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  3. PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations
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 risk
Statins 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 everyone

Evidence profile - potential benefits

Key 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 effect
Recommendation 2Adults considering cardiovascular risk reduction |Receiving high dose statins | Moderatecardiovascular risk
Statins 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 everyone
Ezetimibe 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 everyone
Ezetimibe 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 everyone

Evidence profile - potential benefits

Key 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 effect
Recommendation 3Adults considering cardiovascular risk reduction |Receiving high dose statins | High cardiovascular risk
Statins 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 everyone
Ezetimibe 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 everyone
Ezetimibe 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 everyone

Evidence profile - potential benefits

Key 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 effect
Recommendation 4Adults considering cardiovascular risk reduction |Receiving high dose statins | Very highcardiovascular risk
Statins 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 everyone
Ezetimibe 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 everyone
Ezetimibe 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 everyone

Evidence profile - potential benefits

Key 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 effect
Recommendation 5Adults considering cardiovascular risk reduction |Intolerant to statins | Low cardiovascular risk
No 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 everyone

Evidence profile - potential benefits

Key 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 effect
Recommendation 6Adults considering cardiovascular risk reduction |Intolerant to statins | Moderate cardiovascular risk
No 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 everyone
EzetimibePCSK9 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 everyone
EzetimibeEzetimibe 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 everyone

Evidence profile - potential benefits

Key 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 effect
Recommendation 7Adults considering cardiovascular risk reduction |Intolerant to statins | High cardiovascular risk
No 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 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 everyone
EzetimibePCSK9 inhibitorsorPeople starting alipid-lowering drugWe suggest using 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 everyone
EzetimibeEzetimibe plus PCSK9 inhibitorsorPeople considering furthercardiovascular risk reductionWe suggest adding a PCSK9 inhibitor to ezetimibeStrongAll 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 everyone

Evidence profile - potential benefits

Key todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighAll-cause mortalityEvents per 1000 peopleWithin 5 years27262726No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:HighPCSK9 have little or noimpactFavours:No important differenceCertainty:HighEzetimibe has little orno impactFavours:No important differenceCertainty:ModerateEzetimibe probably haslittle or no impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibeprobably have little orno impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibeprobably have little orno impactCardiovascular mortalityEvents per 1000 peopleWithin 5 years18171716No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:HighPCSK9 have little or noimpactFavours:No important differenceCertainty:HighEzetimibe has little orno impactFavours:No important differenceCertainty:ModeratePCSK9 probably havelittle or no impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibeprobably have little orno impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibeprobably have little orno impactNon-fatal MIEvents per 1000 peopleWithin 5 years92758065No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:PCSK9 inhibitors aloneCertainty:HighPCSK9 inhibitors have asmall but importantbenefitFavours:Ezetimibe aloneCertainty:ModerateEzetimibe probably hasa small but importantbenefitFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave a trivial benefitFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave a trivial benefitFavours:Ezetimibe plus PCSK9inhibitorsCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may have asmall but importantbenefitNon-fatal strokeEvents per 1000 peopleWithin 5 years70525742No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:PCSK9 inhibitors aloneCertainty:HighPCSK9 inhibitors have asmall but importantbenefitFavours:Ezetimibe aloneCertainty:ModerateEzetimibe probably hasa small but importantbenefitFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave a trivial benefitFavours:No important differenceCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave trivial benefitFavours:Ezetimibe plus PCSK9inhibitorsCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may have asmall but importantbenefitUse 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 effect
Recommendation 8Adults considering cardiovascular risk reduction |Intolerant to statins | Very high cardiovascular risk
No 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 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 everyone
EzetimibePCSK9 inhibitorsorPeople starting alipid-lowering drugWe suggest using 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 everyone
EzetimibeEzetimibe plus PCSK9 inhibitorsorPeople considering furthercardiovascular risk reductionWe suggest adding a PCSK9 inhibitor to ezetimibeStrongAll 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 everyone

Evidence profile - potential benefits

Key todiagramsFavors the intervention to whichthe arrow pointsNo important differenceGRADEcertaintyof evidenceratingsVery lowLowModerateHighAll-cause mortalityEvents per 1000 peopleWithin 5 years36343634No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:HighPCSK9 have little or noimpactFavours:No important differenceCertainty:HighEzetimibe has little orno impactFavours:No important differenceCertainty:ModerateEzetimibe probably havelittle or no impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibeprobably have little orno impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibeprobably have little orno impactCardiovascular mortalityEvents per 1000 peopleWithin 5 years24232322No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:No important differenceCertainty:HighPCSK9 have little or noimpactFavours:No important differenceCertainty:HighEzetimibe has little orno impactFavours:No important differenceCertainty:ModeratePCSK9 probably havelittle or no impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibeprobably have little orno impactFavours:No important differenceCertainty:ModeratePCSK9 + Ezetimibeprobably have little orno impactNon-fatal MIEvents per 1000 peopleWithin 5 years1229910686No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:PCSK9 inhibitors aloneCertainty:HighPCSK9 inhibitors have asmall but importantbenefitFavours:Ezetimibe aloneCertainty:ModerateEzetimibe probably hasa small but importantbenefitFavours:No important differenceCertainty:LowPCSK9 inhibitors mayhave a trivial benefitFavours:Ezetimibe plus PCSK9inhibitorsCertainty:LowAdding PCSK9 inhibitorsto ezetimibe may have asmall but importantbenefitFavours:Ezetimibe plus PCSK9inhibitorsCertainty:ModerateAdding PCSK9 inhibitorsto ezetimibe probablyhas a small butimportant benefitNon-fatal strokeEvents per 1000 peopleWithin 5 years94707757No lipid-lowering drugPCSK9inhibitorsaloneEzetimibe aloneEzetimibeplus PCSK9inhibitorsFavours:PCSK9 inhibitors aloneCertainty:HighPCSK9 inhibitors havean important benefitFavours:Ezetimibe aloneCertainty:ModerateEzetimibe probably hasa small but importantbenefitFavours:No important differenceCertainty:LowPCSK9 inhibitorspossibly may have atrivial benefitFavours:Ezetimibe plus PCSK9inhibitorsCertainty:LowAdding ezetimibe toPCSK9 inhibitors mayhave a small butimportant benefitFavours:Ezetimibe plus PCSK9inhibitorsCertainty:ModerateAdding PCSK9 inhibitorsto ezetimibe probablyhas an 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 effect
Common to all recommendationsAdults consideringcardiovascular risk reduction

Evidence profile - potential adverse events - PCSK9 inhibitors

ControlPCSK9 inhibitorsNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Events per 1000 peopleEvidence quality

Serious injection-site reaction15 fewer015HighMore

Based on data from 15 843 patients in 19 studiesPCSK9 inhibitors increasediscontinuation due to injection-sitereaction.HighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

New-onset diabetesNo important difference311308HighMore

Based on data from 37 187 patients in 14 studiesPCSK9 inhibitors have little or nodifference on new-onset diabetesHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Serious flu-like symptomsNo important difference--Very lowMore

Based on data from 995 patients in 5 studiesBaseline risk for flu-like symptomscould not be identified. We areuncertain whether PCSK9 inhibitorsincrease or decrease discontinuation dueto flu-like symptomsVery lowGRADE rating,because of:Risk of biasNo serious concernsImprecisionVery seriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Serious myalgia or muscular painNo important difference2222ModerateMore

Based on data from 1900 patients in 6 studiesPCSK9 inhibitors probably have little orno difference on discontinuation due tomyalgia or muscular pain.ModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Any serious adverse events13 fewer162175LowMore

Based on data from 51 237 patients in 31 studiesPCSK9 inhibitors may increasediscontinuation due to any adverseeventsLowGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Neurocognitive eventsNo important difference6161HighMore

Based on data from 59 334 patients in 19 studiesPCSK9 inhibitors have little or nodifference on neurocognitive eventsHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

CataractNo important difference4542HighMore

Based on data from 51 427 patients in 8 studiesPCSK9 inhibitors have little or nodifference on cataractHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Gastrointestinal hemorrhageNo important difference64HighMore

Based on data from 33 541 patients in 10 studiesPCSK9 inhibitors have little or nodifference on gastrointestinalhemorrhageHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect
See all outcomes

Evidence profile - potential adverse events - Ezetimibe

ControlEzetimibeNo important differenceThe panel found that this difference was not important for most patients,because the intervention effects were negligible and/or very imprecise, forexample confidence intervals that include both important benefit and harm
Events per 1000 peopleEvidence quality

Any cancerNo important difference227229HighMore

Based on data from 22 363 patients in 10 studiesEzetimibe has little or no difference onany cancerHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Any fractureNo important difference7668HighMore

Based on data from 20 291 patients in 8 studiesEzetimibe has little or no difference onany fractureHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Any serious adverse eventsNo important difference501436ModerateMore

Based on data from 27 326 patients in 40 studiesEzetimibe probably has little or nodifference on discontinuation due to anyadverse eventsModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessSeriousInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Serious gastrointestinal eventsNo important difference5675ModerateMore

Based on data from 2432 patients in 20 studiesEzetimibe probably has little or nodifference on discontinuation due to anygastrointestinal adverse eventsModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Serious myalgia or muscular painNo important difference176144HighMore

Based on data from 2438 patients in 25 studiesEzetimibe has little or no difference ondiscontinuation due to myalgia ormuscular painHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

Neurocognitive eventsNo important difference23ModerateMore

Based on data from 19 887 patients in 5 studiesEzetimibe probably has little or nodifference on neurocognitive eventsModerateGRADE rating,because of:Risk of biasNo serious concernsImprecisionSeriousIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect

New-onset diabetesNo important difference2320HighMore

Based on data from 20 319 patients in 8 studiesEzetimibe has little or no difference onnew-onset diabetesHighGRADE rating,because of:Risk of biasNo serious concernsImprecisionNo serious concernsIndirectnessNo serious concernsInconsistencyNo serious concernsPublication biasNo serious concernsGRADE 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 effect
See all outcomes

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Find recommendations, evidence summaries and consultation decision aids for use in your practice
  1. Qiukui Hao, methods co-chair, geriatrician123,
  2. Bert Aertgeerts, chair, general practitioner, methodologist4,
  3. Gordon Guyatt, general internist, methodologist3,
  4. Geertruida E Bekkering, patient partnership liaison, methodologist4,
  5. Per Olav Vandvik, general internist, methodologist56,
  6. Safi U Khan, cardiologist7,
  7. Nicolas Rodondi, general internist, methodologist89,
  8. Rod Jackson, epidemiologist10,
  9. Jean-Luc Reny, general internist1112,
  10. Lubna Al Ansary, general practitioner13,
  11. Mieke Van Driel, general practitioner14,
  12. Willem J J Assendelft, general practitioner15,
  13. Thomas Agoritsas, general internist, methodologist16,
  14. Frederick Spencer, cardiologist17,
  15. Reed A C Siemieniuk, general internist, methodologist317,
  16. Lyubov Lytvyn, patient partnership liaison, methodologist36,
  17. Anja Fog Heen, general internist, methodologist18,
  18. Qian Zhao, general practitioner19,
  19. Irbaz Bin Riaz, medical doctor20,
  20. Dirk Ramaekers, general internist21,
  21. Patrick Mba Okwen, general practitioner22,
  22. Ye Zhu, cardiologist23,
  23. Annabel Dawson, patient partner24,
  24. Mersa Caius Ovidiu, patient partner25,
  25. Willy Vanbrabant, patient partner26,
  26. Sheyu Li, endocrinologist, methodologist2728,
  27. Nicolas Delvaux, general practitioner, methodologist4
  1. 1The Center of Gerontology and Geriatrics/National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
  2. 2School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
  3. 3Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
  4. 4Department of Public Health and Primary Care and MAGIC Primary Care, Academisch Centrum voor Huisartsgeneeskunde, KU Leuven, Belgium
  5. 5Clinical Effectiveness Research Group, Institute of Health and Society, University of Oslo, Oslo, Norway
  6. 6MAGIC Evidence Ecosystem Foundation
  7. 7Department of Cardiology, Houston Methodist DeBakey Heart & Vascular Center, Houston TX, USA
  8. 8Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
  9. 9Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  10. 10School of Population Health, Faculty of Medical & Health Sciences, University of Auckland, New Zealand
  11. 11General Internal Medicine, University Hospital of Geneva, Geneva, Switzerland
  12. 12Faculty of Medicine, Geneva University, Switzerland
  13. 13Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  14. 14Primary Care Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, Australia
  15. 15Department of Primary and Community Care, Radboud University Medical Center, Netherlands
  16. 16Division General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  17. 17Department of Medicine, McMaster University, Hamilton, ON, Canada
  18. 18Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway
  19. 19International Medical Center / Ward of General Practice, West China Hospital, Sichuan University, Chengdu, China
  20. 20Department of Medicine, Hematology Oncology, Mayo Clinic, Arziona, USA
  21. 21KU Leuven Institute for Healthcare Policy, University of Leuven, Kapucijnenvoer 35, 3000 Leuven, Belgium.
  22. 22Effective Basic Services (eBase), Africa, Nkwen Bamenda, Cameroon
  23. 23Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
  24. 24United Kingdom
  25. 25Romania
  26. 26UZ Leuven GHB, Belgium
  27. 27Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
  28. 28Department of Guideline and Rapid Recommendation, Cochrane China Center, MAGIC China Center, Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
  1. Correspondence to: N Delvaux nicolas.delvaux{at}kuleuven.be, S Li lisheyu{at}gmail.com

Abstract

Clinical question In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug?

Current practice Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients’ values and preferences, absolute benefits and harms and potential treatment burdens.

Recommendations The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins.

How this guideline was created An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults’ average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation.

The evidence A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/.

Understanding the recommendations The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient’s risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients’ cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.

Because of the anticipated large variability of patients’ values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.

The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors.

Footnotes

  • Competing interests: All authors have completed the BMJ Rapid Recommendations interest disclosure form and a detailed, contextualised description of all disclosures is reported in web appendix 1. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests were minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions.

  • Disclaimer: Participation in the panel and authorship of this manuscript does not constitute organisational endorsement of the recommendations.

  • Funding This guideline was funded by 1.3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (Nos. 19HXFH011, ZYGD18022 and 2020HXF011). Nicolas Rodondi’s work is partly funded by a grant from the Swiss National Scientific Foundation (SNSF 33IC30_193052) about assessing the role of statins in multimorbid older adults without cardiovascular disease.

  • Transparency: N Delvaux and S Li affirm that the manuscript is an honest, accurate, and transparent account of the recommendation being reported; that no important aspects of the recommendation have been omitted; and that any discrepancies from the recommendation as planned have been explained.

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