Response to the Letter Regarding Article, “Bringing Back Targets to ‘IMPROVE’ Atherosclerotic Cardiovascular Disease Outcomes: The Duel for Dual Goals; Are Two Targets Better Than One?”
Authors: Erin D. Michos, Seth S. Martin, Roger S. Blumenthal
Journal: Circulation (2016)

As noted in our editorial, 1 we agree with Dr Robinson that observational and subgroup analyses, even those prespecified, warrant cautious interpretation.However, our support for low-density lipoprotein cholesterol (LDL-C) target or reference levels extends beyond the single subgroup analysis from the IMProved Reduction of Outcomes: Vytorin Efficacy Internation Trial (IMPROVE-IT) trial 1 and is based on the totality of evidence supporting a causal role of LDL-C in atherosclerotic cardiovascular disease from genetic, animal, observational, and randomized, clinical trial (RCT) data.The 2010 Cholesterol Treatment Trialists meta-analysis pooled patient-level data from 170 000 statin RCT participants and found that the proportional reduction in the rate of major cardiovascular events with statin therapy was about a fifth for each 1.0-mmol/L (39-mg/dL) reduction in LDL-C. 2 Genetic studies have shown that individuals with LDLlowering polymorphisms have a relative reduction in coronary heart disease of 55% per 1-mmol/L-(39-mg/dL-) lower LDL-C. 3From a pragmatic standpoint, we routinely obtain on-treatment lipids in the clinic, as recommended by the guidelines, and having specific reference values for LDL-C can enhance clinician-patient discussion. 4e endorse the risk-based approach in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines to the application of statin therapy, a process that includes a clinician-patient risk discussion factoring in the potential for atherosclerotic cardiovascular disease risk reduction, the potential for adverse events, and patient preferences. 4However, following the guidelines, new RCT evidence from IMPROVE-IT and early data from the PCSK9-inhibitor trials indicate that certain nonstatin lipidmodifying agents added to background statin therapy could further reduce atherosclerotic cardiovascular disease events in high-risk populations.This may fill an unmet need for a group of individuals who have high residual risk for recurrent events despite optimal treatment with lifestyle interventions and statin therapy.We cautiously stated in our editorial that the concept of "even lower is better" should be extended only to therapies with proven outcome benefit and safety.We suggest that LDL-C thresholds could be used to promote further intensification of lifestyle measures and to guide shared decision making about potential add-on pharmacotherapy.We agree with Dr Robinson that an RCT comparing "titration-togoals" strategies for lipid therapy (similar to what was done recently for blood pressure targets 5 ) would be informative.Unfortunately, RCTs are expensive and are not always feasible for every clinical question.In the absence of RCT data for the specific clinical question at hand, clinicians must use their judgment based on the best possible current evidence from the totality of available observational and RCT data.