High benefit from dual lipid-lowering therapy for ACS patients with a prior CABG
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 trialEisen A, Cannon CP, Blazing MA, et al. - Eur Heart J 2016; 37:3576–3584
Patients with a history of coronary artery bypass graft surgery (CABG) are at increased risk for recurrent CV events, and when they present with an ACS, they are at a particularly high risk [1–3].
Ezetimibe leads to reduced intestinal cholesterol absorption. In the IMPROVE-IT study, it led to a 24% additional reduction of LDL-C levels and to a 2.0% absolute reduction of the composite endpoint of CV death, major coronary event, or stroke in patients stabilized within 10 days after an ACS, compared with placebo [4,5].
In current analysis of the IMPROVE-IT study, the effect of adding ezetimibe to statin therapy was evaluated in 18 134 patients after ACS with (9%) or without (91%) a history of CABG.
- At baseline, the median LDL-C level was 81.2 mg/dL (IQR: 69.6-94.0) in patients with prior CABG and 96.7 mg/dL (IQR: 81.0-111.4) in patients without prior CABG (P<0.001). This difference was largely due to the more frequent use of statin therapy in the CABG group.
- The median time-weighted LDL-C levels during the trial were similar between patients with or without prior CABG (62.8 mg/dL; IQR: 49.6-76.5 and 62.1 mg/dL; IQR: 48.6-77.5, respectively, P=0.52).
- The median time-weighted LDL-C level during the trial was 55.0 mg/dL with simvastatin/ezetimibe and 69.9 mg/dL with simvastatin/placebo in patients with prior CABG (P<0.001), and these values were 53.6 and 69.5 mg/dL, respectively, in patients without prior CABG (P<0.001).
- After 7 years of therapy, the rates of the primary composite endpoint were 55.6% in patients with prior CABG and 31.6% in patients without prior CABG (adjusted HR: 1.45; 95% CI: 1.33–1.58; P<0.001).
- In patients with prior CABG, the rate of the primary endpoint at 7 years was 51.2% with simvastatin/ezetimibe and 60.0% with simvastatin/placebo (HR: 0.80; 95% CI: 0.69–0.92; absolute risk difference [ARD]: 8.8%; 95% CI: 3.1–14.6%; NNT=11).
- The greatest reductions with simvastatin/ezetimibe were in MI (ARD: 9.1%; 95% CI: 3.7–14.5%; NNT=11), and coronary revascularization more than 30 days after randomisation (ARD: 8.1%; 95% CI: 2.6–13.7%; NNT=12).
- In patients without prior CABG, the rate of the primary endpoint at 7 years was 30.9% with simvastatin/ezetimibe and 32.2% with simvastatin/placebo (HR: 0.96; 95% CI: 0.90–1.01; ARD: 1.3%; 95% CI: 0–2.6%; P interaction by prior CABG status =0.02).
- There were no significant differences in liver function tests, creatinine kinase levels, gall-bladder related adverse events, rhabdomyolysis, or cancer between patients treated with simvastatin/placebo vs. simvastatin/ezetimibe, in patients with or without prior CABG.
In an analysis of the IMPROVE-IT study, ACS patients with a history of CABG had a greater clinical benefit of ezetimibe therapy on top of statin versus placebo, compared with patients without CABG. These findings support the hypothesis that intensive, dual lipid-lowering therapy is more effective in CABG patients at increased risk for recurrent events.
In their editorial article, Jacoby and Rader state that the current report by the TIMI group published in the European Heart Journal provides the strongest evidence yet that treating the highest risk patients more aggressively confers greater benefit. They argue that the results might be reasonably applied to other very high-risk patients, despite the study limitations that include:
- The lack of subgroup analyses based on the comorbidities of CABG patients, including prior MI, HF, DM, hypertension and PAD.
- The lack of similar data on stable CABG patients, or high-risk patients with other co-morbidities but without ACS.
Finally they reach five conclusions:
‘(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.’