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Macrovascular Residual Risk Studies

5 January 2015
IMPROVE-IT finally reports: Lower LDL is better but residual cardiovascular risk remains
After much delay and speculation, IMPROVE-IT showed that the addition of ezetimbe in patients with a recent acute coronary syndrome (ACS) receiving best standards of care including simvastatin reduced the risk of cardiovascular disease (CVD) events by 6.4% versus simvastatin alone. Despite this, patients still remained at high residual risk of CVD events.
American Heart Association Scientific Sessions 2014. Abstract Latebreaking Clinical Trials 02. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial. Cannon CP et al.
Objective: To test whether the addition of ezetimibe reduced the risk of CVD events compared with simvastatin alone in patients with a recent ACS.  The study also evaluated the safety of long-term combination of ezetimibe/simvastatin therapy.
Study design: Randomised, double-blind, placebo-controlled study 
Study population: Patients aged at least 50 years with a recent (£10 days) ACS stabilised on standard medical and interventional treatment. Patients were required to have a low-density lipoprotein cholesterol (LDL-C) levels 50 to 125 mg/dL (1.3-3.2 mmol/L) or 50 to 100 mg/dL (1.3-2.5 mmol/L) if already using a statin.
Outcomes: • The primary outcome was a composite of total CVD events, defined as the combination of CVD death, nonfatal myocardial infarction (MI), hospital admission for unstable angina (UA), coronary revascularisation (≥30 days after randomisation) and stroke.
• Secondary composite outcomes included 1) all death, MI, UA, coronary revascularisation and stroke; 2) coronary heart disease death, MI and urgent coronary revascularisation; and 3) CVD death, MI, UA, all revascularisation and stroke.
• The safety and tolerability of ezetimibe was also evaluated.
Methods: After stabilisation, eligible patients were randomised to treatment with ezetimibe 10 mg/simvastatin 40 mg or simvastatin 40 mg, against a background of best evidence-based treatment. Patients were uptitrated to simvastatin 80 mg if LDL-C was >79 mg/dL (2.0 mmol/L) (until the change in licensing regarding simvastatin 80 mg in 2011). Patients were followed-up at day 30 and thereafter every 4 months. This was an event-driven trial, with at least 5,250 CVD events over a minimum 2.5 year follow-up period required. 

In total, 18,144 eligible patients (mean age 64 years, 25% female, 36% on prior lipid treatment, median LDL-C at ACS event 95 mg/dL or 2.5 mmol/L) were randomised: 9,067 were allocated ezetimibe 10 mg plus simvastatin 40 mg and 9,077 were allocated simvastatin 40 mg, in addition to current standards of care. Uptitration to simvastatin 80 mg was performed for 27% on simvastatin versus 6% on ezetimibe/simvastatin.

The study showed a 16.7 mg/dL (0.4 mmol/L) difference in LDL-C in favour of ezetimibe/simvastatin at 1 year (median LDL-C levels 53.7 mg/dL versus 69.5 mg/dL on simvastatin alone averaged over the follow-up period). The median follow-up was 6.0 years in the simvastatin arm and 5.9 years in the ezetimibe/simvastatin arm.  Over this period, there was a 6.4% relative reduction in the primary outcome (32.7% versus 34.7% with simvastatin alone, hazard ratio 0.936, 95% CI 0.887 to 0.988, p=0.016). There were also statistically significant reductions in all three pre-specified secondary composite outcomes. The reduction in these outcomes was mainly driven by significant reduction in MI (by 13%, p=0.002) and a marginally significant reduction in stroke (by 14%, p=0.052). There was no impact on all-cause mortality (15.3% with simvastatin versus 15.4% with simvastatin/ezetimibe, p=0.78) (Table).

Ezetimibe/simvastatin was well tolerated with no significant differences in cancer, muscle or gall-bladder-related events.

Table. Effect of the combination of ezetimibe/simvastatin versus simvastatin on outcomes in IMPROVE-IT

Outcome* Simvastatin Ezetimibe/ simvastatin Hazard ratio (95% CI) p-value




0.936 (0.887 to 0.988),






1) All death, MI, UA, coronary revascularisation, stroke



0.948, p=0.034

2) coronary heart disease death, MI, urgent coronary revascularisation



0.912, p=0.016

3) CVD death, MI, UA, all revascularisation, stroke



0.945, p=0.035

Authors’ conclusion: IMPROVE-IT is the first trial demonstrating incremental clinical benefit when adding a non-statin therapy (ezetimibe) to statin therapy. The study reaffirms the LDL hypothesis, i.e. that reducing LDL-C prevents CVD events. The study also confirms the safety profile of ezetimibe.


Following much speculation, IMPROVE-IT showed that compared with statin therapy alone, the addition of non-statin therapy (ezetimibe) further lowered LDL-C levels and reduced CVD events in patients with a recent ACS. It is, however, recognised that the incremental benefit was modest (6.4% reduction over a mean of 6 years follow-up). Additionally, despite the fact that the combination of simvastatin plus ezetimibe arm achieved a 50% reduction in LDL-C levels (versus 35% reduction with simvastatin alone), there was no benefit during the first year of the trial. This contrasts with the findings from PROVE-IT, which compared the effect of high-dose versus low-dose statin treatment in ACS patients, where a similar difference in the percent change from baseline in LDL-C levels resulted in a significant benefit within 30 days.(1) Thus, it is likely that the early and strong beneficial effects of statins are derived in large part from their many pleiotropic actions beyond simple reduction in LDL?C. These effects are not shared by ezetimibe, which acts mainly by further reducing LDL-C, contributing only a small incremental effect on CVD risk reduction. Furthermore, the delay in benefit with ezetimibe supports the notion that an important time factor is needed for evidence of benefit on event rates with LDL-C reduction alone, without the added modulation of triglycerides, high-density lipoprotein cholesterol, inflammation, vascular function and oxidation. In this respect, it is relevant that short term trials which evaluated the effects of adding ezetimibe to statin therapy on carotid intima-media thickness, such as ENHANCE (18 months)(2) or ARBITER 6-HALTS (24 months)(3) were negative, whereas SANDS, which was of longer duration (36 months), was not.(4)

Moreover, it is evident that patients in IMPROVE-IT still remained at high residual risk of CVD events; about one-third of patients in the ezetimibe/simvastatin group continued to experience a CVD event despite attaining LDL-C levels below current targets and while receiving best standards of care. Thus, while IMPROVE-IT provides support for the central role of LDL-C lowering in CVD prevention, there remain unanswered questions. First, should there be a lower limit for LDL-C levels in this very high risk group? Second, would effective targeting of additional risk factors offer further benefit? So far studies that have attempted to address this have failed to show definitive answers with other non-statin treatments, although flaws in the trial design or limits to the potency/selectivity of currently available therapeutic options may have been responsible for negative/neutral findings.

Ultimately, while IMPROVE-IT provides timely support for the LDL hypothesis,(5) it also highlights the unmet need for additional interventional approaches to reduce the high residual risk that persists in such patients despite best evidence-based treatment. Addressing this unmet need is a key mission of the Residual Risk Reduction Initiative.(6)


1. Ray KK, Cannon CP, McCabe CH et al; PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005;46:1405-10.

2. Kastelein JJ1, Akdim F, Stroes ES et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.

3. Villines TC1, Stanek EJ, Devine PJ et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010;55:2721-6.

4. Fleg JL1, Mete M, Howard BV et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol 2008;52:2198-205.

5. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.

6. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.

Key words acute coronary syndrome; non-statin therapy; ezetimibe; low-density lipoprotein cholesterol; residual cardiovascular risk