Aleksandar Knežević

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Uvodnik / EditorialSmjernice i medicina zasnovana na dokazimaGuidelines and evidence-based medicineAleksandar KneæeviÊ*OpÊa bolnica Zadar, Zadar, HrvatskaZadar General Hospital, Zadar, CroatiaThe issue 106 of the journal LijeËniËke novine (MedicalGazette) as of February 2012, contains the publicizedGuidelines for prescribing drugs which should be(though it has not been explicitly stated) followed by all pri-mary and secondary health care physicians, those who arethe members of the Croatian Medical Chamber (HLK).In this way we start a new and questionable practice wherethe HLK members commit themselves to follow the instruc-tions of one insurance company, to be more specific, theCroatian Institute for Health Insurance (HZZO), whose in-structions (called notes by the HZZO) for prescribing drugsfrom their Essential and Co-Pay Drug List have been ac-cepted by HLK as their own instructions, whereas the HLKdeclared them to be the guidelines, even though they arenot called guidelines by the HZZO. Although the HZZO isthe leading and in reality at the moment it is actually the onlyinsurance company which finances almost all of our phar-macotherapy, we wonder what will happen when a new in-surance company emerges on the market in the future im-posing their instructions for the use of drugs and whether theHLK will declare them to be the guidelines and whether theHLK will bind their members to follow such guidelines.The clinical guidelines represent the system of recommen-dations for conducting diagnostics, prevention and treat-ment not only in public health, but also in clinical medicine.Their main purpose is to facilitate a physician — a practitio-ner to use the findings from clinical trials emerging in an in-creasing number in the daily practice and good clinical prac-tices as well, which are jointly referred to as evidence-basedmedicine. They facilitate the enforcement of the higheststandards in the treatment and prevention, although theythemselves are not sufficient for that purpose without apply-ing some other measures that allow adequate availability ofdiagnostic and therapeutic procedures.Good clinical guidelines must be valid, reproducible, realis-tic, applicable in practice, flexible and clear. They must bebased on a multidisciplinary approach, they must promotethe most cost-effective procedures, have good referencesand as simple and understandable tabular and graphic pre-sentations as possible. The process of creation of the guide-lines must be transparent and we must clearly emphasizewhat in such guidelines is based on large controlled clinicalstudies, what is based on the registries and good clinicalpractice and what the experts’ consensus is.  In fact, thereare several systems for analyzing the importance of clinicalevidence and the level of recommendations derived fromsuch evidence.2012;7(5-6):143.Ubroju 106 LijeËniËkih novina iz veljaËe 2012. godineobjavljene su Smjernice za propisivanje lijekova kojihbi se (premda to izrijekom nije navedeno) trebali pridr-æavati svi lijeËnici primarne i sekundarne zdravstvene zaπti-te, a koji su Ëlanovi Hrvatske lijeËniËke komore (HLK).Pri tome se ulazi u jednu novu i upitnu praksu u kojoj se Ëla-novi HLK obvezuju dræati naputaka jedne osiguravajuÊe ku-Êe, u ovom sluËaju Hrvatskog zavoda za zdravstveno osi-guranje (HZZO), Ëije naputke (koje HZZO naziva napome-ne) za propisivanje lijekova s njihove Osnovne i Dopunskeliste lijekova je HLK prihvatila kao svoje te ih je proglasilasmjernicama, premda ih HZZO takvima ne naziva. Iako jeHZZO vodeÊa i u stvarnosti u ovom trenutku zapravo jedinaosiguravajuÊa kuÊa koja financira gotovo svu farmakoterapi-ju u nas, postavlja se pitanje πto Êe biti kad se u buduÊnostipojavi nova osiguravajuÊa kuÊa sa svojim naputcima za pri-mjenu lijekova i da li Êe ih tada HLK proglasiti svojim smjer-nicama te obvezivati svoje Ëlanove da ih se dræe.KliniËke smjernice predstavljaju sustav preporuka za provo-enje dijagnostike, prevencija i lijeËenja kako u javnomzdravstvu tako i u kliniËkoj medicini. Njihova glavna namjeraje olakπati lijeËniku praktiËaru uporabu u svakodnevnoj pra-ksi sve veÊeg broja spoznaja iz kliniËkih studija ali i dobre kli-niËke prakse, πto zajedno zovemo medicinom zasnovanomna dokazima. One omoguÊavaju provedbu najviπih standar-da u lijeËenju i prevenciji premda same po sebi, bez ostalihmjera primarno adekvatne dostupnosti dijagnostiËkih i tera-pijskih postupaka, nisu za to dostatne.Dobre kliniËke smjernice moraju biti: valjane, reproducibilne,realne, primjenjljive u praksi, fleksibilne, jasne. One morajubiti zasnovane na multidisciplinarnom pristupu, promoviratinajekonomiËniji postupke, imati dobre reference te πto jed-nostavnije i razumljivije tabliËne i grafiËke prikaze. Processtvaranja smjernica mora biti transparentan i treba jasno na-glasiti πto je u njima zasnovano na velikim kontroliranim kli-niËkim studijama, πto na registrima i dobroj kliniËkoj praksi,a πto je konsenzus struËnjaka. Pri tome postoji viπe sustavaza analizu jaËine kliniËkih dokaza te stupnja preporuka kojiiz njih proizlaze.Premda su smjernice najviπe zasnovane na dobrim kontroli-ranim kliniËkim ispitivanjima te πto ih viπe potkrepljuje jednutvrdnju to je veÊa razina dokaza i viπi stupanj preporuke,ipak taj pristup ima i odreene slabosti. Randomizirana klin-iËka ispitivanja se provode u relativno maloj i Ëesto nere-prezentativnoj populaciji (npr. strogo su definirani komorbi-diteti bolesnika, dodatna terapija, teæina bolesti itd.) koja neodgovara onim bolesnicima koje lijeËnici uobiËajeno susreÊutako da autori smjernica Ëesto ekstrapoliraju rezultate kliniË-Cardiologia CROATICAkih studija na opÊu populaciju koja zapravo Ëesto nije zastu-pljena u kliniËkim ispitivanjima. U postupku primjene rezulta-ta kliniËkih ispitivanja na preporuke za svakodnevnu praksurazliËiti eksperti Ëesto na osnovu istih rezultata izvode raz-liËite zakljuËke. Najbolji primjere za to su smjernice za lijeËe-nje arterijske hipertenzije gdje ameriËki autori kao prvi lijekpreporuËuju diuretik, engleski autori ACE inhibitor ili kalcijs-ki antagonist dok su kod europskih smjernica svi antihiper-tenzivi ravnopravni.Takoer treba uvijek imati na umu da su smjernice pisaneza prosjeËnog bolesnika, odnosno definiranu populaciju,dok lijeËnik Ëesto ispred sebe ima specifiËnog bolesnika sasvim njegovim posebnostima, Ëega su autori smjernica svje-sni i Ëesto su u njiima opisane situacije u kojima je moguÊeodstupiti od opÊih naËela koje propisuju smjerenice.Smjernice Europskog kardioloπkog druπtva, a koje su isto-vremeno i smjernice Hrvatskog kardioloπkog druπtva (HKD)predstavljaju primjer dobrih i transparentno uraenih smjer-nica utemeljenim na  medicini zasnovanoj na dokazima.Ako s njima usporedimo Smjernice HLK vidimo da one tonisu. Ako analiziramo poglavlje Smjernica iz djelatnosti kar-diologije (koja nas najviπe zanima) onda se preporuka zaprimjenu statina zasniva na vrijednosti ukupnog kolesterolakoji se u najnovijim HKD smjernicama praktiËno ne spominjeveÊ se  indikacija za primjenu i praÊenje uËinkovitosti hipo-lipemiËne terapije bazira na praÊenju LDL kolesterola, aukupni kolesterol se spominje samo ako mu je vrijednost ve-Êa od 8 mmol/L i kada je obavezna terapija. lipolipemikom.No, ako zanemarimo vrijednost LDL kolesterola onda se uSmjernicama HLK preporuka za primjenu statina u sekun-darnoj prevenciji moæe prihvatiti, dok je u primarnoj preven-ciji potpuno neprihvatljiva i neusklaena s recentnim smjer-nicama. Naime, preporuka se temelji samo na vrijednostiukupnog kolesterola koja nakon dijete od tri mjeseca morabiti >7 mmol/L da bi se zapoËela terapija. Pri tome se u pot-punosti zanemaruju ostali Ëimbenici kardiovaskularnogrizika izraæeni SCORE ljestvicom. Po toj smjernici primjericeæena stara 40 godina koja ima nizak kardiovaskularni riziktreba nepotrebno primati statin ako joj je kolesterol >7mmol/L. Istovremeno, osoba s visokim kardiovaskularnimrizikom, a s vrijednosti ukupnog kolesterola od npr. 6,5mmol/L ne smije primati statin premda mu je on prema svimdokazima apsolutno indiciran. Takoer je odrednica za pri-mjenu ezetimiba vezana samo za vrijednost ukupnog kole-sterola >6 mmol/L bez navoenja ukupnog kardiovasku-larnog rizika prema SCORE ljestvici πto je apsolutno nepri-hvatljivo.Temeljem svega navedenog smatram da je neprimjereno daHLK prepisuje naputke o primjeni lijekova jedne osigurava-juÊe kuÊe (makar tako vaæne i dominantne kao πto je HZZOu ovom trenutku u Hrvatskoj) i da ih proglaπava terapijskimsmjernicama bez transparentnog navoenja njihovog stva-ranja te da (πto je najviπe upitno) obvezuje Ëlanove HLK nanjihovu primjenu, a πto nijedne smjernice nemaju, jer su onepo definiciji skup preporuka koje lijeËnik prilagoava pojedi-nom bolesniku.Although the guidelines are mostly based on well-controlledclinical trials, and the more they are supported by evidence,the higher level of evidence and recommendations there is,anyway this approach shows certain disadvantages. Ran-domized clinical trials are conducted in a relatively small andoften non-representative population (e.g. patients’ comor-bidities, additional therapy, disease severity, etc. are strictlydefined) which does not include those patients that physi-cians normally deal with, so the authors of the guidelinesoften extrapolate the results of clinical trials to the generalpopulation, which in fact is not often represented in clinicaltrials. In the process of applying the results of clinical trialsto the recommendations for the daily practice, various ex-perts often reach different conclusions on the basis of thesame results. The best examples for this are the guidelinesfor the treatment of arterial hypertension, where the Ame-rican authors recommend diuretic as the first drug, whereasthe English authors recommend ACE inhibitor or calcium an-tagonist as the first drug, while the European guidelinestreat all the antihypertensive drugs equally. You should also always bear in mind that the guidelines arewritten for an average patient or a defined population, whilea physician often deals with a specific patient including all ofhis/her peculiarities, which the authors of the guidelines areaware of and the guidelines usually include the situationswhere we may deviate from the general principles prescri-bed by the guidelines. The guidelines of the European Society of Cardiology whichare also the guidelines of the Croatian Cardiac Society(HKD) is an example of well and transparently prepared gui-delines based on evidence-based medicine. If we compare the HLK guidelines with them, we shall con-clude that this is not applicable to them. If we analyze theCardiology guidelines section (which we are the most inter-ested in) then the recommendation for the use of statins isbased on the value of total cholesterol, which is in the latestHKD guidelines practically not mentioned, but the indicationfor the use and follow-up of efficiency of the hypolipemictherapy is based on the follow-up of LDL cholesterol, whilethe total cholesterol is mentioned only if the value is greaterthan 8 mmol/L and when the hypolipemic therapy is manda-tory. However, if we ignore the value of LDL cholesterol,then the HLK recommendation in the Guidelines for the useof statins in the secondary prevention is acceptable, while itis completely unacceptable and inconsistent with the recentguidelines in the primary prevention. The recommendationis based only on the value of total cholesterol which follow-ing the three months’ period of a diet must equal >7 mmol/Lin order to start with a therapy. In this way, the other cardio-vascular risk factors indicated in the SCORE scale are com-pletely ignored. According to this guideline, for example a 40year-old woman who has a low cardiovascular risk shouldunnecessary receive a statin if her cholesterol is >7 mmol/L.At the same time, a person with a high cardiovascular risk,having the value of total cholesterol of, for instance, 6.5mmol/L may not receive a statin even though it has beenabsolutely indicated for the patient based on the entire evi-dence. The determinant for using ezetimibe is also onlyrelated with the value of total cholesterol of >6 mmol/L with-out specifying the total cardiovascular risk according toSCORE scale, which is absolutely unacceptable.Based on what has been above mentioned, I find it inappro-priate for HLK to copy the  instructions on the application ofdrugs from one insurance company (regardless of how im-portant and dominant this insurance company may be,2012;7(5-6):144.Cardiologia CROATICA2012;7(5-6):145. Cardiologia CROATICAReceived: 8th Apr 2012*Address for correspondence:  OpÊa bolnica Zadar, Boæe PeriËiÊa 5, HR-23000Zadar, Croatia.Phone: +385-23-505-505E-mail: aleksandar.knezevic@zd.t-com.hr Literature1. Hrvatska lijeËniËka komora. Smjernice za propisavanje lijekova. LijeËniËke novine. 2012;12(106).2. Garber AM. Evidence - based guidelines as a foundation for performance incentives. Health Affairs. 2005;24:174-9.3. Clinical practice guidelines and healthcare decisions: credibility gaps and unfulfilled promises? Nat Clin Pract Oncol. 2005;2:480-1.4. EAS/ESC guidelines for the management of dyslipidemias. Eur Heart J. 2011;32: 1769-818.5. Reiner Æ. ©to novo donose prve smjernice o lijeËenju dislipidemija Europskog kardioloπkog druπtva i Europskog druπtva za aterosklerozu? Kardio list. 2011;6(9-10):119-124.6. ViteziÊ D, KneæeviÊ A. Smjernice u propisivanju lijekova u hipertenziji. U: FrancetiÊ I, ViteziÊ D ur. Osnove kliniËke farmakologije. Zagreb, Medicinska naklada 2007; 234-44.7. KneæeviÊ A, ViteziÊ D. Smjernice u propisivanju hipolipemiËkih lijekova. U: FrancetiÊ I, ViteziÊ D ur. Osnove kliniËke farmakologije. Zagreb, Medicinska naklada 2007;245-52.8. Reiner Æ, Boæikov B, Car N, KneæeviÊ A, KokiÊ S, Metelko Æ i sur. Preporuke Hrvatskih struËnih druπtava o lijeËenju makrovaskularnih i mikrovaskularnih komplikacija u bolesni-ka s metaboliËkim sindromom i πeÊernom bolesti tipa 2 - lijeËenje preostaloga kardiovaskularnog rizika. LijeËn Vjesn. 2009;131:1-3.which is HZZO at the moment in Croatia) and declare themto be the treatment guidelines, thereby not specifying thetransparency of their creation and to (which is the mostquestionable) bind the HLK members  to apply them, whichis not specified in any guidelines, as they are according totheir definition a set of recommendations that a physicianadapts to an individual patient.www.kardio-kongres2012.com

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