Heart disease is the leading cause of death in the United States. Hyperlipidemia is a predominant risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). The statin drug class is the first line therapeutic for lowering atherogenic low-density lipoprotein (LDL) levels by competitively inhibiting 3-hydroxyl-3methyl-glutaryl-coenzyme A (HMGCR) reductase, the rate-limiting enzyme in cholesterol biosynthesis. However, there are patients who are unable to achieve desirable LDL levels despite statin therapy, such as those with familial hypercholesterolemia or those who are statin intolerant. A new therapy was discovered in 2015 to benefit patients with uncontrolled LDL levels by inhibiting Proprotein convertase subtilisin-kexin type 9 (PCSK9), a key protein in LDL receptor metabolism. Evolocumab (Repatha, AMGEN) is a human monoclonal antibody against human PSCK9. Evolocumab is approved to lower LDL-cholesterol in adult patients who have, despite dietary and lifestyle changes and maximally tolerated statin dose continued suboptimal lipid levels with either ASCVD or Heterozygous Familial Hypercholesterolemia (HeFH). Evolocumab has been shown to significantly reduce atherogenic lipid levels and the recent FOURNIER clinical trial showed that evolocumab reduces cardiovascular events. However, the high annual cost of evolocumab has raised questions as to its cost-effectiveness and role in the prevention and treatment of ASCVD. At the present price levels, this therapy does not appear to be cost-effective with multiple analyses suggesting significant price reduction will be necessary before this drug can be used in standard treatment for secondary prevention of cardiovascular disease in the United States.

Sammanfattning Bakgrund Insjuknande i hjärtinfarkt har minskat kraftigt i Sverige de senaste åren men drabbar fortfarande många. Ateroskleros i hjärtats kranskärl är den viktigaste bakomliggande orsaken. Utvecklingen av ateroskleros sker under lång tid och processen är komplex men kan kopplas till inflammatoriska processer, apoB-innehållande lipoprotein och endoteldysfunktion. LDL bedöms av många forskare vara en kausal faktor vid aterosklersutvecklingen. Denna bedömning grundar sig på djurförsök, observationsstudier, resultat från kliniska prövningar med LDL-sänkande läkemedel samt mendelska randomiseringsstudier. Behandlingsrekommendationerna vid sekundärprevention av hjärtinfarktpatienter innefattar behandling med hög dos statin där vissa av rekommendationerna sätter upp ett mål på en LDL-sänking till nivåer under 1.8 mmol/l. Syfte Syftet med detta arbete var att undersöka vilka behandlingseffekter som finns vid läkemedelsbehandling som sänker LDL till låga nivåer vid sekundärprevention för hjärtinfarktpatienter och om de nuvarande behandlingsriktlinjerna på nivåer under 1.8 mmol/l kan anses rimliga. Vidare gjordes en ansats för att belysa frågan om huruvida LDL-sänkning eller pleiotropa effekter kan förklara effekten vid statinbehandling. Resultat Behandling med hög dos statin som sänker LDL till låga nivåer minskar risken för större kardiovaskulära/koronara händelser. Effekten beror främst på minskat antal hjärtinfarkter och revaskulariseringsprocedurer. Effekten på koronar/kardiovaskulär mortalitet förefaller emellertid vara i bästa fall liten. Samma mönster sågs i studier av PCSK9-hämmaren evolocumab och NPC1L1-hämmaren ezetimib. Då dessa läkemedel sänker LDL genom andra mekanismer än statiner indikerar detta att LDL-sänkning i sig har en effekt men pleiotropa effekter kan inte uteslutas. Slutsats Läkemedelsbehandling som sänker LDL till nivåer under 1.8 mmol/l förefaller ha effekt och därmed är det inte orimligt att ha ett sådant behandlingsmål. Det går emellertid inte att finna en optimal nivå för LDL-koncentrationen i plasma baserat på de studier som gjorts. NNT-talen blir relativt höga och en betydande residualrisk kvarstår även vid sänkning till låga LDL-nivåer vilket indikerar potentiell vikt av tidigare insatt LDL-sänkande behandling men även ett behov av nya behandlingsformer / Summary Background Despite substantial reductions in the incidence of myocardial infarction, the incidence remains high. Rupture of an atherosclerotic plaque within the coronary arteries is the most important direct causal factor. Atherosclerosis typically develops slowly and silently and can be described as a build-up of cholesterol-containing plaques within the artery wall. Theories of the causal mechanisms behind atherosclerosis point to a high degree of complexity. Most theories focus on an interaction between inflammatory processes, cholesterol-containing lipoproteins and dysfunction of the endothelial cells within the artery wall. Much focus has been put on the role of cholesterol-containing low-density lipoprotein (LDL). This lipoprotein seems to have a direct causal role in the process. Such a standpoint is based on animal experiments, observational studies, randomized clinical trials with LDL-lowering drugs and Mendelian randomization studies. Treatment guidelines for patients with myocardial infarction therefore recommend LDL-lowering therapy. These guidelines recommend treatment with a high dose statin and some include recommendations to lower LDL to levels below 1.8 mmol/l (69 mg/dl). Objective The aim of this thesis was to look at the treatment effects of lowering LDL to low levels for secondary prevention of myocardial infarction and whether the current recommendations of 1.8 mmol/l or less are reasonable. A second objective was to elucidate the question of whether statins have other, pleiotropic effects beside their LDL-lowering capacity. Searches were conducted in pubmed for randomized clinical statin-trials where low average LDL-levels were obtained. Further, a trial with PCSK9-inhibitor evolocumab and a trial with NPC1L1-inhibitor ezetimibe were included in order that the effects of these drugs could be compared with the effects of statins. Thereby, the question of statin-pleiotropy could be analyzed. Results Treating patients with a high dose statin to obtain lower levels of LDL reduced the risk of major coronary/cardiovascular events when compared with a low dose statin. The absolute risk reduction was however low. The effect was driven mainly by a reduction in the number of myocardial infarctions and coronary revascularization procedures whereas the effects on mortality seem absent or at best rather modest. The same pattern was seen in the FOURIER-trial where PSCK9-inhibitor evolocumab was compared with standard statin treatment. The active treatment group obtained an average LDL-level of 0.78 mmol/l (30 mg/dl). This pattern was also seen in the IMPROVE-IT-trial, where NPC1L1-inhibitor ezetimibe was compared with standard statin treatment. Conclusion Treatment to obtain low levels of LDL have an effect - even at levels below 1.8 mmol/l. LDL-lowering in and of itself seems to have an effect given the results from studies where patients were treated with evolocumab and ezetimibe. The number of patients that need to be treated to prevent one event is however high and a substantial number of patients remain at risk even at very low levels of LDL. This implies the need for other forms of therapy or initiation of LDL-lowering therapies at earlier stages for selected groups of patients before they experience a myocardial infarction

Atherosclerosis is the underlying cause for many serious cardiovascular diseases which causes over 50 % of all deaths in Sweden. Atherosclerotic plaque builds up in the vessel walls over decades that will eventually lead to a complete block of an artery or cause thrombosis when the plaque ruptures, this leads to myocardial infarction and stroke. A major contributing factor to the buildup of plaque is cholesterol, especially low density lipoprotein, LDL. LDL can oxidize and start an inflammation process and together with cells from the immune system form the basis for a plaque. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein which main function is to regulate the amount of LDL-receptors available by promoting their degradation. PCSK9 causes degradation of the receptors with the effect that more LDL is left in the blood stream. Evolocumab is a monoclonal antibody with PCSK9 as the target, with PCSK9 neutralised less LDL will be left in the blood stream which will help prevent atherosclerosis. This is a complex and expensive way of treating atherosclerosis, the primary treatment is statins and secondarily cholesterol absorbtion inhibitors, bile acid sequestrants and fibrates. The purpose of this study was to examine evolocumabs effect on cardiovascular events in high risk patients and for which patient groups it is cost-efficient. The method used was searching the medical database PubMed with the keywords “evolocumab” and “evolocumab cost-effectiveness”. 5 articles was analysed and they showed that evolocumab lowered LDL-cholesterol with 55-60 % and significantly improved the lipid profile of patients. The hazard risk was lowered by 20-25 % for serious cardiovascular events and a 10 % lower rate of death was assessed after 5 years of treatment. Since no large studies have followed up on patients for over 5 years and measured cardiovascular events and deaths it is hard to know for sure how efficient evolocumab is at preventing death. The price of evolocumab is 50 000 SEK for one year of treatment and to assess which patients should be treated proved difficult due to the facts that the Swedish national regions have a side deal with the drug manufacturer Amgen in which they get compensation if evolocumab would prove to not be cost-efficient enough and there is no fixed acceptable price per quality adjusted life year (QALY) in Sweden. / Ateroskleros är grund till många allvarliga hjärt- och kärlsjukdomar och ligger bakom mer än hälften av alla dödsfall i Sverige. Sjukdomen innebär att plack byggs upp i kärlväggarna under flera decennier och till slut täpper igen ett kärl eller brister och en blodpropp bildas vilket leder till hjärtinfarkt och stroke. En bidragande faktor till bildningen av aterosklerotiska plack är kolesterol främst i form av lågdensitetlipoprotein (LDL), oxiderat LDL bidrar till att en inflammationsprocess startar i kärlet. Proprotein konvertas subtilisin/kexin typ 9 (PCSK9) är ett protein vars uppgift är att reglera antalet LDL-receptorer genom att binda in till receptorerna och ”märka” ut dem för nedbrytning. Evolokumab är en antikropp mot PCSK9 vars effekt ökar antalet LDL-receptorer vilket i sin tur minskar mängden LDL i blodet. Evolokumab är ett nytt och dyrt läkemedel, ateroskleros behandlas istället främst med statiner men också med kolesterolabsoptionshämmare, resiner och fibrater. Syftet med arbetet var att undersöka evolokumabs effekt att minska risk för hjärt- och kärlsjukdomar samt för vilka patientgrupper det är kostnadseffektivt. Metoden som användes var att söka artiklar på PubMed med sökorden ”Evolocumab” och ”Evolocumab cost effectiveness”. Fem artiklar undersöktes och de visade att evolokumab sänker LDL-kolesterolet i blodet med 55-60 % och även andra lipidvärden förbättras betydligt. Riskminskningen att drabbas av hjärt- och kärlsjukdomar bedömdes vara 20-25 % och riskminskningen att dö till följd av dessa sjukdomar uppskattades till 10 % efter 5 års behandling för patienter med hög risk att drabbas av dessa sjukdomar. Standardbehandling med evolokumab ger en kostnad på 50 000 kr per år för läkemedlet och angående vilka patienter som bör få Evolokumab är det svårt att göra en gränsdragning då det i Sverige finns en sidoöverenskommelse som innebär att tillverkaren kompenserar landstingen om behandlingen inte är kostnadseffektiv samt att i Sverige finns inget fast värde för ett kvalitetsjusterat levnadsår (QALY).