Cholesterolio koncentracijos kraujyje mažinimas: įrodymais pagrįstos rekomendacijos

Cholesterolio koncentracijos kraujyje mažinimas: įrodymais pagrįstos rekomendacijos

Šiandien tiek gydytojams, tiek pacientams dislipidemijos gydymas kelia nemažai klausimų. Remdamiesi naujausių mokslinių tyrimų duomenimis, dislipidemijai gydyti jau galime pasitelkti net 3 įrodymais pagrįstas gydymo priemones. Kas dieną paskelbiami klinikinių tyrimų rezultatai, o diagnostikos ir gydymo gairės, kuriomis esame pratę vadovautis, neišvengiamai atsilieka ir pateikia ne visuomet naujausią informaciją. Nepaisant to, gydytojas praktikas privalo priimti racionalius ir optimalius sprendimus, gydydamas į jį besikreipiantį pacientą.

Šiame straipsnyje apžvelgiami naujausių mokslinių straipsnių rezultatai ir siekiama pateikti racionalaus dislipidemijos gydymo rekomendacijas.

2013 metais Amerikos kardiologų kolegija / Amerikos širdies asociacija (AKK / AŠA) paskelbė cholesterolio koncentracijos kraujyje mažinimo suaugusiesiems rekomendacijas (1). Tuo metu tik gydymas statinų grupei priklausančiais preparatais buvo pagrįstas geros kokybės mokslinių tyrimų išvadomis. Vėlesnių mokslinių tyrimų duomenys AKK / AŠA rekomendacijose nurodytus teiginius dėl antrinės širdies ir kraujagyslių ligų prevencijos bei didelės rizikos širdies ir kraujagyslių ligai vystytis priskiriamų pacientų gydymo tik sustiprino. Paaiškėjo, kad statinais gydant 10 tūkst. pacientų per 5 metus sukeliamas 1 rabdomiolizės atvejis, 5 miopatijos, 75 nauji cukrinio diabeto atvejai bei 7 hemoraginiai insultai, tačiau net 1 tūkst. pacientų, jau sergančių širdies ir kraujagyslių liga, išvengia pakartotinio nepageidaujamo įvykio, o tarp didele širdies ir kraujagyslių ligų rizika pasižyminčių pacientų nepageidaujamų įvykių sumažėja net 500 (2). Nepaisant tvirtų įrodymų, statinų vartojimas pirminei ir antrinei prevencijai Jungtinėse Amerikos Valstijose (JAV) bei Europoje, ypač didele širdies ir kraujagyslių ligų rizika pasižyminčiose Rytų Europos valstybėse, yra suboptimalus arba net labai menkas. Svarbu pažymėti ir tai, kad šiuo metu nėra aiškių įrodymų ir rekomendacijų apie tam tikrų statinų efektyvumo ir saugumo ypatumus gydant specifines pacientų grupes (3).

Įvairios padidėjusio cholesterolio korekcijos rekomendacijos yra pateiktos atsižvelgiant į paciento širdies ir kraujagyslių ligų riziką. Svarbu suprasti, kad toks gydymo strategijų pateikimas jokiu būdu neatmeta lipidų teorijos kaip vienos pagrindinių aterogenezės grandžių. Parenkant gydymo strategiją pagal paciento širdies ir kraujagyslių ligų riziką, stengiamasi individualizuoti gydymą ir pritaikyti mokslinių tyrimų rezultatus kasdienėje klinikinėje praktikoje. Atliekant daugumą klinikinių tyrimų, buvo vertinamas medikamento pajėgumas pagerinti ligos baigtį, atsižvelgiant į konkretaus paciento riziką, kitaip tariant, buvo tiriamas ne medikamentų gebėjimas sumažinti cholesterolio koncentraciją kraujyje iki tam tikros ribos, o jų poveikis suvaldant širdies ir kraujagyslių ligų pasireiškimo ar progresavimo riziką. Be to, moksliniais tyrimais pavyko įrodyti, kad ne visi medikamentai, kurie iš pirmo žvilgsnio sėkmingai sumažino cholesterolio koncentraciją kraujyje, efektyviai pagerino pacientų ligos baigtis. Tikėtina, kad šie medikamentai buvo neefektyvūs dėl to, kad pasižymėjo ir neigiamu pleotropiniu poveikiu.

Vykdant antrinę prevenciją, šiuo metu jau galima pasitelkti ir kitas įrodymais pagrįstas gydymo priemones. Tyrimo IMPROVE-IT tyrimo rezultatai atskleidė, kad stabiliems ūminiu koronariniu sindromu persirgusiems pacientams, be  efektyvios statinų terapijos, paskyrus ezetimibą mažo tankio lipoproteinų (MTL) koncentracija sumažėja nuo 1,8 mmol/l iki 1,4 mmol/l, o 7 metų aterosklerozės paskatinto nepageidaujamo įvykio rizika sumažėja nuo 34,7 proc. iki 32,7 proc. (4). Tyrimas FOURIER įrodė, kad su efektyvia statinų terapija paskyrus ir evolokumabą (baltymų konvertazės PCSK9 inhibitorių) MTL koncentracija kraujyje sumažėja nuo 2,4 mmol/l iki 0,7 mmol/l, o bendroji širdies ir kraujagyslių nepageidaujamų įvykių riziką per 2,2 metų sumažėja nuo 11,3 proc. iki 9,8 proc., taigi pasiekiamas 15 proc. santykinės rizikos sumažėjimas (5). Svarbu pažymėti, kad tiriant abu medikamentus drauge buvo skiriamas ir gydymas statinais bei pasiektas gana neblogas MTL sumažėjimas dar iki pradedant tyrimą, o abiejų tyrimų dalyviams nustatyta didelė rizika.

Vis dėlto aprašyti nauji įrodymai turi keletą trūkumų. Nors reikšmingų saugumo problemų nei gydant ezetimibu, nei evolokumabu nenustatyta, kai kurie ekspertai vertina, kad jų pridėtinė nauda yra santykinai nedidelė. 2016 metais JAV maisto ir vaistų administracija nusprendė, kad tyrimo IMPROVE-IT rezultatų nepakanka norint praplėsti ezetimibo vartojimo indikacijas ir tarp jų įtraukti miokardo infarkto ir insulto rizikos mažinimą. Šiandien jau sukurtos generinės ezetimibo formos, o pats medikamentas yra prieinamas ir nebrangus. Tuo tarpu evolokumabas yra gana brangus vaistinis preparatas, o apie jo pridėtinę naudą vis dar nemažai diskutuojama. Iki šiol evolokumabo ir statino derinys nėra lygintas su ezetimibo ir statino deriniu, nors šiandienos kontekste tai veikiausiai būtų tinkamiausias palyginamasis tyrimas. Vis dėlto abu medikamentai daugumai pacientų šiandien išlieka antro arba net trečio pasirinkimo gydymo priemonės. Tuo tarpu gydytojai praktikai su nekantrumu laukia šiuo metu tiriamų medikamentų, tokių kaip alirokumabas, anacetrapibas, ikosapento etilis ir su RNR sąveikaujančios medžiagos, klinikinių tyrimų rezultatų, kurie parodys, ar naujieji vaistiniai preparatai papildys įrodymais pagrįstų medikamentų, skirtų dislipidemijai gydyti, grupę.

Naujausių tyrimų duomenimis, dislipidemijos gydymas niacinu yra neefektyvus. Klinikinis tyrimas HPS2-THRIVE, į kurį įtraukti 25 673 aterosklerozine širdies ir kraujagyslių liga sergantys ir didele rizika pasižymintys pacientai, atskleidė, kad gydant prailginto veikimo niacinu ir laropiprantu (naudojamas niacino sukeltam raudoniui slopinti) drauge su efektyvia statinų terapija nepasiekiama jokios klinikinės naudos (6). Šis derinys net padidino nepageidaujamų įvykių dažnį, sumažino sergančiųjų gyvenimo kokybę ir padidino gydymo išlaidas (6).

Skiriant cholesterolio koncentraciją kraujyje mažinantį gydymą širdies ir kraujagyslių liga nesergantiems pacientams, siekiant užtikrinti optimalią pirminę prevenciją, tenka priimti individualizuotą sprendimą ir į kiekvieną pacientą pažvelgti visapusiškai. Cholesterolio koncentraciją kraujyje mažinančios priemonės šiems pacientams turėtų būti parenkamos atsižvelgiant į kompleksinį širdies ir kraujagyslių ligų rizikos įvertinimą. Kuo didesne rizika pasižymintiems pacientams skiriamas cholesterolio koncentraciją kraujyje mažinantis gydymas, tuo geresni gydymo rezultatai pasiekiami. Tuo tarpu daug diskusijų kelia klausimas, kuris rizikos vertinimo įrankis tinkamiausias tam tikrai pacientų grupei. Moksliniuose tyrimuose nustatomas skirtumas tarp įvairių rizikos vertinimo skalių yra nedidelis. Šiandien jau aišku ir tai, kad beveik pusė simptomine aterosklerozine širdies ir kraujagyslių liga nesergančių pacientų, kuriems tradiciniais rizikos vertinimo įrankiais nustatoma didelė rizika, iš tiesų pasižymi gerokai mažesne rizika, o šiuos pacientus identifikuoti padeda vainikinių arterijų kalcio indekso įvertinimas (7).

Svarbu suprasti, kad priimant sprendimą dėl medikamentinės intervencijos labai svarbų vaidmenį atlieka ir pats pacientas, nes su gydymu susijusi rizika prisiimama iš karto pradėjus gydymą, o tikėtina nauda pasiekiama ateityje. Be to, labai skiriasi skirtingų pacientų požiūris į pirminę prevenciją: vieniems kartą per dieną vartojama tabletė reikšmingai pablogina gyvenimo kokybę, kitiems žinojimas, kad tokia elgsena gali padėti išsaugoti sveikatą ir gyvybę, atvirkščiai, leidžia jaustis, jog jie rūpinasi savo sveikata ir neigiamos įtakos gyvenimo kokybei ar savęs vertinimui neturi. Gydytojas, įtraukdamas pacientą į gydymo procesą, turi suteikti visą pacientui būtiną informaciją, supažindinti su galimomis gydymo alternatyvomis, taip pat su širdies kraujagyslių ligų rizikos vertinimo reikšme. Toks modelis įgalina pacientą aktyviai prisidėti prie jo paties gydymo.

Kyla klausimas, kaip šiandien turėtume gydyti dislipidemiją (1 pav.)? Gydant daugumą pacientų sprendimai priimami siekiant sumažinti riziką, o ne pasiekti tam tikras cholesterolio koncentracijos kraujyje vertes. Skiriant  įrodymais pagrįstą gydymą, sumažinama nepageidaujamų širdies ir kraujagyslių ligų riziką net ir tuomet, kai, atrodo, pradinės cholesterolio koncentracijų vertės ir taip yra gana nedidelės. Vadinasi, medikamentai, mažinantys cholesterolio koncentraciją kraujyje, skiriami širdies ir kraujagyslių ligų rizikai suvaldyti. Du žmonės gali pasirinkti visiškai skirtingas gydymo strategijas ir abu jie gali būti teisūs. Esminis gydytojo vaidmuo yra tinkamai ir nešališkai pateikti įrodymus, įvertinti riziką ir supažindinti su gydymo galimybėmis. Siekdami pagerinti pacientų gydymo kokybę, gydytojai turi skatinti bendradarbiavimą ir ne kurti mitus, o juos griauti.

 AŠKL – aterosklerozinė širdies ir kraujagyslių liga.

1 pav. Cholesterolio koncentraciją kraujyje mažinantis gydymas, kuriuo siekiama suvaldyti aterosklerozinės širdies ir kraujagyslių ligos riziką

 

  1. Įvertinkite paciento AŠKL riziką. Jei pacientui AŠKL nėra pasireiškusi jai būdingais simptomais, reikia įvertinti AŠKL riziką naudojant skaičiuokles ir (arba) išmatuoti vainikinių arterijų kalcio indeksą
  2. Paskatinkite pacientą gyventi sveikai (mesti rūkyti, sveikai maitintis, didinti kasdienį fizinį aktyvumą, pasiekti optimalų kūno svorį)
  3. Drauge padiskutuokite apie cholesterolio koncentraciją kraujyje mažinančių vaistų naudą, riziką ir kainą. Kuo didesnė AŠKL rizika, tuo didesnė ir įrodymais pagrįsto gydymo nauda.
  4. Jei pacientas pageidauja gydymo cholesterolio koncentraciją kraujyje mažinančiais vaistais, pasirinkite įrodymais pagrįstus vaistinius preparatus

(langelis 2` Prevention): Antrinė prevencija (kai jau diagnozuota AŠKL)

Pradedamas gydymas didelėmis statinų dozėmis, pavyzdžiui, atorvastatinu po 80–40 mg 1 k./d.

Jei pacientas pageidauja papildomo AŠKL rizikos mažinimo, svarbu aptarti tokio gydymo naudą, galimą žalą ir gydymo kainą. Skiriant įrodymais pagrįstą gydymą, tokiu atveju pirmiausia derėtų apsvarstyti gydymo ezetimibu galimybes, o tik tada įvertinti gydymo evolokumabu tikslingumą.

(langelis 1` Prevention): Pradedamas gydymas mažomis ar vidutinėmis statinų dozėmis, pavyzdžiui, pravastatinu po 20–40 mg 1 k./d. arba atorvastatinu po 10–20 mg 1 k./d.

Jei pacientas pageidauja, galima ir intensyvesnė gydymo strategija siekiant didesnio AŠKL rizikos sumažinimo

 

For mild to.… – Jei pasireiškia nesunkūs ar vidutinio sunkumo statinų netoleravimo reiškiniai, prieš nutraukiant medikamentinį gydymą statinais, reikėtų vieną statinų grupei priklausantį preparatą pabandyti pakeisti kitu

 

Discuss…– Su pacientu reikėtų aptarti pakartotinio cholesterolio koncentracijos kraujyje ištyrimo klausimą ir įvertinti jo bendradarbiavimą

 

  1. Periodiškai vertinkite AŠKL rizikos sumažinimo tikslus, gydymo toleranciją ir koreguokite gydymo planą

 

1 pav. vaizduojamas cholesterolio koncentraciją kraujyje mažinančio gydymo algoritmas, kurį klinikinėje praktikoje sėkmingai gali taikyti tiek gydytojas kardiologas, endokrinologas, nefrologas ar neurologas, tiek ir šeimos gydytojas. Teikiant sveikatos priežiūros paslaugas šiems pacientams, pirmiausia reikia įvertinti aterosklerozinės širdies ligos riziką, remiantis buvusiais įvykiais (kai jau žinoma, kad pacientas serga širdies ir kraujagyslių liga) arba rizikos vertinimo skaičiuoklėmis ir (arba) vainikinių arterijų kalcio indekso matavimu. Gydytojas turi paskatinti kiekvieną pacientą laikytis sveikos gyvensenos principų: mesti rūkyti, sveikai maitintis, didinti kasdienį fizinį aktyvumą, pasiekti optimalų kūno svorį. Kitas žingsnis konsultuojant tokius pacientus turėtų būti įrodymais pagrįstų medikamentinio gydymo alternatyvų aptarimas su pacientu. Svarbu aptarti tokio gydymo galimą naudą ir žalą, su gydymu susijusias išlaidas (kiek kainuoja medikamentai, ar jie kompensuojami), taip pat svarbu išsiaiškinti, kokią įtaką toks gydymas turės paciento gyvenimo kokybei. Vienas gydytojui keliamų uždavinių yra padėti pacientui suprasti, kodėl vienoks ar kitos gydymas jam yra naudingas ir kokie yra su šiuo gydymu susiję galimi pavojai. Jei pacientas priskiriamas didžiausiai rizikos grupei (į ją įeina ir visi pacientai, kuriems praeityje jau buvo diagnozuotas ūminis kardiovaskulinis įvykis), tikslinga gydyti didelėmis statinų dozėmis, pavyzdžiui, atorvastatinu po 80 mg 1 k./d. Toks gydymas šiems pacientams efektyviai ir gerokai sumažina riziką, o su gydymu susiję nepageidaujami reiškiniai nustatomi retai, pats gydymas yra nebrangus. Jei po rizikos vertinimo paaiškėja, kad pacientas priklauso mažesnei rizikos grupei, gydytojas turi paaiškinti, kad tokių asmenų gydymas statinais suteikia mažesnę naudą. Tiesa, nemažai daliai pacientų tikėtina nauda nusveria galimą žalą ir jie pasirenka tolesnį gydymą statinais. Tokiu atveju patariama pradėti gydymą mažesnėmis statinų dozėmis, pavyzdžiui, atorvastatino po 20 mg 1 k./d. Vėliau gydymą galima intensyvinti, atsižvelgiant į paciento norą pasiekti dar geresnį širdies ir kraujagyslių ligų rizikos sumažinimą. Gydant pacientus, kuriems jau buvo pasireiškęs ūminis kardiovaskulinis įvykis ir kurie pageidauja didesnio nei įprastinis rizikos sumažinimo, su statinu galima skirti ezetimibą, o jei gydymas juo negalimas arba yra neefektyvus, svarstytinas gydymo evolokumabu klausimas. Pasireiškus nesunkiems ar vidutinio sunkumo statinų netoleravimo reiškiniams, prieš pereinant prie statinams nepriskiriamų, tačiau įrodymais pagrįstų gydymo alternatyvų, reikėtų vieną statinų grupei priklausantį preparatą pabandyti pakeisti kitu. Jei pasireiškė sunkūs statinų netoleravimo reiškiniai, derėtų iš karto pereiti prie kitų įrodymais pagrįstų gydymo alternatyvų. Pakartotinai vertinant kraujo plazmos cholesterolio koncentraciją, galima daryti prielaidas apie tai, ar pacientas laikosi gydymo plano. Teikiant kokybišką paciento priežiūrą, svarbu periodiškai vertinti paciento poreikius, medikamentinio gydymo planą ir medikamentų toleranciją.

 

Gyd. Justas Simonavičius

Vilniaus universiteto ligoninės Santaros klinikos

 

Parengta pagal Krumholz HM. Treatment of Cholesterol in 2017. JAMA. 2017 Aug 1;318(5):417-418.

Literatūra:

  1. Stone NJ, Robinson JG, Lichtenstein AH, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol. 2014;63(25 pt B):2889-2934.
  1. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-2561.
  2. Green JB, Ross JS, Jackevicius CA, Shah ND, Krumholz HM. When choosing statin therapy. JAMA Intern Med. 2013;173(3):229-232
  3. Cannon CP, Blazing MA, Giugliano RP, et al. IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397
  4. Sabatine MS, Giugliano RP, Wiviott SD, et al. Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500-1509.
  5. Landray MJ, Haynes R, Hopewell JC, et al. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-212.
  6. Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association Cholesterol Management Guidelines. J Am Coll Cardiol. 2015;66(15):1657-1668.

Daugiau skaitykite leidinyje „Internistas“ Nr.9, 2017


407 mintys apie “Cholesterolio koncentracijos kraujyje mažinimas: įrodymais pagrįstos rekomendacijos

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