Additional clinical benefit post-ACS of sustained intensive lipid lowering combination therapy

Murphy SA, Cannon CP, Blazing MA, et al.
J Am Coll Cardiol 2016;67:353–61

Background

In acute coronary syndrome studies, usually only the first event is counted for the combined primary efficacy endpoint, even if patients experience more than one qualifying event during the study. This methodology does not reflect real life practice. Therefore, in some studies comparing high-intensity versus moderate-intensity statins, the total events were analysed [1,2].
This study evaluates the total primary endpoint (PEP) events in the IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study, in which patients with a recent acute coronary syndrome and LDL-C of 50 to 125 mg/dl, were randomised to receive either ezetimibe plus simvastatin, or placebo plus simvastatin [3,4]. Based on the first event methodology, the combination of ezetimibe plus simvastatin was associated with a reduction in the primary composite endpoint of time to first cardiovascular death, nonfatal myocardial infarction, unstable angina requiring hospitalisation, coronary revascularization, or nonfatal stroke over a median 6 years of follow-up, compared to placebo plus simvastatin [5-6]. 

Main results

• 18,144 patients had a total of 9,545 PEP events, out of which

• 56% were first events
• 44% were subsequent events

• Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (RR: 0.91; 95% CI: 0.85 - 0.97; P = 0.007)
• The 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of cardiovascular death, myocardial infarction, or stroke were significantly reduced (RR: 0.88; 95% CI: 0.81 - 0.96; P = 0.002)
• The reduction in total events was driven by

• decreases in total nonfatal myocardial infarction (RR: 0.87; 95% CI: 0.79 - 0.96; P = 0.004)
• total nonfatal stroke (RR: 0.77; 95% CI: 0.65 - 0.93; P = 0.005)

• Risk difference: for every 100 patients treated for 10 years, 11 total PEP events (5 myocardial infarctions, 2 strokes, and 4 revascularizations) were prevented with ezetimibe plus simvastatin
• Evaluating total events more than doubled the number of events prevented compared with examining only the first event (first PEP n = 170 vs. total PEPs n = 421)

Conclusion

In patients with a recent acute coronary syndrome and elevated LDL cholesterol levels, treatment with ezetimibe plus simvastatin decreased the total PEP events compared with simvastatin alone. These data support the continuation of intensive combination lipid-lowering therapy after a recurrent cardiovascular event.

Editorial comment [7]

There has been controversy about the optimal strategy for cardiovascular risk reduction in post-ACS patients treated with lipid-lowering medications: should we pursue a specific LDL-C goal or is the intensity of statin use more important? The data from Murphy et al support the hypothesis that LDL-C values on treatment are more significant in these patients, and that additional risk reduction can be achieved if LDL-C levels are maintained close to 50 mg/dl in the long-term.
Moreover, according to Wright and Murphy ‘data from IMPROVE-IT failed to demonstrate a statistically significant reduction in cardiovascular mortality despite a large sample size and multi-year patient follow-up. It is unclear why reducing the risk of nonfatal myocardial infarction and ischemic stroke did not translate into an overall reduction in cardiovascular mortality. This divergence of cardiovascular events from overall mortality and cardiovascular mortality has been also seen in other cardiovascular lipid-lowering trials. It is also unclear why the authors did not report total mortality data in addition to cardiovascular mortality as total mortality is generally considered a reliable hard endpoint.’

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References

1. Murphy SA, Cannon CP, Wiviott SD, et al. Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial. J Am Coll Cardiol 2009;54:2358–62
2. Tikkanen MJ, Szarek M, Fayyad R, et al. Total cardiovascular disease burden: comparing intensive with moderate statin therapy insights from the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial. J Am Coll Cardiol 2009;54:2353–7
3. Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008;156:826–32
4. Califf RM, Lokhnygina Y, Cannon CP, et al. An update on the IMProved reduction of outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design. Am Heart J 2010;159:705–9
5. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97
6. Blazing MA, Giugliano RP, Cannon CP, et al. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population. Am Heart J 2014;168:205–12.e1
7. Wright RS, Murphy J. PROVE-IT to IMPROVE-IT: Why LDL-C Goals Still Matter in Post-ACS Patients. J Am Coll Cardiol 2016;67:362-4