Improving cardiovascular outcomes by intensifying low density lipoprotein lowering therapy in high-risk patients

This editorial refers to ‘The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial’†, by A. Eisen et al., on page 3576. One of the foundations of preventive cardiology is that the higher risk an individual person is for future cardiovascular events, the more aggressively that individual should be treated to reduce risk. While different medical societies throughout the world have recommended different approaches to assess risk, this premise has been universally accepted and is factored into all guidelines. Reduction in low density lipoprotein cholesterol (LDL-C) is a cornerstone of cardiovascular risk reduction, but questions remain about how aggressively LDL-C should be reduced in high-risk patients. A meta-analysis of statin trials by the Cholesterol Treatment Trialists (CTT) demonstrated every 1.0 mmol/L reduction in LDL-C is associated with a corresponding 20–25% reduction in cardiovascular events over 5 years.1 Based on these abundant data, statins are widely used to reduce risk in high-risk individuals. In contrast, the use of non-statin cholesterol lowering agents in addition to statins to reduce cardiovascular risk has been controversial. Prior to 2015, there were no large randomized trials to assess the benefits of adding a non-statin agent to statin therapy in reducing CV events. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults focused on statin therapy as the primary goal,2 while the 2014 National Lipid Association recommendations for patient-centred management of dyslipidaemia used LDL-C goals with non-statin agents as necessary to achieve them.3 The IMPROVE-IT trial published in 2015 was the first large scale randomized trial to show the benefit of a non-statin agent in reducing cardiovascular events when added to statin therapy.4 The benefits achieved by adding ezetimibe was in line with the benefits from statins shown in the CTT meta-analysis. Thus, the 2016 European Guidelines on Cardiovascular Disease Prevention in Clinical Practice considered statins the drugs of first choice, but supported the notion that LDL-C reduction was key, independent of the approach used.5 The ACC also modified its guideline to re-introduce the achievement of LDL-C goals using the non-statin agent ezetimibe with the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk.6 Based on the IMPROVE-IT trial, the use of non-statin agents in addition to maximally tolerated statin therapy is generally accepted. However, the clinical benefit of ezetimibe in the overall IMPROVE-IT trial was modest, with a hazard ratio of 0.93 and an absolute risk reduction of 2%.4 With this in mind, it has been difficult for clinicians to determine when it is worthwhile to add ezetimibe to a statin as part of a patient’s medical regimen. The current report by the TIMI group published in the European Heart Journal pulls together these important concepts, providing the strongest evidence yet that treating the highest risk patients more aggressively confers greater benefit.7 In IMPROVE-IT, 18 134 post-ACS patients with a mean LDL-C of 93.8 mg/dL were randomized to simvastatin or simvastatin/ezetimibe.4 Of these patients, 1684 (9.3%) had a known history of prior CABG.4 During the 7 years of the IMPROVE-IT trial, the patients with a prior CABG had a significantly higher risk of recurrent events. The prior CABG patients received significantly greater benefit from treatment with ezetimibe in addition to statin therapy. The primary endpoint—a combination of cardiovascular death, major coronary events, or stroke—in patients with a prior CABG occurred in 60% of patients treated with simvastatin alone and in 51.2% with the addition of ezetimibe, for an absolute risk reduction (ARR) of 8.8% and number needed to treat (NNT) of 11.7 In contrast, without prior CABG this endpoint occurred 32.2% of the time with simvastatin, and 30.9% of the time with ezetimibe, with an ARR of 1.3% and a NNT of 77 (see Table 1).7 This report reinforces LDL-C treatment goals, and assists clinical decisions regarding the addition of ezetimibe in high-risk patients. Trial characteristics Eze, ezetimibe; Simva, simvastatin; LDL, low density lipoprotein cholesterol (mg/dL);HR, hazard ratio; ARR, absolute risk reduction; NNT, number needed to treat. Trial characteristics Eze, ezetimibe; Simva, simvastatin; LDL, low density lipoprotein cholesterol (mg/dL);HR, hazard ratio; ARR, absolute risk reduction; NNT, number needed to treat. In IMPROVE-IT, patients with a prior CABG and subsequent ACS had a very high residual risk, with 60% reaching the primary endpoint over 7 years even on statin therapy with an LDL-C <70 mg/dL. This increased risk has been reported in other trials as well, with CABG being the strongest predictor for rehospitalization for ACS, with a hazard ratio of 2.12 on multivariable models.8 IMPROVE-IT patients with a history of CABG were more likely to have multiple other co-morbidities, including prior myocardial infarction (MI), heart failure (HF), diabetes mellitus (DM), hypertension, and peripheral arterial disease (PAD). The current report did not provide separate subgroup analyses of these co-morbidities. Furthermore, the IMPROVE-IT trial enrolled only post-ACS patients, and therefore does not provide data on stable CABG patients, or high-risk patients with other co-morbidities but without ACS. Despite these limitations, one might reasonably apply the findings of this trial to treat not only post-CABG with ACS but also other very high risk patients to more aggressive LDL-C goals. In those IMPROVE-IT patients without prior CABG, the addition of ezetimibe resulted in an ARR of 1.3% and a NNT of 77.7 The authors point out that this result should not be used to deny coverage of ezetimibe in post-ACS patients, but rather should result in a more individualized decision between the clinical provider and the patient. This reinforces the basic premise of preventive cardiology, where higher risk patients derive more benefit from aggressive risk reduction and therefore should routinely receive more intense pharmacologic management, while lower risk patient require more individualization of therapy choices. Should these results impact the current guidelines? As mentioned above, recommendations published after the IMPROVE-IT trial results generally promote an LDL-C goal of < 70 mg/dL for the highest risk patients, to be achieved with maximally tolerated statin therapy and the addition of ezetimibe if needed.3,5,6 The current report showing a more impressive absolute risk reduction in the highest risk patients with prior CABG should lead clinicians and future guideline writers to consider even lower targets. Indeed, IMPROVE-IT is not alone in suggested potential benefit of achieving LDL-Cs well below 70 mg/dL in high-risk patients. An achieved median LDL-C of 55 mg/dL, down from a baseline of 108 mg/dL using rosuvastatin 20 mg in patients with an elevated hsCRP, resulted in a hazard ratio of 0.56 in the JUPITER trial.9 These results are consistent with prior trials of subclinical atherosclerosis, such as ASTEROID, which showed regression of atherosclerosis on IVUS using rosuvastatin 40 mg to achieve a median LDL-C of 60.8 mg/dL.10 The early results of the PCSK9 trials have also suggested risk reduction with achievement of very low LDL-Cs using these powerful agents. In ODYSSEY LONG TERM, treatment with alirocumab resulted in a hazard ratio of 0.52 by achieving an LDL-C of 48.3 mg/dL, while in OSLER, evolocumab reduced the LDL-C to a median of 48 mg/dL resulting in a hazard ratio of 0.47.11,12 That being said, these trials were not powered for CV events, and the fully-powered outcomes trials with PCSK9 inhibitors are ongoing with expected completion dates in late 2017 and 2018.13,14,15 Updated guidelines with formal reinstitution of LDL-C goals and promotion of more aggressive LDL-C targets may wait until these PCSK9 inhibitor trial results are available over the next few years. Whether achieving LDL-C goals can be extrapolated beyond statins and ezetimibe to other non-statin agents such as PCSK9 inhibitors will be the topic of many future conversations. The different pleiotropic effects of medications have long been discussed, but in the field of dyslipidaemia and cardiovascular risk reduction, a benefit of pleiotropic effects has not been proven. The current trial may suggest a benefit of ezetimibe beyond LDL-C lowering in CABG patients, but that is far from proven, and should not change current clinical management. Ezetimibe now holds a clear role as the second line agent for high-risk patients that are close to goal, but have not achieved it. Early data on PCSK9 inhibitors suggest clinical benefit that is appropriate to their degree of LDL-C lowering, though the outcome trials to prove this are currently in progress. We anxiously await their results, and in the interim we will continue to use PCSK9 inhibitors to achieve LDL-C goals when statins and ezetimibe cannot reach them. By considering the impact of ezetimibe in prior CABG patients who have experienced a recent acute coronary syndrome, Eissen et al.7 have provided important insight into cutting edge management of high risk populations. Five conclusions can be drawn: (1) CABG patients, especially those who experience a subsequent event, have very high-residual risk, even on ‘optimal’ medical therapy; (2) Implementation of current guidelines in clinical practice focused on high-intensity statin therapy has not resulted in achievement of the aggressive LDL-C goals or elimination of recurrent CV events; (3) The addition of ezetimibe in CABG patients with subsequent ACS to lower the LDL-C from >70 mg/dL to ∼55 mg/dL resulted in an 8% absolute risk reduction, with a highly favourable number needed to treat of 11; (4) An LDL-C goal of ∼50 mg/dL should be considered for CABG patients who have progression to an ACS event (and potentially for very high risk patients in general); (5) Whether different pharmacologic classes that lower LDL-C provide similar benefits remains uncertain, but is increasingly likely given the positive results for both statins and now ezetimibe. For now, statins remain first line agents for LDL-C reduction, and ezetimibe serves as the second line agent for high-risk patients and those who require additional LDL-C reduction. Conflict of interest: none declared.