A retrospective analysis of the effect of noncompliance on time to first major adverse cardiac event in LIPS.

BACKGROUND: In the main publication for LIPS (Lescol Intervention Prevention Study), a 22% relative risk (RR) reduction for major adverse cardiac events (MACE) was found among those who used fluvastatin after a successful first percutaneous coronary intervention (PCI). However, intent-to-treat (ITT) analysis of clinical studies generally provides an observed treatment effect that is likely to underestimate what the treatment effect would be if compliance were perfect, because compliance in a clinical trial is invariably <100% during long-term follow-up. OBJECTIVE: The aim of this study was to analyze the relationship between compliance and treatment effect in LIPS. METHODS: In LIPS, patients who had undergone a successful first PCI were randomized to receive fluvastatin 40 mg BID or placebo BID for 3 to 5 years. The primary end point was survival time free of MACE (ie, cardiac death, nonfatal myocardial infarction, or reintervention procedure), and a Cox proportional hazards regression model with time-dependent covariates was used to predict the effect that fluvastatin would have had if trial medication had been continued. Logistic regression was used to determine factors influencing discontinuation of trial medication. RESULTS: A total of 1677 patients were enrolled in LIPS: 844 in the fluvastatin group and 833 in the placebo group. In the fluvastatin group, 294 patients (34.8%) discontinued taking trial medication and 73 (8.6%) switched to another lipid-lowering medication, compared with 353 (42.4%) and 187 (22.4%) patients in the placebo group, respectively. The risk factor-adjusted RR of MACE with fluvastatin treatment was 0.74 (P = 0.004; 95% CI, 0.61-0.91). When also adjusted for noncompliance, the RR for fluvastatin versus placebo was 0.68 (P = 0.002; 95% CI, 0.53-0.86). Discontinuing fluvastatin without switching to another lipid-lowering medication increased the risk of MACE compared with that of patients who stayed on fluvastatin (RR = 2.27; P < 0.001; 95% CI, 1.60-3.23) and the increase in the risk of MACE was greater than that associated with discontinuing placebo (P = 0.032). CONCLUSIONS: The present study found a 32% RR reduction for experiencing MACE during fluvastatin treatment after a successful PCI in LIPS, when analysis allowed for noncompliance. This suggests that the ITT analysis discussed in the main LIPS publication underestimated the benefit of fluvastatin treatment. Our survival model also provided tentative evidence that discontinuing lipid-lowering medication might lead to a potentially harmful rebound effect in this patient group.

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