Pojavnost pljučne embolije in globoke venske tromboze v povezavi s farmakoterapijo hospitaliziranih kirurških bolnikov v Pomurju : doktorska disertacija

Kovačič, Alenka (avtor), Mrhar, Aleš (mentor), Petrovič, Danijel (komentor)

Venska tromboza ali venska trombembolija je pogosta bolezen, katere prevalenca je okoli 160/100.000 ljudi letno. Venska tromboza je nastanek strdka v globoki veni in se najpogosteje razvije v venah spodnjih udov (globoka venska tromboza), pljučna embolija pa je najpomembnejši zaplet nezdravljene akutne venske tromboze. Dejavniki tveganja za razvoj venske tromboze enako zvišujejo verjetnost pljučne embolije. Do venske tromboze najpogosteje vodijo spremembe v pretoku krvi ali sestavi krvi in poškodba žilnega endotelija. Dejavniki tveganja za razvoj venske tromboze pri kirurških bolnikih so številni, najpomembnejši in največkrat navedeni so predvsem vrsta operacije, trajanje hospitalizacije, zgodovina predhodne venske tromboze ali onkološke bolezni, nepokretnost, sepsa, prisotnost centralnega venskega katetra, nosečnost ali obdobje dojenja in podedovana ali pridobljena hiperkoagulabilna stanja. Pri hospitaliziranih bolnikih je zato potrebna ustrezna tromboprofilaksa za zaščito pred globoko vensko trombozo in pljučno embolijo. Še posebej je potrebna previdnost in ustrezna tromboprofilaksa pri bolnikih, ki imajo več dejavnikov tveganja in pri bolnikih, ki so izpostavljeni večjim operacijam. Bolniki zato prejmejo profilaktične odmerke nizkomolekularnih heparinov. Za kirurške bolnike se priporoča tromboprofilaksa glede na tveganje bolnika. Znano je, da nekatera zdravila lahko vplivajo na spremembe v sestavi ali pretoku krvi. Zdravila iz krvi kot so sestavni deli plazme, lahko vplivajo na povečano tveganje za vensko trombozo. Prav tako glede na mehanizem delovanja ali součinkovanja lahko povečajo tveganje za vensko trombozo peroralni kontraceptivi, antipsihotiki, nesteroidni antirevmatiki. Bolniki, ki so hospitalizirani na kirurških oddelkih zaradi poškodbe, imajo dvakrat pogosteje izražene neželene učinke zdravil. Pri bolnikih s polifarmakoterapijo, ki prejemajo osem ali več zdravil hkrati, je verjetnost za nastanek potencialnih interakcij med zdravili velika. Ne glede na starost bolnika, je ob uporabi več zdravil hkrati večja verjetnost za neželene učinke zdravljenja z zdravili in za hospitalizacije zaradi zdravil. Vsekakor pa je težko izločiti sočasne dejavnike tveganja pri ugotavljanju vpliva polifarmakoterapije na končne klinične izide v opazovalnih študijah. Optimizacija terapije z zdravili je zato osnovni del ustreznega zdravljenja bolnika. Povezava med polifarmakoterapijo, interakcijami med zdravili in pojavnostjo globoke venske tromboze ali pljučne embolije še ni bila dokazana. Namen doktorske naloge je bil oceniti vpliv ustreznosti tromboprofilakse pri kirurških bolnikih na postoperativno pojavnost globoke venske tromboze in pljučne embolije ter oceniti pojavnost globoke venske tromboze in pljučne embolije v povezavi s krvnimi pripravki, številom zdravil, interakcijami med njimi ter vrsto zdravil, ki jih bolniki prejemajo. V prvem delu doktorske disertacije smo z retrospektivno raziskavo primera s kontrolo pregledali ustreznost tromboprofilakse glede na smernice zdravljenja pri kirurških bolnikih in posledično vpliv na pojavnost globoke venske tromboze in pljučne embolije. Raziskavo smo izvedli v Splošni bolnišnici Murska Sobota, kjer smo vključili vse bolnike, ki so bili hospitalizirani na kirurškem oddelku v Splošni bolnišnici Murska Sobota od 1. 1. 2007 do 31. 12. 2011, ki so imeli kot glavno ali kot spremljevalno diagnozo »pljučna embolija« ali »globoka venska tromboza« in ki so imeli pljučno embolijo ali globoko vensko trombozo diagnosticirano prvič. Iz bolnišničnega programa smo najprej poiskali vse bolnike z diagnozo »pljučna embolija« ali »globoka venska tromboza«. Nato smo pregledali, kateri od teh bolnikov so imeli to diagnozo diagnosticirano prvič in so bili hkrati v zadnjih 180 dneh hospitalizirani na kirurškem oddelku. Pregledali smo, kakšen kirurški poseg so imeli. To je bila skupina primerov. Nato smo izbrali enako število bolnikov, ki so bili v istem obdobju hospitalizirani na kirurškem oddelku in so imeli podoben kirurški poseg, niso pa imeli v naslednjih 180 dneh diagnosticirane pljučne embolije ali globoke venske tromboze. To je bila kontrolna skupina. Po trenutno veljavnih smernicah za tromboprofilakso pri kirurških bolnikih smo s pomočjo Caprini modela bolnike razvrstili v ustrezne razrede tveganja za pojav venske tromboembolije in pregledali ustreznost tromboprofilakse. V kontrolni skupini je 77 % bolnikov prejemalo terapijo za preprečevanje venske trombembolije v skladu s smernicami, medtem ko je ta delež v skupini primerov znašal 56 %. Med skupinama smo s pomočjo statističnega testa hi kvadrat dokazali značilno razliko med prejemanjem ustrezne tromboprofilakse (p < 0,05). Dokazali smo, da je verjetnost za pojav venske trombembolije (globoke venske tromboze ali pljučne embolije) večja, če preventivna terapija za preprečevanje venske trombembolije ni v skladu s smernicami. Članek iz tega dela rezultatov smo objavili v reviji Zdravniški vestnik. Drugo retrospektivno raziskavo primera s kontrolo smo izvedli pri istih bolnikih, pri katerih smo poleg ustreznosti tromboprofilakse pregledali tudi porabo krvnih pripravkov in vitamina K pri vsakem posameznem bolniku v preoperativnem obdobju v obeh skupinah. Skupino primerov smo ločili glede na vrsto zapleta, na skupino ki je razvila globoko vensko trombozo in na skupino, ki je razvila pljučno embolijo. Zato smo uporabili statistično metodo multivariabilne multinomialne logistične regresije, s katero smo vpliv dejavnikov tveganja ločeno opredelili za skupino bolnikov z globoko vensko trombozo in skupino bolnikov s pljučno embolijo. Dokazali smo, da je zdravljenje s koncentriranimi eritrociti povezano s statistično značilnim večjim tveganjem za pojav pljučne embolije [OR 4,589 (95 % CI: 1,689-12,471), p < 0,05], ne pa tudi za pojav globoke venske tromboze. Pri zdravljenju s sveže zamrznjeno plazmo nismo uspeli dokazati razlike med kontrolno skupino in skupino bolnikov z globoko vensko trombozo ali pljučno embolijo. Razlog je bil najverjetneje premajhen vzorec, saj je bila sveže zamrznjena plazma aplicirana le 2 bolnikoma v skupini z globoko vensko trombozo (4 %), 10 bolnikom v skupini s pljučno embolijo (11 %) in 5 bolnikom (3,5 %) v kontrolni skupini. Vitamin K je prejelo le 6 bolnikov v skupini s pljučno embolijo, nobeden bolnik v skupini z globoko vensko trombozo in 5 bolnikov v kontrolni skupini. Razlika ni bila statistično značilna. Zaključili smo, da je zdravljenje s koncentrirnimi eritrociti povezano s pojavnostjo postoperativne pljučne embolije pri kirurških bolnikih. Zato bi bilo potrebno bolnike, ki tekom zdravljenja prejmejo koncentrirane eritrocite, bolj previdno spremljati v pooperativnem obdobju, saj je pri njih večje tveganje za razvoj pljučne embolije. Članek iz tega dela rezultatov smo objavili v reviji Clinical and Applied Thrombosis/Hemostasis. V tretjem delu raziskave smo se osredotočili na povezavo med posameznimi skupinami zdravil, interakcije zdravil in polifarmakoterapijo ter pojavnostjo globoke venske tromboze ali pljučne embolije pri kirurških bolnikih. Pregledali smo število zdravilnih učinkovin, ki so jih prejemali bolniki in interakcije med zdravili s pomočjo programa Lexi-Comp®. V medicinski dokumentaciji smo pregledali tudi zapise, ki so bili na voljo in bi lahko nakazovali na neželene učinke zdravil, ki so jih bolniki prejemali. Dosegljivi so bili večinoma le laboratorijski izvidi (hiponatriemija, trombocitopenija, trombocitoza). Pregledali smo uporabo nesteroidnih protivnetnih zdravil, tramadola, paracetamola, peroralnih kontraceptivov, antipsihotikov, anksiolitikov, antidepresivov ter diuretikov. V model smo vključili tudi ustreznost tromboprofilakse in uporabo koncentriranih eritrocitov. Če je bolnik prejemal 8 ali več zdravil hkrati, smo označili, da gre pri bolniku za polifarmakoterapijo. Vpliv dejavnikov tveganja za razvoj globoke venske tromboze ali pljučne embolije smo ocenili z uporabo multivariabilne logistične regresije. Dokazali smo statistično pomembno razliko med skupino primerov in kontrolno skupino (p < 0,05) glede na polifarmakoterapijo, ki je bila povezana z večjo verjetnostjo za nastanek globoke venske tromboze ali pljučne embolije [OR 2,021 (95 % CI: 1,032-3,957)]. Spremljali smo tudi dodatne diagnoze (atrijska fibrilacija, srčno popuščanje ali druge kardiovaskularne bolezni) pri bolnikih in jih vključili v regresijski model. Pri pregledu interakcij med zdravili pri bolnikih nismo potrdili razlik med skupino primerov in kontrolno skupino. V skupini primerov smo zaznali eno farmakokinetično interakcijo tipa X med zdravili, ki je opisana kot večja verjetnost za trombembolični zaplet (esomeprazol – klopidogrel) in 12 farmakokinetičnih interakcij tipa D med zdravili, ki lahko povečajo tveganje za trombembolične zaplete. V skupini primerov smo zaznali tudi 23 potencialnih interakcij tipa D med zdravili, kjer je opisana večja verjetnost krvavitev. Večina teh interakcij so bile farmakodinamične interakcije (npr. kombinacija nesteroidnih protivnetnih zdravil in inhibitorjev ponovnega privzema serotonina). V kontrolni skupini ni bilo nobene potencialne interakcije tipa X ali D, ki bi bile opisane oz. katerih posedica bi lahko bila večja verjetnost trombemboličnih dogodkov. V kontrolni skupini je bilo zaznanih le 5 potencialnih interakcij tipa D, pri katerih je bila opisana večja verjetnost krvavitev. Glede na rezultate v naši raziskavi lahko predpostavimo, da so potencialne interakcije med zdravili, katerih posledica je vpliv na povečano verjetnost trombemboličnih dogodkov, klinično bolj pomembne od potencialnih interakcij, ki imajo vpliv na večjo verjetnost krvavitev. Glede na univariantno analizo (test hi kvadrat) ni bilo statistično pomembih razlik med skupino primerov in kontrolno skupino pri bolnikih, ki so prejemali nesteroidne antirevmatike, antipsihotike, uspavala, antidepresive, metamizol ali tramadol in paracetamol, zato jih nismo vključili kot faktorje v model multivariabilne logistične regresije. V tej raziskavi je bila v univariantni analizi razlika med skupino primerov in kontrolno skupino (p = 0,018) pri jemanju diuretikov. V skupini primerov je več bolnikov prejemalo diuretike (43 %) kot v kontrolni skupini (29 %). Vseeno pa nato z multivariabilno logitično regresijo nismo dokazali večje verjetnosti za pojav postoperativne globoke venske tromboze ali pljučne embolije v povezavi z diuretiki. Ugotovili smo, da je v skupini primerov manj bolnikov prejemalo metamizol kot v kontrolni skupini (p = 0,039). Iz tega bi lahko sklepali, da ima metamizol zaščitno vlogo pred razvojem globoke venske tromboze ali pljučne embolije, vendar metodologija v naši raziskavi ni bila zastavljena tako, da bi lahko na tak način interpretirali rezultate, bi pa bilo smiselno to raziskovati v prihodnje. Skupino primerov in kontrolno skupino smo primerjali tudi glede pojavnosti trombocitopenije, trombocitoze in hiponatriemije, ki bi lahko bili izraženi neželeni učinki določenih zdravil, ki so jih bolniki prejemali. Z uporabo univariantne analize ni bilo statistično pomembih razlik med skupinama pri bolnikih, ki so imeli diagnosticirano hiponatriemijo, trombocitopenijo ali trombocitozo. Hiponatriemijo smo kljub temu vključili tudi v model multivariabilne logistične regresije, vendar povezava med hiponatriemijo in pooperativno pojavnostjo globoke venske tromboze ali pljučne embolije ni bila statistično značilna. Glede na rezultate naše raziskave smo zaključili, da bi morala biti polifarmakoterapija in zdravljenje s koncentriranimi eritrociti vključena v Caprini model in ovrednotena vsaj z eno točko. Članek iz tega dela rezultatov smo objavili v reviji International Journal of Clinical Pharmacy.

• Jezik: Slovenski jezik
• Ključne besede: venska tromboembolija, neželeni učinki zdravil, kirurški bolniki, venska tromboza, farmakoterapija, pljučna embolija
• Vrsta gradiva: Doktorska disertacija
• Tipologija: 2.08 - Doktorska disertacija
• Organizacija: FFA - Fakulteta za farmacijo
• Kraj izida: Ljubljana
• Založnik: [A. Premuš Marušič ]
• Leto izida: 2017
• Št. strani: 145 str.
• PID: 20.500.12556/RUL-137401
• UDK: 616.14-005.6+616-085(043.3)
• COBISS.SI-ID: 4302961
• Datum objave v RUL: 16.06.2022

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: The incidence of pulmonary embolism and deep vein thrombosis in conjunction with pharmacotherapy in hospitalized surgical patients in Pomurje

Izvleček

Venous thrombosis or venous thromboembolism (VT) is a common disease; annual prevalence is about 160/100,000. VT is the formation of a clot in a deep vein that most often develops in the veins of lower limbs. Pulmonary embolism is the most important complication of a non-treated acute venous thrombosis. Risk factors for developing venous thrombosis increase equally with the likelihood of pulmonary embolism. Changes in blood flow or composition of blood and damage of the vascular endothelium can lead to venous thrombosis. Risk factors for the development of venous thrombosis in surgical patients are numerous, the most important and most frequently mentioned are the type of surgery, duration of hospitalization, history of previous venous thrombosis or oncological diseases, immobility, sepsis, presence of a central venous catheter, pregnancy, or lactation period and inherited or acquired hypercoagulability states. Therefore, adequate thromboprophylaxis to protect against deep vein thrombosis and pulmonary embolism in hospitalized patients is required. Caution and proper dosage are especially necessary in patients who undergo complex surgeries and have multiple risk factors. Patients therefore receive prophylactic doses of low molecular weight heparins. Proper thromboprophylaxis considering the risk of surgical patients is recommended. It is known that some medicines can affect the changes in the structure of blood or blood flow. Blood products, such as plasma components, may affect the increased risk of venous thrombosis. Also, the drugs’ mechanism of action or drug-drug interaction may increase the risk of venous thrombosis; this applies for contraceptives, antipsychotics, NSAIDs. Patients who are injured have expressed adverse drug reactions twice as often as patients who did not suffer injury. In patients with polypharmacy - receiving eight or more drugs - the probability of potential drug interactions is high. Use of multiple drugs is associated with greater likelihood of side effects and increased likelihood of hospitalization, independent of the patient's age. However, it is difficult to isolate the concurrent risk factors and determine the impact of polypharmacy on the final clinical outcome in observational studies. Optimizing drug therapy is, therefore, the basic part of proper treatment of the patient. The relationship between polypharmacotherapy, interactions between drugs and the incidence of deep vein thrombosis or pulmonary embolism has not yet been proved. The purpose of the doctoral thesis was to evaluate the impact of thromboprophylaxis compliance in postoperative surgical patients on the incidence of deep vein thrombosis and pulmonary embolism and also to assess the incidence of deep vein thrombosis and pulmonary embolism in relation to given blood products, the number of drug interaction and the type of drugs that patients receive. The first part of the doctoral dissertation was a case control retrospective study. We examined the adequacy of thromboprophylaxis according to treatment guidelines for surgical patients and the impact of inappropriate prescribing in the incidence of deep vein thrombosis and pulmonary embolism. The research was carried out in the General Hospital Murska Sobota, where we included all patients who were hospitalized in the surgical department at the General Hospital Murska Sobota from 1 January 2007 to 31 December 2011 who had the main or an accompanying diagnosis of "pulmonary embolism" or "deep vein thrombosis" and who had a pulmonary embolism or deep vein thrombosis diagnosed for the first time. We compared the case group with patients who did not suffer post-operative deep vein thrombosis or pulmonary embolism. According to the current thromboprophylaxis guidelines for surgical patients, we classified patients into appropriate groups depending on the risks for the development of venous thromboembolism. To determine the adequacy of thromboprophylaxis, we used Caprini score. In the control group, 77% of patients were receiving therapy for the prevention of venous thromboembolism in accordance with guidelines, while this proportion in the case group amounted to 56%. For statistical analysis among groups we used chi-square test. Significant difference between adequate and inadequate thromboprophylaxis was shown (p<0.05). We have shown that the probability for the occurrence of venous thromboembolism (deep vein thrombosis or pulmonary embolism) is greater if preventive therapy for venous thromboembolism is not in accordance with the guidelines. Article from this part of the results was published in the Slovenian Medical Journal. The second retrospective study was carried out on the same patients, in addition to the adequacy of thromboprophylaxis, we also examined the use of blood products and the use of vitamin K in each patient in the preoperative period in the case and the control group. Case group was separated according to the type of complication, to the group that developed a deep vein thrombosis (DVT group) and the group that developed a pulmonary embolism (PE group). We used multinomial logistic regression to evaluate the statistical significance. We demonstrated a statistically significant difference between the case and the control group (p<0.05) relative to the receiving of packed red blood cells. Treatment with concentrated red blood cells was associated with an increased risk of pulmonary embolism [OR 4.589 (95% CI: 1.689 to 12.471)], but not with deep vein thrombosis. Comparing the treatment with fresh frozen plasma between the case and control group did not show a statistically significant difference. Probably the reason was a too small sample, since fresh frozen plasma was used in only 2 patients in the DVT group (4%), 10 patients in the PE group (11%) and 5 patients (3.5%) in the control group. Even less use of Vitamin K was seen, only 6 patients in the PE group, none in the DVT group and 5 patients in the control group. The difference was not statistically significant. We concluded that treatment with red blood cells can be associated with the incidence of postoperative pulmonary embolism in surgical patients. Therefore, it would be necessary to monitor the patients who received red blood cells during surgical treatment more carefully, because they are at greater risk for developing pulmonary embolism. Article from this part of the results was published in Clinical and Applied Thrombosis/Hemostasis. The third part of the study focused on the link between individual groups of drugs, drug interactions and polypharmacotherapy and the incidence of deep vein thrombosis and pulmonary embolism in surgical patients. We reviewed the number of drugs that patients received and the drug-drug interactions with Lexi-Comp® software. We reviewed the medical records that were available and may indicate drugs’ side effects. In most cases, only laboratory findings were available (hyponatremia, thrombocytopenia, thrombocytosis). We have reviewed the use of NSAIDs, tramadol, paracetamol, contraceptives, antipsychotics, anxiolytics, antidepressants, and diuretics. The model also included (in)appropriate use of thromboprophylaxis and the use of red blood cells. If a patient was treated with 8 drugs or more, we considered this as polypharmacotherapy. The influence of risk factors for the development of deep vein thrombosis or pulmonary embolism was evaluated using multinomial logistic regression. We demonstrated a statistically significant difference between the case and control group (p<0.05) relative to polypharmacotherapy, which was associated with a greater likelihood of developing deep vein thrombosis or pulmonary embolism [OR 2.021 (95% CI: 1.032 to 3.957)]. We also monitored additional diagnosis (atrial fibrillation, heart failure and other cardiovascular diseases) of patients, but no statistically significant impact was demonstrated in the occurrence of deep vein thrombosis or pulmonary embolism postoperatively. We evaluated the impact of drug interactions and the occurrence of deep vein thrombosis and pulmonary embolism, but no statistically significant differences between the case and control group were seen. In the case group, there was one pharmacokinetic drug-drug interaction type X, which is described as increased risk of negative cardiovascular-related outcomes (esomeprazole – clopidogrel) and 12 pharmacokinetic drug-drug interactions type D, which could increase the likelihood of thromboembolic events. In the case group, we also detected 23 type D potential interactions between drugs, which describe a greater likelihood of bleeding. Most of these interactions were pharmacodynamic interactions (e.g. a combination of NSAIDs and serotonin reuptake inhibitors). In the control group, there was no potential interaction of type X or D, in relationship with a higher risk of thromboembolic events. In the control group, there were only 5 potential interactions of type D that would cause greater probability of bleeding. According to the results of our study, we assume that the potential drug-drug interactions, which result in an impact on the increased likelihood of thromboembolic events, are clinically more important than the potential interactions that have an impact on the increased likelihood of bleeding. According to the univariate analysis (chi-square test), there were no statistically significant differences between the case and control group of patients receiving nonsteroidal anti-inflammatory drugs, antipsychotics, hypnotics, antidepressants, metamizole or tramadol and paracetamol, therefore none has been included as a factor in the multivariable logistic regression model. In our study, there was in univariate analysis a statistically significant difference between the case and control group (p=0.018) in patients taking diuretics. In the case group, the number of patients receiving diuretics was higer (43%) than in the control group (29%). Nevertheless, with multivariable logistic regression we could not prove a greater probability of occurrence of postoperative deep venous thrombosis or pulmonary embolism due to the use of diuretics. We have found that in the case group patients received less metamizole than in the control group (p=0.039). We could suspect that metamizole may have a protective effect, but methodology in our study was not designed to identify such effect. However, this effect should be studied further. Case and control groups were compared regarding the incidence of thrombocytopenia, thrombocytosis and hyponatremia, which may all be linked to drugs’ side effects in patients receiving them. However, with the use of a univariate analysis (chi-square test) we failed to prove statistically significant differences between the case and control group in patients diagnosed with hyponatremia, thrombocytopenia, or thrombocytosis. Hyponatraemia was included in the multivariable logistic regression model, but the correlation between hyponatremia and postoperative incidence of deep vein thrombosis or pulmonary embolism was not statistically significant. According to the results of our study, we concluded that the polypharmacotherapy and the treatment with concentrated red blood cells are important factors that should be included in the Caprini score model and evaluated by at least one point. Article from this part of the results was published in International Journal of Clinical Pharmacy.