Practice Rapid Recommendations PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations BMJ 2022; 377 doi: https://doi.org/10.1136/bmj-2021-069066 (Published 04 May 2022) Cite this as: BMJ 2022;377:e069066 Visual summary of recommendation Population This recommendation applies only to people with these characteristics: Adults with elevated low-density lipoprotein (LDL) cholesterol Over 70 mg/dL Over 1.8 mmol/L Using high dose statins or intolerant to statins Wanting to reduce the risk of major cardiovascular events People using high dose statins Recommendation Risk of experiencinga major adversecardiovascular eventwithin 5 years People intolerant to statins MACE Low <5% 1 Recommendation 5 Recommendation Moderate 5-15% 2 Recommendation 6 Recommendation High 15-20% 3 Recommendation 7 Recommendation Very high >20% 4 Recommendation 8 Interventions compared Statins alone Ezetimibeplus statins Ezetimibe plusPCSK9 inhibitorsplus statins PCSK9 inhibitorsplus statins People receiving high dose statins No lipid- lowering drug Ezetimibealone Ezetimibe plusPCSK9 inhibitors PCSK9 inhibitorsalone People intolerant to statins Recommendation 1Adults considering cardiovascular risk reduction |Receiving high dose statins | Low cardiovascular riskStatins aloneAdding a second lipid-lowering drugorPeople consideringcardiovascular risk reductionWe recommend against adding a secondlipid-lowering drugStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEvidence profile - potential benefitsKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighAll-cause mortalityEvents per 1000 peopleWithin 5 years3333Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:ModeratePCSK9 + statinsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably has little or noimpactFavours:No important differenceCertainty:LowEzetimibe + statins mayhave little or no impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactCardiovascular mortalityEvents per 1000 peopleWithin 5 years2222Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:ModeratePCSK9 + statinsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably has little or noimpactFavours:No important differenceCertainty:LowEzetimibe + statins mayhave little or no impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactNon-fatal MIEvents per 1000 peopleWithin 5 years7665Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:ModeratePCSK9 + statinsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably has little or noimpactFavours:No important differenceCertainty:LowPCSK9 + statins mayhave little or no impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactNon-fatal strokeEvents per 1000 peopleWithin 5 years7564Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:ModeratePCSK9 + statinsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably has little or noimpactFavours:No important differenceCertainty:LowPCSK9 + statins mayhave little or no impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactUse the interactive multiple comparisontool to compare and choose treatmentsThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effectRecommendation 2Adults considering cardiovascular risk reduction |Receiving high dose statins | Moderatecardiovascular riskStatins aloneAdding a second lipid-lowering drugorPeople consideringcardiovascular risk reductionWe suggest not adding a second lipid-lowering drugStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEzetimibe plus statinsPCSK9 inhibitors plus statinsorPeople adding a secondlipid-lowering drugWe suggest adding ezetimibe firstStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEzetimibe plus statinsEzetimibe plus PCSK9 inhibitorsplus statinsorPeople considering furthercardiovascular risk reductionWe recommend not adding a PCSK9 inhibitor toezetimibe plus statinsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEvidence profile - potential benefitsKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighAll-cause mortalityEvents per 1000 peopleWithin 5 years9999Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:ModeratePCSK9 + statinsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably has little or noimpactFavours:No important differenceCertainty:LowEzetimibe + statins mayhave little or no impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactCardiovascular mortalityEvents per 1000 peopleWithin 5 years6666Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:ModeratePCSK9 + statinsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably has little or noimpactFavours:No important differenceCertainty:LowEzetimibe + statins mayhave little or no impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe +statins may have little orno impactNon-fatal MIEvents per 1000 peopleWithin 5 years25202218Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:ModerateAdding PCSK9 inhibitorsto statins probably has atrivial benefitFavours:No important differenceCertainty:ModerateAdding ezetimibe tostatins probably haslittle or no benefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto statins may have littleor no benefitFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors andstatins may have little orno benefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto statins and ezetimibemay have a trivialbenefitNon-fatal strokeEvents per 1000 peopleWithin 5 years23171914Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:ModerateAdding PCSK9 inhibitorsto statins probably has atrivial benefitFavours:No important differenceCertainty:ModerateAdding ezetimibe tostatins probably has atrivial benefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto statins may have littleor no benefitFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors andstatins may have a trivialbenefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto statins and ezetimibemay have a trivialbenefitUse the interactive multiple comparisontool to compare and choose treatmentsThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effectRecommendation 3Adults considering cardiovascular risk reduction |Receiving high dose statins | High cardiovascular riskStatins aloneAdding a second lipid-lowering drugorPeople consideringcardiovascular risk reductionWe suggest adding a second lipid-lowering drugStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEzetimibe plus statinsPCSK9 inhibitors plus statinsorPeople adding a secondlipid-lowering drugWe suggest adding ezetimibe firstStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEzetimibe plus statinsEzetimibe plus PCSK9 inhibitorsplus statinsorPeople considering furthercardiovascular risk reductionWe suggest not adding a PCSK9 inhibitor toezetimibe plus statinsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEvidence profile - potential benefitsKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighAll-cause mortalityEvents per 1000 peopleWithin 5 years24232423Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:HighPCSK9 + statins havelittle or no impactFavours:No important differenceCertainty:HighEzetimibe + statins haslittle or no impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably have little orno impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibe +statins probably havelittle or no impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibe +statins probably havelittle or no impactCardiovascular mortalityEvents per 1000 peopleWithin 5 years15141514Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:HighPCSK9 + statins havelittle or no impactFavours:No important differenceCertainty:HighEzetimibe + statins haslittle or no impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably have little orno impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibe +statins probably havelittle or no impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibe +statins probably havelittle or no impactNon-fatal MIEvents per 1000 peopleWithin 5 years63515545Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:PCSK9 inhibitors plus statinsCertainty:ModerateAdding PCSK9 inhibitorsto statins probably has asmall but importantbenefitFavours:No important differenceCertainty:ModerateAdding ezetimibe tostatins probably has atrivial benefitFavours:No important differenceCertainty:ModerateAdding PCSK9 inhibitorsto statins probably haslittle or no benefitFavours:No important differenceCertainty:ModerateAdding ezetimibe toPCSK9 inhibitors andstatins probably has atrivial benefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto statins and ezetimibemay have a trivialbenefitNon-fatal strokeEvents per 1000 peopleWithin 5 years60444936Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:PCSK9 inhibitors plus statinsCertainty:ModerateAdding PCSK9 inhibitorsto statins probably has asmall but importantbenefitFavours:Ezetimibe plus statinsCertainty:ModerateAdding ezetimibe tostatins probably has asmall but importantbenefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto statins may have atrivial benefitFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors andstatins may have a trivialbenefitFavours:Ezetimibe plus PCSK9inhibitors plus statinsCertainty:LowAdding PCSK9 inhibitorsto statins and ezetimibemay have a small butimportant benefitUse the interactive multiple comparisontool to compare and choose treatmentsThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effectRecommendation 4Adults considering cardiovascular risk reduction |Receiving high dose statins | Very highcardiovascular riskStatins aloneAdding a second lipid-lowering drugorPeople consideringcardiovascular risk reductionWe suggest adding a second lipid-lowering drugStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEzetimibe plus statinsPCSK9 inhibitors plus statinsorPeople adding a secondlipid-lowering drugWe suggest adding ezetimibe firstStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEzetimibe plus statinsEzetimibe plus PCSK9 inhibitorsplus statinsorPeople considering furthercardiovascular risk reductionWe suggest adding a PCSK9 inhibitor to ezetimibeplus statinsStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEvidence profile - potential benefitsKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighAll-cause mortalityEvents per 1000 peopleWithin 5 years32303230Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:HighPCSK9 + statins havelittle or no impactFavours:No important differenceCertainty:HighEzetimibe + statins haslittle or no impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably have little orno impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibe +statins probably havelittle or no impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibe +statins probably havelittle or no impactCardiovascular mortalityEvents per 1000 peopleWithin 5 years19181817Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:No important differenceCertainty:HighPCSK9 + statins havelittle or no impactFavours:No important differenceCertainty:HighEzetimibe + statins haslittle or no impactFavours:No important differenceCertainty:ModerateEzetimibe + statinsprobably have little orno impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibe +statins probably havelittle or no impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibe +statins probably havelittle or no impactNon-fatal MIEvents per 1000 peopleWithin 5 years84687359Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:PCSK9 inhibitors plus statinsCertainty:ModerateAdding PCSK9 inhibitorsto statins probably has asmall but importantbenefitFavours:No important differenceCertainty:ModerateAdding ezetimibe tostatins probably has atrivial benefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto statins may have atrivial benefitFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors andstatins may have a trivialbenefitFavours:Ezetimibe plus PCSK9inhibitors plus statinsCertainty:LowAdding PCSK9 inhibitorsto statins and ezetimibemay have a small butimportant benefitNon-fatal strokeEvents per 1000 peopleWithin 5 years80596648Statins alonePCSK9inhibitorsplus statinsEzetimibe plus statinsEzetimibeplus PCSK9inhibitorsplus statinsFavours:PCSK9 inhibitors plus statinsCertainty:HighAdding PCSK9 inhibitorsto statins has animportant benefitFavours:Ezetimibe plus statinsCertainty:ModerateAdding ezetimibe tostatins probably has asmall but importantbenefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto statins may have atrivial benefitFavours:Ezetimibe plus PCSK9inhibitors plus statinsCertainty:LowAdding ezetimibe toPCSK9 inhibitors andstatins may have a smallbut important benefitFavours:Ezetimibe plus PCSK9inhibitors plus statinsCertainty:ModerateAdding PCSK9 inhibitorsto statins and ezetimibeprobably have a smallbut important benefitUse the interactive multiple comparisontool to compare and choose treatmentsThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effectRecommendation 5Adults considering cardiovascular risk reduction |Intolerant to statins | Low cardiovascular riskNo lipid-lowering drugEzetimibe or PCSK9 inhibitorsorPeople consideringcardiovascular risk reductionWe recommend against using a lipid-lowering drugStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEvidence profile - potential benefitsKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighAll-cause mortalityEvents per 1000 peopleWithin 5 years3333No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:ModeratePCSK9 inhibitorsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe probably haslittle or no impactFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave little or no impactFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave little or no impactFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may havelittle or no impactCardiovascular mortalityEvents per 1000 peopleWithin 5 years2222No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:ModeratePCSK9 inhibitorsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe probably haslittle or no impactFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave little or no impactFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave little or no impactFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may havelittle or no impactNon-fatal MIEvents per 1000 peopleWithin 5 years10897No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:ModeratePCSK9 inhibitorsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe probably haslittle or no impactFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave little or no impactFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave little or no impactFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may havelittle or no impactNon-fatal strokeEvents per 1000 peopleWithin 5 years8675No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:ModeratePCSK9 inhibitorsprobably have little orno impactFavours:No important differenceCertainty:ModerateEzetimibe probably haslittle or no impactFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave little or no impactFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave little or no impactFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may havelittle or no impactUse the interactive multiple comparisontool to compare and choose treatmentsThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effectRecommendation 6Adults considering cardiovascular risk reduction |Intolerant to statins | Moderate cardiovascular riskNo lipid-lowering drugEzetimibe or PCSK9 inhibitorsorPeople consideringcardiovascular risk reductionWe suggest not using a lipid-lowering drugStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEzetimibePCSK9 inhibitorsorPeople starting alipid-lowering drugWe suggest adding ezetimibe firstStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEzetimibeEzetimibe plus PCSK9 inhibitorsorPeople considering furthercardiovascular risk reductionWe suggest not adding a PCSK9 inhibitor toezetimibeStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeakMost people would likely want the interventionto the left. Benefits would outweigh harms forthe majority, but not for everyoneWeakMost people would likely want the interventionto the right. Benefits would outweigh harmsfor the majority, but not for everyoneStrongAll or nearly all informed people would likelywant the intervention to the right. Benefitswould outweigh harms for almost everyoneEvidence profile - potential benefitsKey todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighAll-cause mortalityEvents per 1000 peopleWithin 5 years11101110No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:ModeratePCSK9 probably havelittle or no impactFavours:No important differenceCertainty:ModerateEzetimibe probably haslittle or no impactFavours:No important differenceCertainty:LowPCSK9 may have little orno impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe mayhave little or no impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe mayhave little or no impactCardiovascular mortalityEvents per 1000 peopleWithin 5 years7777No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:ModeratePCSK9 probably havelittle or no impactFavours:No important differenceCertainty:ModerateEzetimibe probably haslittle or no impactFavours:No important differenceCertainty:LowPCSK9 may have little orno impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe mayhave little or no impactFavours:No important differenceCertainty:LowPCSK9 + Ezetimibe mayhave little or no impactNon-fatal MIEvents per 1000 peopleWithin 5 years36293125No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:ModeratePCSK9 inhibitorsprobably have a trivialbenefitFavours:No important differenceCertainty:ModerateEzetimibe probably hasa trivial benefitFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave little or no benefitFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave trivial benefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may havetrivial benefitNon-fatal strokeEvents per 1000 peopleWithin 5 years27202216No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave a trivial benefitFavours:No important differenceCertainty:ModerateEzetimibe probably hasa trivial benefitFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave little or no benefitFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave trivial benefitFavours:No important differenceCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may havetrivial benefitUse the interactive multiple comparisontool to compare and choose treatmentsThe panel found that this difference wasnot important for most patients, becausedifferences were only observed in fewerthan 10 per 1000 people includedGRADE certainty ratingsHighThe authors have a lot ofconfidence that the trueeffect is similar to theestimated effectModerateThe authors believe thatthe true effect is probablyclose to theestimated effectLowThe true effect might bemarkedly different fromthe estimated effectVery lowThe true effect isprobably markedlydifferent from theestimated effectRecommendation 7Adults considering cardiovascular risk reduction |Intolerant to statins | High cardiovascular riskNo lipid-lowering drugEzetimibe or PCSK9 inhibitorsorPeople consideringcardiovascular risk reductionWe recommend using a lipid-lowering drugStrongAll or nearly all informed people would likelywant the intervention to the left. Benefitswould outweigh harms for almost everyoneWeak