Holdaas H, Fellstrom B, Jardine AG, Holme I, Nyberg G, Fauchald P et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003; 361: 2024-2031

Uppsala University Hospital, Uppsala, Uppsala, Sweden
The Lancet (Impact Factor: 45.22). 07/2003; 361(9374):2024-31. DOI: 10.1016/S0140-6736(03)13638-0
Source: PubMed


Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population.
We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0-9.0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat.
After a mean follow-up of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0.83 [95% CI 0.64-1.06], p=0.139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0.65 [0.48-0.88] p=0.005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups.
Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.

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    • "In kidney [12], liver [5] and heart [13] transplantation, a significant association has been shown between increased total cholesterol and cardiovascular events and represents one of the major modifiable risk factors. Indeed, an elevated cholesterol level confers a greater increase in risk for ischemic heart disease following kidney transplantation compared to non-transplanted controls [12] "
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    ABSTRACT: Post-transplant dyslipidemia is exacerbated by mammalian target of rapamycin (mTOR) inhibitors. Early clinical trials of mTOR inhibitors used fixed dosing with no concomitant reduction in calcineurin inhibitor (CNI) exposure, leading to concerns when consistent and marked dyslipidemia was observed. With use of modern concentration-controlled mTOR inhibitor regimens within CNI-free or reduced-exposure CNI regimens, however, the dyslipidemic effect persists but is less pronounced. Typically, total cholesterol levels are at the upper end of normal, or indicate borderline risk, in kidney and liver transplant recipients, and are lower in heart transplant patients under near-universal statin therapy. Of note, it is possible that mTOR inhibitors may offer a cardioprotective effect. Experimental evidence for delayed progression of atherosclerosis is consistent with evidence from heart transplantation that coronary artery intimal thickening and the incidence of cardiac allograft vasculopathy is reduced with everolimus versus cyclosporine therapy. Preliminary data also indicate that mTOR inhibitors may improve arterial stiffness, a predictor of cardiovascular events, and may reduced ventricular remodeling and decreased left ventricular mass through an anti-fibrotic effect. Post-transplant dyslipidemia under mTOR inhibitor therapy should be monitored and managed closely, but unless unresponsive to therapy should not be regarded as a barrier to its use.
    Full-text · Article · Aug 2014 · Transplantation Reviews
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    • "A total of 1,139,584 subjects, including 15,297 haematological malignancies cases were involved. Of the 20 included studies, eight studies were conducted in Europe [20], [25], [27], [29], [33]–[36], nine studies in America [21]–[23], [26], [28], [31], [32], [38], [39], and remaining three studies in other countries [24], [30], [37]. Nine studies were hospital-based [21], [22], [24], [34]–[39], and 11 studies were population-based [20], [23], [25]–[33]. "
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    ABSTRACT: Several observational studies have shown that statin use may modify the risk of haematological malignancies. To quantify the association between statin use and risk for haematological malignancies, we performed a detailed meta-analysis of published studies regarding this subject. We conducted a systematic search of multiple databases including PubMed, Embase, and Cochrane Library Central database up to July 2013. Fixed-effect and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by meta-regression. Subgroup analyses and sensitivity analysis were also performed. A total of 20 eligible studies (ten case-control studies, four cohort studies, and six RCTs) reporting 1,139,584 subjects and 15,297 haematological malignancies cases were included. Meta-analysis showed that statin use was associated with a statistically significant 19% reduction in haematological malignancies incidence (RR = 0.81, 95% CI [0.70, 0.92]). During subgroup analyses, statin use was associated with a significantly reduced risk of haematological malignancies among observational studies (RR = 0.79, 95% CI [0.67, 0.93]), but not among RCTs (RR = 0.92, 95% CI [0.77, 1.09]). Based on this comprehensive meta-analysis, statin use may have chemopreventive effects against haematological malignancies. More studies, especially definitive, randomized chemoprevention trials are needed to confirm this association.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "Traditional risk factors like smoking, hypertension, and hypercholesterolaemia can be identified but do not explain the full magnitude of the increment in risk [2] [3] [4]. In addition, treatment with statins has not resulted in a decreased cardiovascular mortality in ESRD or kidney transplant patients, indicating that other mechanisms of atherosclerotic disease are important [5] [6] [7] [8]. Within the circulating CD4 + T cells population, a subset of cells can be identified that have lost the expression of the costimulatory molecule CD28 on their cell surface. "
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    ABSTRACT: Proinflammatory CD4(+) T cells without the costimulatory molecule CD28 (CD4(+)CD28null T cells) are expanded in patients with end-stage renal disease (ESRD) and associated with atherosclerotic vascular events (AVE). In a prospective study, the number of circulating CD4(+)CD28null T cells was established in 295 ESRD patients prior to receiving a kidney allograft. Within the first year after transplantation, an AVE occurred in 20 patients. Univariate analysis showed that besides a history of cardiovascular disease (CVDpos, HR 8.1, P < 0.001), age (HR 1.04, P = 0.02), dyslipidaemia (HR 8.8, P = 0.004), and the % of CD4(+)CD28null T cells (HR 1.04 per % increase, 95% CI 1.00-1.09, P = 0.01) were significantly associated with the occurrence of a posttransplantation AVE. In a multivariate analysis, only CVDpos remained a significant risk factor with a significant and positive interaction between the terms CVDpos and the % of CD4(+)CD28null T cells (HR 1.05, 95% CI 1.03-1.11, P < 0.001). Within the CVDpos group, the incidence of an AVE was 13% in the lowest tertile compared to 25% in the highest tertile of % of CD4(+)CD28null T cells. In conclusion, the presence of circulating CD4(+)CD28null T cells is associated with an increased risk for a cardiovascular event shortly after kidney transplantation.
    Full-text · Article · Oct 2013 · Journal of Transplantation
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