Methods

The MADIT-CRT trial protocol and results were previously published. In a brief, 1,820 patients with left ventricular ejection fraction <30%, QRS duration ≥130 ms, ischemic cardiomyopathy and New York Heart Association (NYHA) class I to II symptoms, or nonischemic cardiomyopathy class and NYHA class II were randomly assigned to CRT-D or ICD treatment arms. Exclusion criteria included NYHA class III or IV symptoms; coronary artery bypass graft surgery, percutaneous coronary intervention, or myocardial infarction within 90 days before enrollment; second or third-degree heart block; chronic AF; and co-morbidities such as uremia (BUN >70 mg/dl or creatinine >3.0 mg/dl) and liver failure.

MADIT-CRT was carried out from December 22, 2004, through June 22, 2009. After publication of the primary results, posttrial follow-up was conducted for all surviving study participants (n = 1691) until September 10, 2010 (phase I of the extended follow-up). Statin therapy (type of drug and dosage) was prescribed at the consideration of the treating physician. The study was in compliance with the Declaration of Helsinki, and the protocol had been approved by the Research Subjects Review Board at the University of Rochester, Medical Center, Rochester, New York, and at each local institutional review board at all enrolling sites. All patients provided written informed consent before enrollment.

A prespecified protocol was used for device programming. All devices were interrogated 1 month after enrollment and thereafter every 3 months and adjudicated by an independent core laboratory for predefined categories of appropriate or inappropriate therapy. Only episodes that lasted >5 seconds and rendered appropriate or inappropriate ICD therapy were adjudicated.

SVA definition included AF, atrial flutter, atrial tachycardia, atrioventricular nodal reentry tachycardia, atrioventricular reentry tachycardia, and supraventricular tachycardia of undefined type; the last 3 were defined as supraventricular tachycardia. An SVA episode was defined when device-rendered therapy, including anti tachycardia pacing or shock, was inappropriately delivered. All SVAs were documented by the device if it lasted >5 seconds. (Specific definitions are provided in the Appendix .) In this study, only device-recorded SVAs were considered.

Patients were divided into 2 subgroups based on the baseline statin therapy, either on statins or off statins. In addition, time-dependent changes in medical therapy with statins during follow-up were incorporated into the end point analysis. The primary end point of the present study was the first occurrence of a SVA. The secondary end point was recurrent SVA.

Baseline clinical characteristics were compared between patients by their baseline statin therapy (either on or off), using the chi-square test or Fisher’s exact test for categorical variables and the Wilcoxon signed-rank test for continuous variables. Categorical data are presented as frequencies and percentages and continuous variables as mean ± SD.

Multivariate Cox proportional hazards regression analysis was used to assess the effect of statins on the risk for SVA. For the analysis of recurrent SVAs, the conditional models of Prentice, Williams, and Peterson were used. These models were stratified by event and used the robust sandwich covariance estimate. If a subject had >8 events, they were censored at the eighth event. Statin therapy was assessed in the multivariate model in a time-dependent manner by incorporating data for each patient that identifies the effect of each follow-up time “on” and “off” statin therapy during the trial. The effects of time-dependent statin therapy on the end points in each treatment arm were assessed with interaction-term analysis. The Cox model was adjusted for relevant clinical covariates that were either predictive for SVA or unbalanced between the groups using the best subset regression modeling (including body mass index ≥30, QRS interval, previous ventricular arrhythmia, previous revascularization, female gender, and PR ≥200 ms). Interaction p values were computed and reported between the groups.

All statistical tests were 2 sided; a p value of <0.05 was considered statistically significant. Analyses were carried out with SAS software version 9.4 (SAS Institute, Cary, North Carolina).

Results

Of 1,790 study patients, 1,209 (68%) were statin users. The baseline clinical and echocardiographic characteristics are provided in Table 1 . Overall, patients with statin usage at baseline were more likely to be older males from the white race. They had more frequent cardiovascular risk factors including diabetes, hypertension, and slightly elevated creatinine levels than patients not using statins. The statin nonusers were less likely to have ischemic cardiomyopathy and had lower frequency of atrial arrhythmias at more than 3 months before enrollment. Statin users were more frequently treated with aspirin and amiodarone but received digitalis less frequently. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β blockers were equally used.

Data regarding statins doses and frequencies are provided in Table 2 . The most frequently prescribed statins were simvastatin with a median dose (q1 to q3) of 30 mg (20 to 40) and atorvastatin 20 mg (10 to 40).

During a follow-up time of 3.7 ± 1.4 years, 160 patients had SVA event, and the total number of recurrent events was 335. The most frequent SVA was supraventricular tachycardia followed by AF ( Figure 1 ). The rate of SVA events by statin use status at the time of the first atrial event is shown in Figure 2 . Statin users had statistically significant lower rates of SVA (p value = 0.032). We also evaluated the effect of time-dependent statin usage on event rate of all types of SVAs which were consistently reduced ( Figure 3 ). Accordingly, multivariable Cox proportional hazards regression analysis showed that time-dependent statin therapy was associated with a significant reduction of both SVA and recurrent SVA ( Table 3 ). The reduction of both SVA and recurrent SVA with statins was consistent in both ICD and CRT-D treatment arms (all p values for statin therapy by treatment arm interaction >0.10) interactions, implying that the effect of statins was independent of the device. We further performed a sensitivity analysis and included other medications in the multivariate model (i.e., digoxin, amiodarone) in a time-dependent manner, and the results were similar.

SVAs by types.

The rate of the first SVA event by statin use status at the time of the event.

Risk of SVA events by statin treatment. Event rates per 100 person-years were calculated by dividing the number of events during the period of statin therapy or the absence of statin therapy by person-years and multiplying the results by 100.

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