1 Department of Medicine, Division of Nephrology, Washington University School of Medicine, St Louis, MO and 2 Department of Health Research and Policy, Division of Epidemiology, Stanford University School of Medicine, Stanford CA, USA
Correspondence and offprint request to: Krista L. Lentine, MD, Division of Nephrology, Washington University Medical Center, Campus Box 8219, 660 S. Euclid Avenue, St Louis, MO 63110, USA. Email: lentine.krista{at}stanfordalumni.org
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Abstract |
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Methods. We performed a systematic review of randomized, controlled intervention trials of statins among renal allograft recipients. Clinical trials published between January 1, 1993 and January 1, 2004 were identified by systematic search of electronic databases. Eligible studies measured the impact of therapy on acute allograft rejection, surrogates of cardiovascular risk and/or cardiovascular morbidity and mortality. We abstracted descriptive summaries of trial design elements and primary effect estimates, and assessed trial quality with a standardized quality evaluation tool.
Results. Thirteen eligible trials were identified. Statin therapy was associated with less acute allograft rejection in two early studies but was ineffective in three subsequent, larger trials. Therapeutic benefit was also seen in six of seven small studies that evaluated cardiovascular risk surrogates. Statin use did not significantly alter the primary composite outcome in a single large cardiac events trial, but was associated with reductions in secondary end-points of cardiac death analysed alone or with myocardial infarction. Important design distinctions included statin preparation and dose, concomitant interventions, study power and randomization methods. Median total quality scores were 52 for the rejection trials, 41 for the studies of cardiovascular risk surrogates and 69 for the cardiac events trial, and showed a trend towards variation by outcome measure (P = 0.05).
Conclusions. Heterogeneous study designs and method ological quality contribute to discrepant conclusions on the benefit of statin therapy to renal allograft recipients. Trial-based clinical evidence does not support the use of statins to lower acute rejection risk after kidney transplantation, but does indicate effectiveness for improvement in cardiovascular risk markers and possibly for reduction of clinical cardiac events.
Keywords: HMG-CoA reductase inhibitors; kidney transplantation; quality evaluation; randomized clinical trials; statins
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Introduction |
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Randomized clinical trials (RCTs) are considered the most definitive tool for the evaluation of clinical research [8]. A number of small to moderately sized RCTs employed HMG-CoA reductase inhibitors, commonly called statins, for reduction of renal transplant rejection, with conflicting results [913]. Small, short-term studies indicate that statins improve cardiovascular disease surrogates in this population [1420], but a large, long-term trial assessing clinical cardiac events failed to show significant benefit for the primary composite outcome [21]. Thus, the utility of statins in the care of kidney transplant recipients remains controversial.
Variation in clinical trial design and quality probably contributes to current discrepant conclusions on the benefit of HMG-CoA reductase inhibitors in patients with kidney transplants. To help clarify the disparity in the literature, we undertook a systematic review and quality evaluation of RCTs employing statins for intervention upon three primary outcomes in this population: acute allograft rejection; cardiovascular disease surrogates; and major cardiac events and mortality. We aimed to identify study strengths, weaknesses and design differences as a guide to the interpretation of existing data and the planning of future, more definitive research.
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Methods |
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We categorized studies into groups according to one of three primary outcome measures of interest: (i) incidence and severity of acute kidney allograft rejection after transplantation (rejection group); (ii) surrogate measures of atherosclerotic vascular disease risk (AVD surrogate group); and (iii) cardiovascular morbidity and/or mortality of renal allograft recipients (cardiac events group).
Quality elements and domains
To obtain an objective measure of study quality, we applied a quality assessment instrument developed by Balas et al. for appraisal of elements relevant to clinical trial validity [22]. This tool allocates a portion of 100 possible quality points among 20 questions in proportion to estimated relative importance to study validity. The content of the component questions has been described previously [22]. To facilitate partitioned analysis of quality components, we grouped the questions into six domains: (i) representativeness (three questions/13 possible points); (ii) randomization (two questions/20 possible points); (iii) intervention and outcomes definitions (three questions/13 possible points); (iv) blinding and observation (three questions/nine possible points); (v) data quality and results presentation (four questions/24 possible points); and (vi) statistical analysis (five questions/21 possible points).
Data collection
One investigator (K.L.) reviewed each manuscript and evaluated quality using the standardized form. The same investigator abstracted summary descriptions of each study's site, participants, the intervention, concomitant immunosuppression, primary outcome measures and effect estimates. We did not attempt to mask the identity of article author, source institution or journal due to evidence that such masking is ineffective in removing potential reviewer bias [23].
Statistical analyses
We calculated median quality scores for the sample of studies as a whole and after stratification by outcome category and/or quality domain. We used the KruskalWallis test as a non-parametric, omnibus evaluation of differences in quality scores among groups of trials, and the Wilcoxon rank-sum test for pairwise score comparisons. All calculations were performed with SAS for Windows software, version 8. Statistical significance was defined as a P-value <0.05.
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Results |
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Among the rejection RCTs, two defined acute rejection outcomes in terms of biopsy-demonstrated histopathological findings meeting standardized criteria (Banff criteria) [9,11]. One study ascertained rejection as an event for which the patient completed a course of high-dose steroids [12]. In the remaining two studies, the primary outcome was described as biopsy-proven acute rejection without specification of the standard for biopsy interpretation [10,13].
Three AVD surrogate trials reported longitudinal change in total cholesterol and fractionated lipid levels vs baseline in each arm of the intervention (statin therapy and control) as the main outcome [1416], whereas one considered differences in lipid values between statin-treated and control groups as the primary effect measure [16]. Radiographic indices of atherosclerotic risk included longitudinal changes in ultrasonographic measures of arterial vasodilation [18] and carotid artery intima-media thickness [19], and cross-sectional differences in microvascular reactivity by laser Doppler between treatment arms at trial termination [20]. The single cardiac events study defined its primary end-point, major cardiac events, as cardiac death, coronary revascularization or non-fatal myocardial infarction characterized by pre-specified electrocardiographic findings; each of the individual events and certain event combinations were also analysed as secondary outcomes.
Participants
Sample size in the 13 studies ranged from 26 to 2102. Specifically, the rejection studies enrolled 48363 patients, the AVD surrogate trials had 2672 participants, and the cardiac events trial was notably the largest with 2102 participants. Characteristics of the samples including age entry criteria, gender representation, location of the study centres, and specification of HLA-matching criteria and donor source are listed in Table 1.
In 11 studies, including all from the rejection and cardiac events categories, every participant received cyclosporin-based immunosuppressive regimens [913,15,16,1821]. Among the rejection RCTs, azathioprine and steroids were also universally administered as part of triple-drug therapy in two trials [10,13], one of which added anti-thymocyte induction therapy for recipients of grafts from deceased donors [10]. Anti-metabolite therapy was precluded in one rejection study [9], administered as mycophenolate mofetil to 85% participants in another [11], and given as azathioprine to an unspecified number (<100%) in the last [12]. In four AVD surrogate studies, all (or nearly all) participants received azathioprine and prednisone [14,15,17,20]. Concomitant immunosuppressive therapy in the cardiac events trial included steroids in 81%, azathioprine in 65%, and mycophenolate mofetil in 15%.
Interventions
Ten trials compared a single statin with placebo or with no study drug use [9,1215,1721]; three studies also included a third arm with assignment to an alternative statin or to fibric acid [10,11,16]. Statin preparations and doses are shown in the intervention column of Table 1. Doses were low to moderate in all trials.
In the rejection studies, intervention was initiated in the peri-transplant period, between 3 and 14 days after surgery. The cardiac events trial and five AVD surrogate RCTs [14,16,18,19] required passage of at least 6 months between transplantation and enrolment. One AVD surrogate study specified stable renal function for 6 months prior to enrolment as an entry criterion [15] and one began treatment in the peri-transplant period [20]. Intervention durations ranged from 2 months in one AVD surrogate trial [14] to 5 years (average) in the cardiac event study, but were from 3 to 6 months in most studies [9,1113,15,16,18,20].
Effect estimates
Acute allograft rejection
The first two published investigations of the impact of statin therapy on acute allograft rejection reported significantly lower rejection rates in statin-treated patients vs controls [9,10]. Point estimates of absolute and relative risk reductions ranged from 33 to 39% and 57 to 61%, respectively. The subsequent three rejection RCTs found no significant differences between the intervention and control arms [1113].
Cardiovascular events or surrogates
All of the AVD surrogate RCTs using serum lipid changes (longitudinal or directly compared with control) as the basis of the outcome measure observed significant benefit with statin therapy. Those analysing longitudinal changes [1416] found average 1833% total cholesterol reductions, 2042% low-density lipoprotein (LDL) declines, 023% triglyceride reductions, and 013% high-density lipoprotein (HDL) increases contrasted with no significant longitudinal changes among controls. The trial comparing lipid levels relative to control values noted 22% total cholesterol and 35% LDL reductions after statin administration at the end of the observation period [17]. Significantly improved endothelial function with statin use was seen in the study using a brachial artery flow-mediated vasodilation surrogate (134% increase in the statin group vs no improvement among controls) [18], but not in the trial measuring microvascular reactivity by laser Doppler [20]. One trial reported improved progression of atherosclerosis based on a reduction in carotid intima-media thickness and plaque height in 48 and 54% of statin-treated patients vs unspecified proportions of control participants (P<0.01 and P<0.01) [19]. In the trial ascertaining major cardiac events, statin therapy was associated with a non-significant trend towards reduction in the primary composite of cardiac death, non-fatal myocardial infarction or coronary interventions. Among 12 secondary outcomes, there were significant reductions (2838% by point estimates) in cardiac death analysed alone or with non-fatal myocardial infarctions.
Adverse events
All studies monitored some adverse events or safety markers, but only five also statistically analysed adverse events according to intervention assignment [10,12,15,17,21]. The studies lasting up to 1 year, comprising 327 total patient-years of experience, reported only one episode of significant myalgias [18] and no episodes of rhabdomyolsis or hepatitis among statin-treated patients. The cardiac events trial, by enrolling the largest sample for the longest follow-up (>10 000 patient-years), afforded the greatest power for detecting drug-related side effects. This study found no difference in the frequencies of total or types of adverse events among patients treated with fluvastatin compared with placebo, including no difference in rates of infections and malignancies [21].
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Quality Assessment |
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Randomization domain
Quality scores for randomization varied widely, ranging from three to the full 20 possible points, with a median of six. Only one study, a rejection trial [12], received the maximum domain score, including full points for the description of the randomization method. The participant allocation scheme did not qualify as randomized in one study from the rejection group that employed an alternating assignment [9]. Another rejection trial randomized patients between statin preparations but based assignment to the control arm on lipid status [10]. Testing of randomization demonstrated baseline comparability in four trials [9,12,15,21]. Total randomization quality was similar across the primary outcome categories (P = 0.37).
Intervention and outcomes definitions domain
For the domain encompassing intervention and outcomes definitions, quality scores ranged from five to 13 out of 13 possible points, with a median of 8. Replicable descriptions of the intervention, including details of content, timing and periodicity, rules shaping administration, and persons targeted were provided in one AVD surrogate study [15], whereas the other papers gave moderate quality descriptions (two of five points). In seven trials, the definition of the main effect measure was both complete and consistent between the methods and results sections [9,12,15,18,21]. Domain quality did not vary significantly based on the primary outcome measure (P = 0.38).
Blinding and observation domain
The median score for blinding and observation quality was five, and ranged widely from 0 to the full nine of nine possible points. Participants were blinded with respect to treatment assignment in nine studies [1115,17,18,21]. Five papers expressly noted that measurement of effect was blinded to group assignment [9,10,12,18,21], and an additional five papers implied evaluator blinding [11,13,15,17,20]. Only two trials, one from the rejection group [12] and the cardiac event study, reported blinding of providers to cumulative trial results; these two trials achieved full domain quality. There was a trend towards a difference in domain quality across the primary outcome categories (P = 0.12) due to superior quality of the cardiac events study.
Data quality and results presentation domain
Scores for trial data and results presentation quality were generally strong, with a median of 14 out of 24 points and a range of 824. Seven trials optimally minimized participant withdrawals to <5% for studies shorter than 3 months, or <10% for longer studies [911,13,16,17,19]. All rejection RCTs, the cardiac event trial and three AVD surrogate studies analysed withdrawals appropriately either according to initial randomization or by several methods [16,18,19]. Details of the timing of trial events, including starting and stopping dates, were published by all rejection studies, were partially available in the cardiac event report and were not included in the AVD surrogate papers. Overall domain quality was similar regardless of the primary study question (P = 0.23).
Statistical analysis domain
The median quality score for the statistical analysis domain was 8 out of 24 points and ranged from three to 16. Exact power for detection of an anticipated group difference was specified in four trials, including two from the rejection group [11,12], one AVD surrogate RCT [15] and the cardiac events report. The cardiac event study provided hypothesis testing for intervention-related differences in the primary and secondary outcomes, along with statistical estimation of the effect sizes. Hypothesis testing alone for primary and for secondary outcomes was given in nine [912,14,15,17,19,20] and seven reports [1012,15,17,19,21], respectively. The total statistical analysis quality did not differ significantly among the study groups (P = 0.29).
Total quality
Median overall quality for the sample of studies was 50.0 out of 100 possible points (range 3675). There was a nearly significant trend towards differential quality based on the primary study question (P = 0.05), due to lower total quality in the AVD surrogate category (median = 41) compared with the rejection (median = 52; P = 0.03) and cardiac event trials (total quality = 69; P = 0.12). Within the rejection group, average quality was similar in the studies with positive vs negative findings (P = 0.56).
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Discussion |
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The evidence that statins may blunt acute rejection after solid organ transplantation derives from retrospective study of patients with lung transplants [6] along with RCT data among heart [5] and renal allograft recipients [9, 10]. Although generalization of positive findings across several fields supports an immunomodulatory effect, negative trials [1113] and the observational basis of some of the data raise concern that detected associations are limited by design features to source samples, or, worse, reflect uncontrolled bias. Among the RCTs in patients with kidney transplants, we found that design variation included smaller sample sizes in the two positive studies [9,10], a feature that may magnify chance-related outcome disparities. Neither of the positive trials specified pre-study power or sample size calculations; thus, the basis for determining sufficient enrolment is unclear. These two studies reported unusually high control acute rejection rates of 58 and 64% over 4 months and 1 year, respectively. These rates are not explained by sampling criteria or described recipient characteristics, but could in part reflect concomitant interventions. Use of anti-metabolite-free maintenance immunosuppression in Katznelson's study may have contributed to a higher acute rejection rate in the control graph than expected with triple-drug therapy, and perhaps to an immunological risk profile more amenable to statin-related benefit; however, it is difficult to explain the high rejection rate after Tuncer's potent regimen of antibody induction in deceased donor graft recipients combined with three-drug maintenance for all patients. In both trials, the rejection rate after statin therapy overlaps the range seen after statin use in the negative studies. Trial designs in this category also differed by the specific statin preparations and primary outcome definitions, but such heterogeneities spanned studies with both positive and negative trials and are unlikely to account for the discrepant results.
The overall quality of RCTs employing statins for prevention of acute allograft rejection was near average for the total sample of studies, but varied with trial results in particular quality domains. Randomization is by definition a central method for reduction of bias in RCTs. Full randomization domain quality in a negative trial contrasts with the critical threat to validity introduced by use of a predictable allocation schemes in the positive studies, i.e. alternating assignment to statin vs control in one [9], and control assignment based solely on lipid levels in the other [10]. Absence of participant and physician blinding in one of the positive trials also poses a major concern for validity [10]. The highest quality trial in this review is a rejection trial with negative findings, suggesting that it represents the best available evidence; however, the other negative rejection studies are of similar overall quality to the positive studies. Of additional relevance to the question of the benefits of statins for renal protection, there was no difference in the secondary end-point of graft loss or doubling of serum creatinine in the long-term cardiac events trial [21], but derivation from a secondary hypothesis renders these data preliminary.
The utility of statins for cardiac risk reduction after kidney transplantation was addressed in RCTs with both surrogate and clinical outcomes. Although clinical end-points are most relevant for patient care, trials using surrogate measures can provide preliminary evidence with much less time, resources and expense. We found that the quality of the AVD surrogate studies showed a trend towards lower scores than the events trial overall, with most notable disparity in domains of representativeness and of blinding and observation. However, given the nature of the study questions, this may be acceptable. For example, ascertainment of lipid levels is probably less susceptible to bias than clinical outcomes even without evaluator blinding. The consistency of findings with a variety of statin preparations supports that trial quality is adequate for demonstration of short-term AVD surrogate reduction in kidney transplant recipients on cyclosporin-based immunosuppression, particularly after the immediate peri-transplant period [1419]. Perhaps more relevant is the finding of high overall quality of the cardiac events trial, as this effectively excludes poor methodology as the cause for the failure to detect a significant reduction in the clinical composite outcome with statin use.
With respect to design features, trials ascertaining AVD surrogates enrolled markedly fewer participants for shorter durations. Again, this difference is reasonable based on the nature of the study questions. Despite rare inclusion of pre-study power calculations, the small sample sizes in the AVD surrogate trials were generally adequate due to the greater power for detection of significant intervention-related difference afforded by these laboratory surrogates compared with clinical end-points. The two categories of trials were similar in terms of participant ethnicity, commonly required internals since transplantation, and administration rates of immunosuppressants known to affect cardiovascular risk markers. One relevant design distinction was the difference in study statin preparations. The cardiac events study employed fluvastatin, the newest and least potent statin [24]; among the AVD surrogate studies, only the studies of endothelial function used fluvastatin, one of which did not show therapeutic benefit [20]. Recent studies suggest that intensive lipid-lowering regimens, such as atorvastatin used at maximum doses, afford greater protection against subsequent cardiac events than less potent regimens [25]. However, because cyclosporin raises statin blood levels and thereby increases the risk of toxicity including myositis, aggressive dosing of currently available statins above the moderate range in patients taking calcineurin inhibitors is not recommended [26].
The inadequate power of the cardiac events trial for the primary outcome is placed in broader perspective by considering that RCTs conducted for primary and secondary prevention of cardiac events and death in the general population enrolled 210 times the number of participants [4]. Even after extension of recruitment in the RCT among kidney transplant recipients, the trial appeared under-powered. The trends towards statin-related reduction in the primary outcome and the significant improvements in several important secondary end-points including cardiac death or myocardial infarction suggests, albeit on weaker grounds, promise for event reduction in this population.
Systematic quality assessment reviews of this sort have several limitations. Selection of the study sample itself is limited by publication bias, leading to exclusion of relevant trials that were conducted but never published. In terms of the quality evaluation procedure, while the assessment tool has been externally validated and is similar to those used to evaluate literature from other fields of medicine [27], there is no current consensus about the best way to measure the quality of clinical studies [28]. Finally, quality scores do not distinguish reported trial procedures from what was actually done in a trial.
In summary, this systematic review shows that, when used at low to moderate doses among patients with renal transplants receiving cyclosporin-based immunosuppression, there is inadequate evidence to support use of statins for lowering the risk of acute allograft rejection. The body of evidence does, however, indicate effectiveness for improvement in cardiovascular risk markers and possibly for reduction of clinical cardiac events in this population, and suggests reasonable short- and long-term safety profiles at the studied doses. Further research on the use of statins for cardiovascular protection after kidney transplantation should be invested in multicentre investigations of clinically relevant end-points, with particular attention paid to pre-study power calculations that incorporate the potency of the study regimen. As statin use among renal allograft recipients grows in popularity for pleiotropic indications, it is crucial to consider study quality to ensure that the evidence guiding practice is as bias free as possible and that generalizations from other settings are appropriate.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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