Understanding IMPROVE-IT and LDL-C Lowering in CVD
Understanding IMPROVE-IT and LDL-C Lowering in CVD
The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT; ClinicalTrials.gov Identifier NCT00202878) randomized 18 000 patients who had an acute coronary syndrome event (STEMI, NSTEMI, unstable angina) within the previous 10 days to simvastatin 40/80 mg or to simvastatin 40 mg plus ezetimibe 10 mg (Figure 1). When the study was first designed (pre-2005), a sample size of 10 000 patients was selected based on an anticipated event rate at 2 years of 23.5% in the control arm. This would have given statistical power to detect a 10% relative risk reduction. However, with the release of the CTT analyses in 2005 and 2010, these assumptions were revised during the course of the study and a larger sample size of ~18 000 patients was mandated in the third amendment. Trial termination is now event-driven and patients will be followed until at least 5250 subjects experience a primary end-point which consists of the first occurrence of cardiovascular death, non-fatal myocardial infarction, re-hospitalization for unstable angina, coronary revascularization, or stroke. The trial will provide definitive answers regarding the safety of the drug.
(Enlarge Image)
Figure 1.
Design of the IMProved Reduction of Outcomes: VYTORIN Efficacy International Trail (IMPROVE-IT). *if consecutive in-trial measures of LDL-C are >79 mg/dL, simvastatin dose will be increased to 80 mg. **primary end-point is the first occurrence of cardiovascular death, non-fatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (occurring at least 30 days after randomization), or stroke.
IMPROVE-IT tests two hypotheses at the same time. One is that lower LDL-C is better even at very low LDL-C. The second is that adding another LDL-lowering drug to a statin reduces outcomes. Several aspects of the design are worth noting in light of recent similar trials. First, the comparison is statin plus placebo vs. statin plus ezetimibe, so the study will not provide information on the effects of ezetimibe monotherapy or on differences between statin-mediated compared with ezetimibe-mediated LDL lowering. Secondly, LDL-C was not titrated or matched in the two treatment arms (unlike AIM-HIGH) to similar levels in the statin vs. the statin + ezetimibe group. The LDL-C of the trial patients at baseline was 97 mg/dL. If consecutive measures of in-trial LDL-C exceeded 79 mg/dL in the statin plus placebo group, the simvastatin daily dose was increased from 40 to 80 mg. It can be surmised, therefore, that LDL-C in the control group is likely to be <70 mg/dL and ezetimibe is being tested for its ability to generate an incremental clinical benefit in a well-treated population on statins with an already very low LDL-C. In interpreting this benefit, it is important to remember that the absolute risk reduction for the same relative LDL-C lowering diminishes for the same relative LDL-C lowering with lower baseline LDL-C (Figure 2). The 'IMPROVE-IT therapeutic scenario' is thus far removed from day-to-day clinical practice where ezetimibe is prescribed to patients with high LDL-C that cannot be controlled with statin monotherapy.
(Enlarge Image)
Figure 2.
Diminishing risk reduction for the same relative LDL-C lowering with lower baseline LDL-C. Calculations based on the CTTC analysis.
Design and Scientific Rational
The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT; ClinicalTrials.gov Identifier NCT00202878) randomized 18 000 patients who had an acute coronary syndrome event (STEMI, NSTEMI, unstable angina) within the previous 10 days to simvastatin 40/80 mg or to simvastatin 40 mg plus ezetimibe 10 mg (Figure 1). When the study was first designed (pre-2005), a sample size of 10 000 patients was selected based on an anticipated event rate at 2 years of 23.5% in the control arm. This would have given statistical power to detect a 10% relative risk reduction. However, with the release of the CTT analyses in 2005 and 2010, these assumptions were revised during the course of the study and a larger sample size of ~18 000 patients was mandated in the third amendment. Trial termination is now event-driven and patients will be followed until at least 5250 subjects experience a primary end-point which consists of the first occurrence of cardiovascular death, non-fatal myocardial infarction, re-hospitalization for unstable angina, coronary revascularization, or stroke. The trial will provide definitive answers regarding the safety of the drug.
(Enlarge Image)
Figure 1.
Design of the IMProved Reduction of Outcomes: VYTORIN Efficacy International Trail (IMPROVE-IT). *if consecutive in-trial measures of LDL-C are >79 mg/dL, simvastatin dose will be increased to 80 mg. **primary end-point is the first occurrence of cardiovascular death, non-fatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (occurring at least 30 days after randomization), or stroke.
IMPROVE-IT tests two hypotheses at the same time. One is that lower LDL-C is better even at very low LDL-C. The second is that adding another LDL-lowering drug to a statin reduces outcomes. Several aspects of the design are worth noting in light of recent similar trials. First, the comparison is statin plus placebo vs. statin plus ezetimibe, so the study will not provide information on the effects of ezetimibe monotherapy or on differences between statin-mediated compared with ezetimibe-mediated LDL lowering. Secondly, LDL-C was not titrated or matched in the two treatment arms (unlike AIM-HIGH) to similar levels in the statin vs. the statin + ezetimibe group. The LDL-C of the trial patients at baseline was 97 mg/dL. If consecutive measures of in-trial LDL-C exceeded 79 mg/dL in the statin plus placebo group, the simvastatin daily dose was increased from 40 to 80 mg. It can be surmised, therefore, that LDL-C in the control group is likely to be <70 mg/dL and ezetimibe is being tested for its ability to generate an incremental clinical benefit in a well-treated population on statins with an already very low LDL-C. In interpreting this benefit, it is important to remember that the absolute risk reduction for the same relative LDL-C lowering diminishes for the same relative LDL-C lowering with lower baseline LDL-C (Figure 2). The 'IMPROVE-IT therapeutic scenario' is thus far removed from day-to-day clinical practice where ezetimibe is prescribed to patients with high LDL-C that cannot be controlled with statin monotherapy.
(Enlarge Image)
Figure 2.
Diminishing risk reduction for the same relative LDL-C lowering with lower baseline LDL-C. Calculations based on the CTTC analysis.