New ACC guidelines endorse LDL goal!!
for those of
you who have lived through and survived my seemingly endless rantings
about the 2013 ACC/AHA guidelines on lipid management, and particularly
their negating the utility of treating to a more specific LDL target, may
be pleased to know that alas they seem to be returning to an LDL
target.... (see doi.org/10.1016/j.jacc.2017.07.745). This guideline was developed by the ACC
Task Force on Expert Consensus Decision
Pathways (ECDP).
Details:
--there have been several studies with PCSK9 inhibitors demonstrating clinical benefit for these drugs: eg, the FOURIER trial, Sabatine MS. New Engl J Med 2017; 376: 1713, of 27K patients with atherosclerotic disease with mean LDL of 92 mg/dl on a statin, who had a 59% further LDL decrease to 30mg/dl on the drug, then had a 15% decrease in the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina or coronary revascularization, and a 20% decrease in the hard clinical endpoints of cardiovascular death (nonsignificant by itself), MI (27% decrease) or stroke (21% decrease), after 2.2 years
--ECDP still promotes the primary target of LDL reduction of at least 50%, but "may consider LDL < 70mg/dl or non-HDC <100 mg/dl for all patients with clinical ASCVD and baseline LDL 70-189 mg/dl" (emphasis theirs)
--and they do consider it "reasonable" to add either ezetimibe or a PCSK9 inhibitor in those with ASCVD and comorbidities and baseline LDL 70-189 mg/dl.
--they favor adding ezetimibe in patients where an additional <25% lowering of LDL is "required": an acute coronary syndrome in past 3 months, patient preference, heart failure, hypertension, age >75, diabetes, stroke, CABG, PAD, eGFR<60, and smoking.
--and PCSK9 inhibitor in those requiring a greater reduction and willing to have a (very expensive) injection
--they identified patients at high cardiac risk as per the FOURIER study: those with ASCVD and at least one of: age >65, prior MI or non-hemorrhagic stroke, current daily cigarette smoking, symptomatic PAD with prior MI or stroke, history of non-MI related coronary revascularization, residual coronary artery disease with >40% stenosis in >1 large vessel, HDL <40 mg/dl for men or <50 mg/dl in women, hs-CRP >2 mg/L, or metabolic syndrome
Commentary:
--the new guidelines were catapulted forward based on the decreases in LDL levels by moderately effective nonstatin drugs (eg ezetimibe) and profoundly effective ones (PCSK9 inhibitors), and the associated decrease in clinical atherosclerotic events
--but, as per my prior blogs (eg, see http://gmodestmedblogs.blogspot.com/2013/12/further-thoughts-on-am-heart-assn-2013.html ), there really is pretty consistent and convincing evidence that it really is the achieved LDL and not the specific use of "high intensity" vs "moderate intensity" statins.
--so, though the impetus for the change was these new (and really expensive, especially the PCSK9 inhibitors) drugs (which were likely studied by those high up in the various cardiology associations, who no doubt have influence on ECDP recommendations), i think that the same argument for aggressive therapy to lower LDL levels would apply to statins themselves, though this is not even mentioned in their quite long document.
--for example, I certainly see lots of high risk patients who get very low LDLs (eg in 40 mg/dl range) on atorvastatin 10mg (a "moderate intensity statin", defined as atorvastatin 10 or 20 mg, lovastatin 40mg, pitorvastatin 2 or 4mg, rosuvastatin 5 or 10mg, or simvastatin 20 or 40mg). And lots of people who get down to an LDL of only around 110 mg/dL on atorvastatin 40 mg ("high intensity statin", defined as atorvastatin 40 or 80mg, rosuvastatin 20 or 40mg), yet have significant further decreases when switched to rosuvastatin 40mg.
--one concern about this recommendation is that they suggest the goal LDL be <70, but the baseline LDL was already pretty low in both the PCSK9 inhibitor studies (eg FOURIER study baseline LDL was 92, but they did find similar clinical benefit in those with median baseline LDL of 74 mg/dl) and in the IMPROVE-IT study with ezetimibe (baseline LDL of 69.5 mg/dl, decreasing 24% to 53.7 mg/dl on ezetimibe and associated with a 6% decrease in their primary clinical endpoint. see critique of this study)
--so, makes it really hard to get a handle on what the real target should be. Is <70 mg/dl enough? should it be 30 mg/dl as in the FOURIER study?????
--another change over the 2013 recommendations is to be more aggressive in older patients, which does reflect their increased absolute risk for a cardiac event. This more aggressive stance, I think, is because they are using non-statin therapies which have fewer adverse events in the elderly noted so far. So their recommendations still stand for "moderate intensity" statins in those >75yo, though I have been using higher doses of statins pretty regularly in high risk elderly, with rare problems.
--conspicuously absent from their list of high-risk conditions includes diabetes. And they are using mildly elevated hs-CRP as a condition leading to more aggressive therapy, probably because it would likely subsume several of the higher risk infectious or inflammatory conditions (eg chronic hepatitis, perhaps HIV, rheumatoid arthritis, etc). these specific absences seem to be because they adopted the criteria from a specific study (FOURIER)
--i should mention that in 2016, the EDCP writing committee was already moving toward a focus on the achieved LDL level, though this is more codified in the 2017 recommendations above.
--as a side issue, in patients who have statin intolerance or difficulty with daily meds, some of the long half-life statins (atorvastatin, rosuvastatin, pitavastatin) can be given 3x/week or even weekly. also, since most of the effect of statins is at the lowest dose, patients can be rechallenged with a different statin at the lowest dose.
so, still several unanswered questions.
--what really is the goal/best target for LDL cholesterol? though older studies have found that lowering the LDL by 30% was equally beneficial with higher LDL vs lower LDL levels, but the range of LDL was small and it is not clear that lowering an LDL 30% from 50 mg/dl would have the same benefit as if the LDL were lowered 30% to 120 mg/dl.
--and is there any difference whether the LDL target were achieved by increasing the dose of the statins (which do have several beneficial pleiotrophic effects, such as being anti-inflammatory, anti-oxidant, improving endothelial function, etc) vs the nonstatin drugs above? Eg: the IMPROVE-IT study of ezetimibe achieved pretty small clinical benefit (a 6% decrease in clinical events and a 2% absolute decrease over 6 years, even though there was a 25% decrease in LDL levels)
--why did they not comment on augmenting the statin dose to the max (rosuvastatin 40mg), when there is a dose-response curve for clinical events (eg, see the Treating to New Targets study comparing atorvastatin 10 vs 80mg, also reviewed some in the IMPROVE-IT study )? and perhaps lower the statin dose for some high risk patients who achieve very low LDL levels on moderate statin doses?
--my approach will still be the same: if the LDL is somewhat higher than desired (eg >70 in very high risk person), my initial approach will still be to increase the statin intensity to rosuvastatin 40 (doing it more gingerly and with closer followup in those >75). i would then consider adding ezetimibe if necessary, though i am less impressed with its protective effect and the only trial was adding ezetimibe 10mg to simvastatin 40mg (unfortunately, a drug-company sponsored trial, using hardly the optimal statin potency)
Details:
--there have been several studies with PCSK9 inhibitors demonstrating clinical benefit for these drugs: eg, the FOURIER trial, Sabatine MS. New Engl J Med 2017; 376: 1713, of 27K patients with atherosclerotic disease with mean LDL of 92 mg/dl on a statin, who had a 59% further LDL decrease to 30mg/dl on the drug, then had a 15% decrease in the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina or coronary revascularization, and a 20% decrease in the hard clinical endpoints of cardiovascular death (nonsignificant by itself), MI (27% decrease) or stroke (21% decrease), after 2.2 years
--ECDP still promotes the primary target of LDL reduction of at least 50%, but "may consider LDL < 70mg/dl or non-HDC <100 mg/dl for all patients with clinical ASCVD and baseline LDL 70-189 mg/dl" (emphasis theirs)
--and they do consider it "reasonable" to add either ezetimibe or a PCSK9 inhibitor in those with ASCVD and comorbidities and baseline LDL 70-189 mg/dl.
--they favor adding ezetimibe in patients where an additional <25% lowering of LDL is "required": an acute coronary syndrome in past 3 months, patient preference, heart failure, hypertension, age >75, diabetes, stroke, CABG, PAD, eGFR<60, and smoking.
--and PCSK9 inhibitor in those requiring a greater reduction and willing to have a (very expensive) injection
--they identified patients at high cardiac risk as per the FOURIER study: those with ASCVD and at least one of: age >65, prior MI or non-hemorrhagic stroke, current daily cigarette smoking, symptomatic PAD with prior MI or stroke, history of non-MI related coronary revascularization, residual coronary artery disease with >40% stenosis in >1 large vessel, HDL <40 mg/dl for men or <50 mg/dl in women, hs-CRP >2 mg/L, or metabolic syndrome
Commentary:
--the new guidelines were catapulted forward based on the decreases in LDL levels by moderately effective nonstatin drugs (eg ezetimibe) and profoundly effective ones (PCSK9 inhibitors), and the associated decrease in clinical atherosclerotic events
--but, as per my prior blogs (eg, see http://gmodestmedblogs.blogspot.com/2013/12/further-thoughts-on-am-heart-assn-2013.html ), there really is pretty consistent and convincing evidence that it really is the achieved LDL and not the specific use of "high intensity" vs "moderate intensity" statins.
--so, though the impetus for the change was these new (and really expensive, especially the PCSK9 inhibitors) drugs (which were likely studied by those high up in the various cardiology associations, who no doubt have influence on ECDP recommendations), i think that the same argument for aggressive therapy to lower LDL levels would apply to statins themselves, though this is not even mentioned in their quite long document.
--for example, I certainly see lots of high risk patients who get very low LDLs (eg in 40 mg/dl range) on atorvastatin 10mg (a "moderate intensity statin", defined as atorvastatin 10 or 20 mg, lovastatin 40mg, pitorvastatin 2 or 4mg, rosuvastatin 5 or 10mg, or simvastatin 20 or 40mg). And lots of people who get down to an LDL of only around 110 mg/dL on atorvastatin 40 mg ("high intensity statin", defined as atorvastatin 40 or 80mg, rosuvastatin 20 or 40mg), yet have significant further decreases when switched to rosuvastatin 40mg.
--one concern about this recommendation is that they suggest the goal LDL be <70, but the baseline LDL was already pretty low in both the PCSK9 inhibitor studies (eg FOURIER study baseline LDL was 92, but they did find similar clinical benefit in those with median baseline LDL of 74 mg/dl) and in the IMPROVE-IT study with ezetimibe (baseline LDL of 69.5 mg/dl, decreasing 24% to 53.7 mg/dl on ezetimibe and associated with a 6% decrease in their primary clinical endpoint. see critique of this study)
--so, makes it really hard to get a handle on what the real target should be. Is <70 mg/dl enough? should it be 30 mg/dl as in the FOURIER study?????
--another change over the 2013 recommendations is to be more aggressive in older patients, which does reflect their increased absolute risk for a cardiac event. This more aggressive stance, I think, is because they are using non-statin therapies which have fewer adverse events in the elderly noted so far. So their recommendations still stand for "moderate intensity" statins in those >75yo, though I have been using higher doses of statins pretty regularly in high risk elderly, with rare problems.
--conspicuously absent from their list of high-risk conditions includes diabetes. And they are using mildly elevated hs-CRP as a condition leading to more aggressive therapy, probably because it would likely subsume several of the higher risk infectious or inflammatory conditions (eg chronic hepatitis, perhaps HIV, rheumatoid arthritis, etc). these specific absences seem to be because they adopted the criteria from a specific study (FOURIER)
--i should mention that in 2016, the EDCP writing committee was already moving toward a focus on the achieved LDL level, though this is more codified in the 2017 recommendations above.
--as a side issue, in patients who have statin intolerance or difficulty with daily meds, some of the long half-life statins (atorvastatin, rosuvastatin, pitavastatin) can be given 3x/week or even weekly. also, since most of the effect of statins is at the lowest dose, patients can be rechallenged with a different statin at the lowest dose.
so, still several unanswered questions.
--what really is the goal/best target for LDL cholesterol? though older studies have found that lowering the LDL by 30% was equally beneficial with higher LDL vs lower LDL levels, but the range of LDL was small and it is not clear that lowering an LDL 30% from 50 mg/dl would have the same benefit as if the LDL were lowered 30% to 120 mg/dl.
--and is there any difference whether the LDL target were achieved by increasing the dose of the statins (which do have several beneficial pleiotrophic effects, such as being anti-inflammatory, anti-oxidant, improving endothelial function, etc) vs the nonstatin drugs above? Eg: the IMPROVE-IT study of ezetimibe achieved pretty small clinical benefit (a 6% decrease in clinical events and a 2% absolute decrease over 6 years, even though there was a 25% decrease in LDL levels)
--why did they not comment on augmenting the statin dose to the max (rosuvastatin 40mg), when there is a dose-response curve for clinical events (eg, see the Treating to New Targets study comparing atorvastatin 10 vs 80mg, also reviewed some in the IMPROVE-IT study )? and perhaps lower the statin dose for some high risk patients who achieve very low LDL levels on moderate statin doses?
--my approach will still be the same: if the LDL is somewhat higher than desired (eg >70 in very high risk person), my initial approach will still be to increase the statin intensity to rosuvastatin 40 (doing it more gingerly and with closer followup in those >75). i would then consider adding ezetimibe if necessary, though i am less impressed with its protective effect and the only trial was adding ezetimibe 10mg to simvastatin 40mg (unfortunately, a drug-company sponsored trial, using hardly the optimal statin potency)
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