treating LDL to target? more evidence

A recent Korean multicenter observational study found that patients with coronary artery disease who achieved an LDL <70 mg/dl had very significantly decreased atherosclerotic plaque progression than those with higher LDL, further supporting the concept of treating-to-target to specific LDL levels (see lipids intensive LDL lowering dec CAD progression JACC2016 , or doi.org/10.1016/j.jcmg.2016.04.013).

Details:

--147 patients with visible plaques on coronary CT angiography (CTA) who had another CTA at least 2 years later (median 3.2 years), as well as lab values within 1 month of both the baseline and followup CTAs

--mean age 62, 57% male, BMI 25, hypertension 65%, diabetes 33%, active smoker 20%, NCEP ATPIII risk score <10 in 55%/10-20 in 32%/>20 in 13%, Framingham risk score <10 in 63%/10-20 in 29%/>20 in 9%. Of note, those who achieved an LDL<70 were sicker: 1.95 vs 1.54 cardiac risk factors, 54% vs 26% with diabetes. though overall not a high risk group.

--initially, 57% asymptomatic, 8% noncardiac chest pain, 29% atypical chest pain, 3% typical chest pain and 3% shortness of breath

--labs:

   --prior to initial CTA: cholesterol 183 mg/dl, HDL 48, LDL 114, TG 154, and 40% were on a statin

   --prior to followup CTA: cholesterol 162, HDL 48, LDL 92, TG 122, and 73% on statin

   --mean LDL initially in those who had followup LDL<70: 106 mg/dl (vs 116 mg/dl in those with LDL>70) [so, those who achieved a lower LDL started with a lower LDL]

   --mean follow-up LDL in those who had  LDL<70: 57 mg/dl (vs 104 in those with LDL>70). All patients who achieved LDL<70 were on a statin.

Results:

--univariate associations for annual plaque volume change: BMI (p=0.045), hypertension (p=0.040),follow-up LDL<70 (p=0.018)

--multivariate association: only the achieved LDL on followup CTA exam was associated with less plaque volume change (p=0.021)

--in the subgroup on statins: comparing those achieving LDL <70 (n=37) vs >70 (n=70):

   --change in plaque volume: 12.7 vs 41.8 mm³, p=0.009

   --annual change in plaque volume: 4.6 vs 14.5 mm³, p=0.015

Commentary:

--there are some limitations to this study, including its retrospective/observational design (eg, there could be missing unknown biases which influenced the aggressiveness of patient treatment), lack of information on the particular statins and doses used, and lack of data on consistency of statin use (data only for the month before the CTAs)

--However, the conclusions of this study are impressive in terms of differences in plaque progression, and add to the already pretty abundant literature finding that achieved LDL is an important target to therapy in those with coronary artery disease. And, I might add that even the 2013 AHA/ACC guidelines, which call for statin intensity determined by demographic or comorbidity criteria and not "treating-to-target" (ie, not using patient-level achieved LDL levels) do implicitly incorporate a treat-to-target approach in that they support more aggressive LDL reduction in some patients over others. But, they argued that since there were no clear RCTs stratifying patients to specific LDL goals, they should therefore not recommend using  LDL targets. This reasoning was suspect to me (as per prior blogs), since pretty much all of the other AHA recommendations were based on even​ less rigorous data​

--There are several older studies which supported treating LDL to target instead of prescribing high- vs moderate-intensity statins based on categories of risk.

   --studies have shown pretty unambiguously that the achieved LDL determines the risk of cardiac events (there is a summary of the evidence in the ezetimibe blog referenced below)

   --older studies using IV ultrasounds have also shown decreased plaque progression with statins. Coronary CTA, as in the above study, has been shown to be reproducible, correlates well with IVUS measurements, is noninvasive (other than radiation…)​, and supports the prior more-invasive IVUS studies

--several new studies have reinforced the utility of trying to decrease LDL to a lower target:

   --IMPROVE-IT trial found that adding ezetimibe to simvastatin in 18,144 patients led to a 24% reduction in LDL levels (down to 53.7 mg/dl), associated with a 6% decrease in a composite of cardiovascular outcomes.   See http://gmodestmedblogs.blogspot.com/2015/06/improve-it-trial-ezetimibe.html  for a critique of that study, along with more detailed arguments for targeting-to-treat LDL levels, plus an argument for adding HDL into the treatment decision model.

   --FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study, just released of 27,564 patients followed over 2.2 years (see lipids PCSK9 evolocumab nejm2017 in dropbox, or DOI: 10.1056/NEJMoa1615664) found that adding PCSK9 inhibition, vs statin therapy alone (70% on high-intensity, 30% on moderate-intensity) led to a mean LDL of 30 mg/dl from a baseline of 92 mg/dl, and an associated 15% reduction in the combined primary endpoint (MI, stroke, hospitalization for chest pain, stent placement, death), a reduction from 11.3% to 9.8% of patients. [this was less of a reduction than the anticipated 20% reduction, which, by the way, led to a significant reduction in the value of the company in the stock market…]. In terms of secondary outcomes: 20% reduction of the combination of cardiovascular death, MI, or stroke; 27% decrease in risk of MI;  21% decrease in stroke, and 22% decrease in coronary revascularization, with clinical benefit evident within 6 months and increasing thereafter. There was no significant reduction in cardiovascular deaths or hospitalizations for unstable angina. I personally am not pushing these very expensive injectable drugs at this point (and have never prescribed them), but bring up this study as further evidence that targeting a low LDL seems to be beneficial.

--I suspect that some of the rationale for pushing the statin intensity argument, as opposed to the treat-to-target, is that if there is not a really simple guideline, many patients will not be treated at all with statins.  And I do respect that argument. The rationale for starting statins when patients are in the hospital with an atherosclerotic cardiovascular event is that otherwise they might never get the statin....

--but, there is large inter-patient variability in what the achieved LDL will be on different doses of statins, some of which depend on the initial pretreatment LDL and some on just individual variation (eg, some of my very high risk patients on atorvastatin 10mg achieve LDLs of 40 or so. Do they need more aggressive treatment? with the attendant increase in adverse reactions?)

--and, on the other hand, I certainly have several patients who did not achieve their LDL goal even with the "high-intensity" atorvastatin 40 or even 80mg, but who did when switched to rosuvastatin 40mg. 

--so one consequence of not using a target LDL is that we may be undertreating some high-risk patients, even without needing to go to the newer agents. and the other is that we may be overtreating others by starting off with too high a dose of statins. 

--and, i think it makes reasonable sense to target the LDL levels on a per-patient and per-statin basis (ie, not on a community scale, where the dose is determined by age, comorbidities, etc).  it's a bit like treating hypothyroidism by the T4 level, where normal is a bell-shaped curve based on community data, vs TSH, which reflects the individual's response to their own ambient T4 level​ 

--my major concern with statins really is the finding that many patients stop doing general lifestyle changes (and perhaps many clinicians do not continue to focus on them) because of the pretty dramatic lipid improvement with statins.  But the data are pretty consistent that a healthy lifestyle has a multitude of positive physical and psych effects beyond just the cardiovascular ones, and it is important to me that we continue to help motivate patients to improve their diet and exercise in particular.

 

--so, my sense is that there really are consistent data from an array of different types of studies suggesting that lower LDL levels lead to less accumulation of atherosclerotic plaque (as in the above study) as well as fewer atherosclerotic events (per both older statin studies as well as the newer studies with the newer agents), that titrating statin dose to the individual patient seems reasonable based on this, that we can pretty often achieve LDL levels <70 through that titration (likely to the benefit of the individual patient, especially important in secondary prevention),  but that we should be vigilant in reinforcing healthy lifestyle changes.