Press Rewind: The 2018 AHA guidelines bring back LDL targets, frequent monitoring, and non-statin therapies
EBM Focus - Volume 13, Issue 41
Reference: J Am Coll Cardiol 2018 Nov 8 early online
Last week the EBM Focus examined the 2018 AHA guidelines on management of blood cholesterol for primary prevention. Now it is time to take a look at the guideline recommendations for secondary prevention. To better determine the benefits of additional therapies among patients taking statins, the guideline authors commissioned a systematic review and meta-analysis examining the efficacy of nonstatin therapy for secondary prevention. For many, the guideline may be a reminder of the 2004 ATP guidelines with specific treatment targets and sequential therapy based upon frequent monitoring.
Similar to prior recommendations, for patients aged younger than 75 years with clinical atherosclerotic cardiovascular disease (ASCVD), there is a strong recommendation for beginning high intensity statin therapy first. The guideline emphasizes the importance of shared decision making when prescribing these medications. For those over age 75, much of the evidence is based upon post hoc analysis of prior trials which suggests that in in this population, statins reduce cardiovascular events, but not mortality. The authors advise that clinicians engage in shared decision making when prescribing to this population in particular.
This guideline also brings back the focus on LDL goal and the use of nonstatin therapies after initiation of maximally tolerated statin. The guideline recommends frequent monitoring and defines effective treatment as a greater than 50% reduction in LDL, with a goal LDL to a value of <70 mg/dL in patients at very high risk of further ASCVD events. Those at very high risk include patients with a history of a major vascular event and additional risk factors (such as a patient over 65 with diabetes and known coronary artery disease). For all patients with clinical ASCVD, it states that aiming for an LDL of <70 mg/dL is reasonable. To achieve this goal, the guideline recommends adding ezetimibe first and then considering a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9), while at the same time acknowledging the cost-prohibitive nature of the PCSK9 inhibitors for many patients.
The recommendation for ezetimibe stems from the IMPROVE IT trial which demonstrated an absolute reduction of 2% in the rates of myocardial infarction among patients with an acute coronary syndrome treated with ezetimibe plus simvastatin as compared to simvastatin alone. The benefit seen in IMPROVE-IT is comparable to the results of a recent Cochrane review examining use of ezetimibe for the prevention of cardiovascular disease. It too found a decrease in cardiac events but no mortality benefit. The IMPROVE-IT trial was notable for the high discontinuation rate of 42% and the use of a moderate intensity statin. Patients on high-intensity statin therapy were excluded. The guideline authors acknowledge this weakness and point to two simulation studies which demonstrated an expected significant reduction in LDL therapy with ezetimibe. This recommendation to drive the LDL as low as possible seems to be based upon data from the newly published trials of PCSK9 inhibitors, in which LDL values of 25 to 50 mg/dL were associated with a reduced risk of vascular events. The authors may have extrapolated data from these trials focused on PCSK9 inhibitor therapy in which vascular events and LDL levels were both reduced to justify the recommendation of adding ezetimibe therapy. Ezetimibe improves LDL by 12-25 mg/dL in most studies. Notably, only 3-5% of PCSK9 trial participants were taking ezetimibe. Additionally, they recommend ezetimibe therapy across all ages, although the average age in IMPROVE IT was 63 years. The authors cite the cost-prohibitive nature, uncertain long-term effects, and risk of antibody formation with use of the PCSK9 inhibitors as limitations to the widespread use of this class of medications. As such, PCSK9 inhibitors receive a value statement of “low value” based upon 2018 prices. While it is true that ezetimibe lowers LDL, the correlation between a lower LDL and lower event rate was stronger in the PCKS9 inhibitor trials.
Focus Point: Further driving down LDL with nonstatin therapy for patients with known atherosclerotic cardiovascular disease may reduce the risk of heart attack or stroke by about 2% without affecting mortality. The benefit is likely greatest for those at highest risk and is most uncertain for low-risk or elderly patients. For patients who require PCSK9 inhibitors, it is important to discuss with them the anticipated patient the cost of medication so that they can weigh that against the modest expected risk reduction.
DynaMed Plus EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Faculty Development and Information Mastery Fellow and Clinical Instructor at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed Plus and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Assistant Professor in Family Medicine at the University of Virginia and Clinical Editor at DynaMed Plus.