statins: treat-to-target LDL

 A Korean non-inferiority study compared the effects of prescribing high-intensity statins versus a treat-to-target approach in patients with coronary artery disease , in a noninferiority randomized clinical trial (see lipids treat to target JAMA2023 in dropbox, or doi:10.1001/jama.2023.2487) 

 

Details: 

-- 4400 patients from 12 centers in South Korea who had coronary artery disease were randomized to a high intensity statin versus a treat-to-target approach to achieve in LDL between 50-70 gmg/dL

-- mean age 65, 28% female 

-- BMI 25, history of hypertension 67%/diabetes 33%/previous percutaneous coronary intervention 57%/previous CABG 7% 

-- current smoking 14%, eGFR 88 

-- baseline lipid levels LDL 86/HDL 47/triglycerides 138 

-- cardiovasc history at randomization: acute MI 7%/ >1yr from MI 15%/unstable angina or revascularization 17%/ >1yr after unstable angina or revascularization 41%/ asymptomatic CAD 19% 

 

- statin intensity: moderate intensity statins were atorvastatin 20 mg or rosuvastatin 10 mg , high intensity were atorvastatin 40 mg or rosuvastatin 20 mg  

-- in the treat-to-target group, statin-naïve patients were started on a moderate intensity statin, those already on a statin were maintained on an equivalent intensity statin if their LDL <70 mg/dL, the statin intensity was up-titrated when the LDL >70; this was further up- or down-titrated as needed to keep in the 50 to 70 mg/dL range 

-- those in the high intensity group stayed on a high intensity statin without adjustment, regardless of their follow-up LDL level 

-- non-statin add-on therapy (e.g. ezetimibe) was not recommended strongly, even when the target was not achieved with high intensity statin 

-- risk factor modification (blood pressure, glucose control, dietary changes, weight reduction, exercise, and smoking cessation) was encouraged at follow-up visits at 6 weeks, then at 3, 6, 12, 24, and 36 months, and lipid analysis was done at 6 weeks, then at 12, 24, and 36 months

-- safety monitoring included plasma glucose, AST, ALT, creatinine, CK, and hemoglobin A1c 

 

-- primary endpoint: 3-year composite of death, myocardial infarction, stroke, or coronary revascularization, with a noninferiority margin defined as 3.0 percentage points 

-- secondary endpoints: new onset diabetes, hospitalization for heart failure, DVT or pulmonary thromboembolism, endovascular revascularization for peripheral arterial disease, aortic intervention or surgery, end-stage kidney disease, discontinuation of study drugs from intolerance, cataract operation, and a composite of laboratory abnormalities 

 

Results: 

-- treat-to-target group: 43% were taking a moderate intensity statin and 54% a high intensity statin

    -- statin titration in treat-to-target group: up-titrated in 17%, down-titrated in 9%, and remained without changes in 73% 

-- high intensity statin group: 91% were on a high intensity statin 

-- 99% of the patients completed the trial, with 6449 person-years of follow-up 

-- mean achieved LDL over 3 years: 

    -- treat-to-target group: 69 mg/dL

    -- high intensity statin group: 68 mg/dL

-- primary endpoint: 

    -- treat-to-target group: 177 patients (8.1%) 

    -- high intensity statin group: 190 patients (8.7%) 

        -- absolute difference -0.6 percentage points, p<0.001 for noninferiority 

 

-- there was no significant difference between the groups in all-cause mortality, MI, or stroke, either by intention-to-treat or per-protocol evaluations 

-- adverse effects, comparing treat-to-target versus high-intensity statin groups: statistically significant differences in new-onset diabetes (5.6% versus 7.0%, p=0.07, almost statistically significant), end-stage kidney disease 0.1% versus 0.5%, p=0.05, and especially significant for the composite of new onset diabetes, ALT/AST elevation, CK elevation, and end-stage kidney disease: 6.1% versus 8.2%, p=0.009 

 

-- In the treat-to-target  group: only 58% met the 50-70mg/dL target   

 

Commentary: 

-- there actually have been a couple of studies that have suggested strongly that LDL treating-to-target was beneficial: 

    --  the treating to new targets study (TNT) found that atorvastatin 10 mg versus 80 mg was associated with the same clinical outcomes when the same LDL level was achieved (they also found that the achieved HDL level contributed significantly to cardiovascular benefit; this graph assessed the achieved LDL to HDL ratio levels, and found no difference in outcomes for those on atrovastatin 10 vs 80mg)

 

    -- a stroke trial that randomized people to LDL targets of <70mg/dL vs 90-110 mg/dL, using adjustable doses of statins and ezetimibe as needed, found that the LDL <70mg/dL group had a 22% reduction in the composite endpoint of ischemic stroke, MI, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes (see https://gmodestmedblogs.blogspot.com/2019/11/stroke-treating-ldl-to-target.html ) 

 

-- A few comments about the treat-to target approach: 

    -- my rather extensive experience with statins has indicated that some patients on lower dose statins achieve LDL levels as low as the 30-40 mg/dL range, whereas some with high dose statins (eg rosuvastatin 40mg) never get down below 100 mg/dL and need to have added ezetimibe. some of this is the starting point of LDL level of the patients, but some seems to be from individual variability of statin response. 

    -- this treating-to-target approach does involve more lipid monitoring, which I personally do on an annual basis. I believe this is very important for 2 reasons: 

        -- adherence to statins overall is not that great, so monitoring lipid levels provides a window into adherence, creating a time to reinforce both medication adherence and important life-style changes with the patients

        -- and this is all in the setting that statins are remarkably effective in decreasing cardiovascular effects both in primary and in secondary prevention (both in the 30+ percent range), with very uncommon serious adverse effects: even if there is a higher level of diabetes created, analysis suggests that the benefits of statins outweigh those risks. see https://gmodestmedblogs.blogspot.com/2017/11/statin-use-and-diabetes-is-that-real.html; also there is an interesting argument that low LDLs are associated with increased risk of diabetes (ie, it's not the statins): see https://gmodestmedblogs.blogspot.com/2015/09/low-ldl-and-diabetes-risk.html

    -- there are unkownns in this treating-to-target approach in choosing the appropriate target and doing what is necessary to do to achieve it.  

        -- for example, an observational study of high risk patients found that there was clinical cardiovasc benefit down to an LDL of 21 mg/dL, with no attendant harms [see (https://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html ), as well as an evaluation of the FOURIER trial, included in this observational study, finding a benefit of lowering the LDL to <40 mg/dL (https://gmodestmedblogs.blogspot.com/2021/12/ldl-less-than-40-in-high-risk-patients.html )] 

        -- the target in this current study of an LDL between 50 and 70 mg/dL was informed by the new European guidelines of a goal LDL of 55 mg/dL in high risk people.

    -- also, the concept of statin intensity is a bit fraught: not only do people respond differently to the same statin dose in terms of LDL levels, but there is really a big difference in LDL levels from atorvastatin 40 mg versus rosuvastatin 40 mg, both of which considered to be “high intensity”; as well as from atorvastatin 10mg vs either simvastatin 40mg or rosuvastatin 10mg, all of which are considered "moderate intensity"

    -- one other word of caution: the cardiac risk calculators are based on populations (Framingham etc). But individual patients may have well-documented risk factors that elevate their personal risk (eg chronic inflammation from collagen-vascular diseases such as lupus and rheumatoid arthritis; or from chronic infections including even well-treated HIV or hepatitis B) and some others (atherosclerotic disease elsewhere, bests studied being peripheral arterial disease and stroke), and even migraine, or being on atypical antipsychotic medication, as well as some perhaps more common ones, such as microalbumin (eg see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358423/ ) or creatinine >1.1.

    -- the issue here is that if one assesses a large population, even a strong cardiovascular risk factor if present in a minority of people would not qualify for the risk calculators

    -- there are a multitude of risk calculators, though very few deviate much from blood pressure, lipids, smoking, and diabetes (though this is a binary variable, and we know that the level of A1c pretty substantially alters the risk). a few have family history. but none seem to have peripheral artery disease or other atherosclerotic diseases (PAD, stroke)

    -- the UK uses an enhanced QRISK3 calculator, which includes the usual culprits, but also family history of angina or heart attack, atrial fibrillation, migraines, rhematoid arthritis, lupus, CKD stage 3-5, severe mental disease (schizophrenia, bipolar, moderate/severe depression), being on atypical antipsychotics or steroids, or having erectile dysfunction (see https://gmodestmedblogs.blogspot.com/2017/08/a-new-atherosclerosis-risk-calculator_2.html )

    -- and, of note, the more complex QRISK3 calculator seems to be a better cardiovascular event predictor than the Framingham Study (see https://www.frontiersin.org/articles/10.3389/fendo.2022.1077632/full , finding it bested the Framingham risk core in diabetic patients

    -- my general approach is one of "gestalt": assess the usual risk factors for a given patient, then add in the other known factors that are known increase cardiac risk, and basically guess what is an appropriate target LDL (realizing that the likely benefit with be more than the risk). for example, i would be more aggressive for a person with documented CAD with multiple cardiovascular risk factors and continued smoking, or someone with several traditional risk factors but who has HIV or rheumatoid arthritis or PAD, whom I might treat to a goal LDL of 40 mg/dL, which is frequently achievable with rosuvastatin 40 but often with ezetimibe. all, of course, with a discussion with the patient of risks/benefits 

Limitations: 

-- in this trial they did not achieve the goal of the current European guidelines of 55 mg/dL. In the treat-to-target group, they could have done better than their achieved 69 mg/dL: both by up-titratin the statins if needed or by adding ezetimibe

-- the patients in the treat-to-target group were randomized to rosuvastatin 10 mg or atorvastatin 20mg for the moderate intensity statin group, and rosuvastatin 20mg or atorvastatin 40mg for the high-intensity group. and, as mentioned above, given the different LDL outcomes between rosuvastatin 10mg vs atorvastatin 20mg, or between atorvastatin 40mg vs rosuvastatin 20mg, it might have been helpful to change statins within the specific statin-intensity group. though a tad anecdotal, i personally have increased patients from atorvastatin 40mg (high intensity) to atorvastatin 80mg with significant benefit, and then from atorvastatin 80mg to rosuvastatin 40mg, if needed, with significantly more LDL reduction)

-- and, with the achieved LDL level of 69 mg/dL in the study, only about 58% of the patients in the treat-to-target group actually achieved the target of 50-70 per mg/dL range; there was no difference in the those in the high intensity statin group. i think the reason for these higher LDL levels is that the study wanted to show that many patients could achieve the same LDL level with many fewer on high intensity statins and have the same outcomes. But the real clinical goal for us clinicians would be to show that target-to-treat could lead to much better LDL control and have (presumably) much better subsequent clinical outcomes.

 

So, 

-- not so surprising that there was no significant difference in the clinical endpoints, since the achieved LDL was the same in both groups (ie, they achieved non-inferiority)

-- it was a significant outcome, however, that the adverse effects were significantly more in those on the consistently higher dose of statins in the high-intensity group (though not a very large absolute difference between the groups, and basically non-serious problems)

-- but in light of the array of studies finding that the lower the LDL, the better for clinical outcomes, i personally have been developing personal per-patient LDL goals (and i do take into account the achieved HDL somewhat) and titrating the statin type and dose, sometimes with ezetimibe, as noted above

   -- and promoting a treat-to-target approach for LDL levels, i think, is really important, especially since cardiovascular disease is such a prominent cuase of disability and death. And especially in the setting of increasing obesity and diabetes in the population, likely to elevate these cardiovascular issues more in the future......

geoff

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