diop o ec ion [14, 15]. Con a y o ou expec a ion, pe sis ence wi h s a in he apy in Hunga y was no as g ea as in de eloped coun ies. Compa ed wi h he 1-mon h median pe sis ence we ound, Kamal-Bahl e al., using less s ic c i e ia han he cu en s udy o de e mining discon inua ion, ound a median pe - sis ence o 27.5 mon hs in he Uni ed S a es (US) [27]. In ano he US s udy, Foody e al. used discon- inua ion c i e ia simila o his s udy, and ound 12-mon h pe sis ence o a o as a in in p ima y p e en ion o be abou 40%, nea ly wice as high as ou inding o 20.9%; o sim as a in, hey ound 12-mon h pe sis ence o be abou 30%, compa ed o 20.5% o ou pa ien s [28]. La sen e al., using a 30-day g ace pe iod, ound ha only 11.2% o Dan- ish pa ien s d opped ou o he apy a e 1 mon h [29], compa ed wi h 54% o Hunga ian pa ien s. The Man el-Teeuwisse e al. s udy in he Ne he - lands showed signi ican ly be e 1-yea pe sis ence han in ou s udy: 61.5% s. 20.1% [30]. Pe sis ence a es highe han hose in ou s udy we e also obse ed by Pe eaul e al. in Quebec [31], Helin- Salmi aa a e al. in Finland [32], Deamb osis e al. in I aly [33], and Chodick e al. in Is ael [34]. Howe e , ou s udy is no he only one o ha e ound a disappoin ingly apid d op in d ug usage a e ini ia ion o he apy o p ima y o seconda y p e en ion o ch onic condi ions. In se e al la ge, e ospec i e coho s udies o s a in use in he US and Canada, he g ea es decline in pe sis ence occu ed du ing he i s 3-6 mon hs o ea men , wi h 25% o almos 50% o pa ien s discon inuing s a ins wi hin 6 mon hs o s a ing he apy [35]. In a No h Ame ican coho s udy o elde ly pa ien s (65 yea s o olde ), almos 15% o he coho dis- con inued lipid-lowe ing he apy a e hei ini ial p esc ip ion ill, and mo e han one- hi d o pa ien s discon inued ea men wi hin 1 yea [36]. The s udy by Chodick e al. in Is ael ound ha nea ly one- hi d o he p ima y-p e en ion coho and one- qua e o he seconda y-p e en ion coho dis- con inued s a in ea men a e only one p e- sc ip ion ill [34]. These obse a ions a e consis en wi h he heal h belie model, acco ding o which he likelihood o adhe ence o a medica ion egi- men is de e mined by he pe cei ed h ea o dis- ease (suscep ibili y and se e i y) and pe cei ed ben- e i s o he apy [37]. Gi en ha hype lipidemia is an asymp oma ic disease un il a ca dio ascula e en occu s, he pe cei ed h ea o disease and bene i s o lipid-lowe ing he apy may no be an- gible o many pa ien s, comp omising adhe ence and pe sis ence. Ou s udy included ai ly adhe en pa ien s, by es ic ing da a analyses o pa ien s who we e ak- ing 0.75-1.25 imes he numbe o able s p esc ibed o hem. We could no de e mine whe he pa ien s who ook wice as long as hey should ha e o ob ain a enewal p esc ip ion we e cu ing hei able s in hal and we e egula ly aking hal hei p esc ibed dose daily o we e aking a ull able e e y o he day. Resul s we e a ec ed o a non-sig- ni ican ex en (by 8% o 17%) by elimina ing om he analysis he da a om hose pa ien s who e illed p esc ip ions egula ly bu less equen ly (< 0.75) o mo e equen ly (> 1.25) han called o by hei p esc ip ion. Medica ion adhe ence and pe sis ence a e in e - ela ed, and bo h impac clinical ou comes o ea - men [12]. Wisniowska and Skow on in Poland ound pe sis ence wi h s a in he apy o be 160 days o highly adhe en (≥80%) pa ien s and 90 days o poo ly adhe en (< 80%) pa ien s [38]. The di e - ence in ou s udy be ween 1-yea pe sis ence based on 60- and 180-day g ace pe iods indica es ha ewe han 7% o pa ien s who we e non-adhe en o a 60-day g ace pe iod esumed he apy du ing he subsequen 120 days. A ecen sys ema ic e iew o 19 s udies exam- ining he ela ionship be ween adhe ence o pe - sis ence o s a in he apy and clinical ou comes indica ed ha high le els o adhe ence and longe du a ions o pe sis ence wi h s a ins a e associa - ed wi h p og essi ely inc easing clinical bene i s in p ima y and seconda y p e en ion popula ions, including signi ican educ ions in all-cause mo - ali y (OR 0.49-0.66), a al and non a al co ona y hea disease e en s (OR 0.74-0.83), and hospi al- iza ions (OR 0.19-0.70) [15]. A ecen compa a i e cos -e ec i eness analysis de e mined ha bo h eminde s/educa ional ma e ials and pha ma- cis /nu se managemen p og ams we e cos -e ec- i e in e en ions o imp o e adhe ence wi h CVD medica ions associa ed wi h inc emen al cos -e ec- i eness a ios (ICER) o $4984 and $6358 pe qual- i y-adjus ed li e-yea (QALY) gained, espec i ely [39]. Acco ding o a Wo ld Heal h O ganiza ion epo on medica ion adhe ence o long- e m he - apies, “Inc easing he e ec i eness o adhe ence A ch Med Sci 3, June / 2013 415 Pe sis ence wi h s a in he apy in Hunga y in e en ions may ha e a a g ea e impac on he heal h o he popula ion han any imp o emen in speci ic medical ea men s” [40]. The inc eased pe sis ence obse ed in ou s udy when compa ing he apy begun in 2008 wi h ha begun in 2007 was no ma kedly imp o ed, bu may signal a end owa d con inuing imp o emen o e ime. We ound ha discon inua ion o he apy de - c eased wi h inc easing age; olde pa ien s ended o be mo e adhe en o physicians’ ins uc ions. In he six h mon h o he apy, he e was app oxi- ma ely a 30% di e ence in median pe sis ence be ween he younges and oldes age g oups. Al - hough his di e ence was s a is ically signi ican (p < 0.001), he median pe sis ence o all g oups was only 1 mon h. One mon h was also he medi- an pe sis ence o he o al s a in g oup and he g oups o use s o indi idual s a ins (o he han osu as a in, which had a median pe sis ence o 2 mon hs). Thus, he pe cen o pa ien s d opping ou o he apy ea ly is conside able o all age and he apy g oups, ega dless o any s a in swi ching o dose changing ha may ha e aken place. The causes o he discon inua ion we e no s udied. On eason migh be ha he s a in induced muscle complain s, he equency o which in obse a ion s udies could be 5-10% [41]. In a p ospec i e coho s udy in es iga ing he e ec o physical ac i i y and s a ins conduc ed on mo e han 10 000 pa ien s du ing a 10-yea ollow-up he mo ali y isk was si gni ican ly be e in people aking s a ins han in hose no aking s a ins (18.5% s. 27.7%) (p < 0.0001). In pa ien s who ook s a ins, mo al- i y isk dec eased as i ness inc eased (a simila end be ween i ness and mo ali y was obse ed in pa ien s wi hou s a ins) [42]. O he s udies ha e yielded con lic ing esul s ega ding associa ion o pe sis ence wi h age. Se - e al ound, as ha e we, ha pe sis ence imp o es wi h inc easing pa ien age (up o a ce ain ‘ h esh- old’ in some cases [e.g., 55-64 yea s o age], beyond which pe sis ence declines) [30, 43, 44], while o h- e s ound olde age o be a p edic o o poo long- e m pe sis ence [28, 36]. The median pe sis ence wi h combined eze im- ibe and s a in he apy – whe he eze imibe was added on o a s a in o was p esc ibed as an eze- imibe-s a in ixed combina ion – was 3 mon hs, which was longe han he 1-mon h pe sis ence wi h o al s a in he apy. G ea e pe sis ence wi h combina ion eze imibe and s a in he apy han wi h o al s a in he apy was obse ed h ough a ull yea : 25.5% wi h eze imibe add-on he apy and 27.5% wi h ixed-combina ion he apy compa ed o 20.1% a 12 mon hs o o al s a in pe sis ence. Based on he Hunga ian subsidy sys em, we we e able o conside ea men s con aining eze- imibe p esc ibed o pa ien s wi h CVD as sec- onda y p e en ion ea men s. We could no de e - mine whe he s a in mono he apy was used o p i- ma y o seconda y p e en ion, o he han o a o as a in 80-mg he apy, which, in Hunga y, is subsidized only o seconda y p e en ion. Se e al g oups o in es iga o s ha e epo ed ha pa ien s ecei ing seconda y-p e en ion he apy we e mo e adhe en o hei d ug egimen han hose ecei - ing p ima y-p e en ion he apy, possibly due o an inc eased app ecia ion o he impo ance o man- aging hei isk ac o s) [33, 43, 44]. Kamal-Bahl e al. s udied a US popula ion wi h p i a e heal h insu ance and ound ha , using a 180-day g ace pe iod, pe sis ence a e 1 yea was g ea e o s a in use s (71.1%) han o eze imibe use s (67%) [27]. These in es iga o s did no spec- i y whe he he apy was used o p ima y o sec- onda y p e en ion. The e is a limi a ion o his in es iga ion in ha we s udied only hose p esc ip ions ha we e sub- sidized by he Na ional Heal h Insu ance Fund. Undoub edly he e we e pa ien s who we e pe - sis en wi h s a in he apy bu we e unknown o us because hey we e able o con inue aking a d ug o longe han he 60-day g ace pe iod wi hou applying o a und subsidy. These pa ien s may ha e ecei ed he d ug while in he hospi al, been discha ged om he hospi al wi h a supply o he d ug, used d ugs le o e om a ela i e’s o iend’s supply, o ecei ed samples o d ugs. We did no assess p opo ions o pa ien s mak- ing and keeping appoin men s o ollow-up lipid es s and physician isi s, ac o s which can impac adhe ence o he apy. In a la ge coho s udy, Ben- ne e al. demons a ed ha pa ien s who ecei ed ollow-up physician isi s and lipid es s we e 45% mo e likely o be adhe en (95% CI 1.34-1.55) o lipid- lowe ing he apy [45]. In conclusion, we can s a e ha he low a e o pe sis ence wi h s a in he apy ha we obse ed in Hunga y is likely associa ed wi h occu ence o ca dio ascula e en s o dea hs ha o he wise migh ha e been p e en ed by app op ia ely long- e m con inua ion o s a in he apy. These da a a e consis en wi h a likely inancial d ain on na ional esou ces used o subsidize subop imal s a in he - apy, wi h insu icien yields o heal h imp o emen in he Hunga ian popula ion. Pe sis ence wi h lipid- lowe ing he apy among Hunga ian pa ien s needs o be inc eased. The key o imp o emen is he pa ien -physician ela ion. E e y ime a pa ien mee s a heal h ca e p o essional he a en ion o he impo ance o aking he pills p ope ly has o be d awn up. The possible side e ec s mus be dis- cussed in de ail. The pa ien s’ mo i a ion could be inc eased by explaining he ole o choles e ol in he p e en ion o a he oscle osis. 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