Renal transplant recipients have a greatly increased risk of premature cardiovascular disease. The ALERT study was a multicenter, randomized, double-blind, placebo-controlled trial of fluvastatin (40–80 mg/day) in 2102 renal transplant recipients followed for 5–6 years. The main study used a composite cardiac end-point including myocardial infarction, cardiac death and cardiac interventions. Although reduced by fluvastatin, this primary end-point failed to achieve statistical significance thus precluding analysis of predefined subgroups. Therefore, in the present survival analysis, we used an alternative primary end-point of cardiac death or definite nonfatal myocardial infarction (as used in other cardiac outcome trials) which was significantly reduced by Fluvastatin therapy and permits subgroup analysis. Fluvastatin reduced LDL-cholesterol by 1 mmol/L compared with placebo, and the incidence of cardiac death or definite myocardial infarction was reduced from 104 to 70 events (RR 0.65; 95% CI 0.48, 0.88; p = 0.005). Fluvastatin use was associated with reduction in cardiac death or nonfatal myocardial infarction, which achieved statistical significance in many subgroups. The subgroups included patients at lower cardiovascular risk, who were younger, nondiabetic, nonsmokers and without pre-existing CVD. These data support the early introduction of statins following renal transplantation.
Premature cardiovascular disease (CVD) is the leading cause of death and, as a consequence of death with a functioning graft, of graft failure in renal transplant recipients (1–3). Many transplant recipients have pre-existing CVD and CV risk factors at the time of transplantation. Additional risk factors (including diabetes, hypertension and hyperlipidemia) may develop, or be aggravated by immunosuppressive therapy, following transplantation (4).
In view of the success of statin therapy in reducing the risk of cardiovascular disease (5–7), subsequently confirmed in diverse patient populations (8–13), we performed a long-term outcome study in renal transplant recipients (ALERT (Assessment of LEscol in Renal Transplantation)]. In the main study, the results of which have been reported (14,15), we compared fluvastatin with placebo in 2102 stable transplant recipients [RTR] followed for 5–6 years. The chosen primary end-point of the main study was a composite of cardiac death, definite or probable myocardial infarction (MI), and coronary revascularisation. Fluvastatin therapy reduced this composite end-point by 17%[112 vs. 134 events; relative risk (RR) – 0.83 (0.64, 1.06)]. The failure of the primary end-point to achieve statistical significance, a consequence of atypical presentation of myocardial infarction and a high threshold for coronary intervention, prevented the analysis of subgroups predefined in the study protocol [a summary of which has been published (14)]. To some extent, the choice of primary end-point in prospective outcome trials is arbitrary. Had definite myocardial infarction or cardiac death been used as the primary end-point of the ALERT study [as used in the WOSCOPS (6) and other studies] then a highly significant reduction in cardiovascular events would have been reported (15). Thus, in this posthoc analysis, we used the end-point of cardiac death and definite nonfatal myocardial infarction (6) to allow analysis of the effects of fluvastatin therapy in transplant recipients subgrouped by factors such as age, sex, diabetes and cigarette smoking.
One of the findings of the ALERT study (15) was that a much larger study would be required to investigate cardiovascular risk reduction following renal transplantation. Given this limitation and, specifically, the low statistical power, the findings of the current report are exploratory. Our findings should be interpreted in the light of our understanding of cardiovascular pathophysiology in transplant recipients and the benefits of statins in other populations.
The ALERT study (14,15) recruited 2102 cyclosporine-treated renal transplant recipients in Europe and Canada, whose transplant had been performed more than 6 months previously. Male and female patients, aged 30–75 years, with stable graft function and a serum cholesterol concentration between 4.0 and 9.0 mmol/L (155–348 mg/dL), were recruited. Patients with familial hypercholesterolemia, a recent acute rejection episode, MI (within the previous 3 months), prior statin therapy or predicted life expectancy of less than 1 year were excluded. The study adhered to the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki, and all participants provided written informed consent.
Patients were initially randomized to fluvastatin 40 mg/day or matching placebo. The dose (of fluvastatin or placebo) was doubled after approximately 2 years (14,15), owing to emerging data on fluvastatin and from other cardiac outcome trials (8,9,14,15). Patients were followed for a minimum of 5 and a maximum of 6 years. Measurements of serum lipids, renal function and routine biochemistry were made at annual intervals; the investigators were not permitted to make local measurements of serum lipids. A 12-lead electrocardiogram (ECG) recording was performed at annual intervals and analyzed using the Minnesota code. As described earlier, in the present analysis cardiac death or definite nonfatal MI (6,15) was used as the composite primary end-point. The definition and classification of end-points was performed by an independent end-point committee (14,15).
Pre-defined subgroups included the following: age, sex, diabetes, previous CMV infection, cigarette smokers, total time on renal replacement therapy, time since transplantation, number of renal transplants, baseline lipid levels, systolic and diastolic blood pressure, serum creatinine, history of hypertension or prior cardiovascular events, and the presence of albuminuria.
The statistical analysis has previously been described and was an intention-to-treat Cox survival analysis (14,15). Briefly, we recorded occurrence of independently adjudicated (14,15), major adverse cardiac events, defined as cardiac death, nonfatal MI [definite or probable (6,14,15)] verified by hospital records, or coronary revascularisation procedure [including coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI)]. The sample size was based on a 25% placebo event rate [estimated from Registry data (2,14,15)] after 5 years of follow up and a 25% size effect. It was increased to 2050 patients to allow for a lower-than-predicted event rate (as previously described) and the dose of fluvastatin was doubled (to 80 mg) after 2 years, in the light of emerging studies (15), to maximize the potential success of the study.
The primary efficacy analysis is based on a log-rank test stratified by country and coronary heart disease (CHD) status at time of randomization, with cardiac death or definite nonfatal myocardial infarction as the chosen primary end-point in the present analysis. Cumulative incidence curves were generated by the Kaplan-Meier method; the Cox proportional hazards model and the Cochran-Mantel-Haenszel test were used to assess risk reduction and to compare the incidence of the endpoints, respectively. Subgroups were identified either by the presence of a given parameter (e.g. diabetes) or by subdivision by the median, or into quartiles, as appropriate. Analysis of outcomes in subgroups was performed as described earlier, and interaction tests were performed to determine whether the differences in effects between subgroups were statistically significant. No correction was made for repeated analysis in this exploratory posthoc analysis.
The present report is a posthoc analysis of the main study. As the chosen primary end-point did not achieve statistical significance, analysis of predefined subgroups was proscribed. However, the analysis of secondary end-points revealed that had we chosen an alternative composite – such as cardiac death, definite nonfatal MI or specifically, cardiac death OR nonfatal MI (the primary end-point of the WOSCOPS study) – then the trial would have had a statistically significant outcome. In order to maximize the contribution of the ALERT study to our understanding of the pathogenesis and treatment of cardiovascular disease in transplant recipients, we re-analyzed the study using cardiac death or nonfatal MI as an alternative primary end-point, which allowed analysis of subgroups defined in the original protocol.
Role of funding source
ALERT was designed and co-ordinated by an investigator-led, independent steering committee including members from each of the countries involved in the study. Data management, analysis and reporting of the data were independent of the funding source (15).
The ITT population comprised 2102 patients [randomly assigned to receive either fluvastatin (n = 1050) or placebo (n = 1052)] recruited between June 1996 and October 1997 (15). The median follow up was 65.5 months in the fluvastatin group and 65.3 months in the placebo group. The baseline characteristics of the study population have previously been reported (15), and were well balanced between treatment groups (Table 1). The dose of study medication was doubled in 65% of patients in both groups after a mean follow-up duration of 2.8 years. Over the duration of the study, 7% and 14% of patients in the fluvastatin and placebo groups, respectively, took lipid-lowering treatments, primarily statins, usually ‘open label’ fluvastatin. The majority of patients were male, with a mean age of 50 years (Table 1). Approximately 74% of patients had hypertension, and 19% had diabetes. Detailed information on the safety and side-effects of fluvastatin therapy has been published (15).
Table 1. Demographic data on the study population
Fluvastatin (n = 1050)
Placebo (n = 1052)
Data are shown as mean (SD) or percentage total as described.
Demographic and clinical
Age in years
Diastolic BP (mmHg)
Systolic BP (mmHg)
Total cholesterol (mmol/L)
LDL cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Time on renal replacement
Type of last transplant
Serum creatinine (μmol/L)
Cardiovascular risk factors
History of angina pectoris
History of cerebrovascular disease
History of PVD
As reported previously, fluvastatin (40–80 mg/day) lowered LDL cholesterol levels by 32.0% (95% CI, − 33.0, − 30.0) compared with placebo (mean reduction 7.9%, 95% CI, −10.2,− 5.7). On average, there was a net difference of 1.0 mmol/L between treatment groups throughout the study. Mean total cholesterol and mean triglycerides were also significantly reduced by fluvastatin, and HDL-cholesterol increased. The lipid levels are shown in Figure 1.
Fluvastatin therapy was associated with a significant reduction in cardiac death (36 vs. 54 events; RR-0.62; 95% CI, 0.40, 0.96; p = 0.031) and definite nonfatal myocardial infarction (46 vs. 66; RR-0.68; 95% CI, 0.40, 1.0; p = 0.048), resulting in a significant reduction in the combined primary end-point (70 vs. 104; 0.65 [0.48–0.88], p = 0.005; Figure 2).
The main subgroup analyses of the study were predefined, but were not reported in the main publication (15) owing to failure of the chosen primary end-point to achieve significance. Table 2 shows the number of events in each group and the RR reduction (with 95% confidence intervals) attributable to fluvastatin therapy. Most subgroups were divided by the median value and are therefore of equal size. In the placebo group, the percentage event rates over the duration of the study were numerically, but not significantly, higher in men than women (10.9 vs. 7.9%), older subjects (12.1 vs. 7.6%; subdivided by median of 49.3 years), and diabetics (17.1 vs. 8.2%). A history of ‘hypertension’ had no significant impact (9.8 vs. 10.2%) and both ex-smokers (13.7%) and – to a lesser extent – current smokers (8.6%) had a higher event rate (albeit nonsignificant) than nonsmokers (7.7%). Subdivision of renal function by a median serum creatinine of 134 μmol/L demonstrated a slightly higher event rate in those with impaired function (10.5 vs. 9.3%) and there was an increase in those with highest levels of albumin excretion (13.7 vs. 10.1%).
Table 2. Subgroup analyses. Data are shown for individual subgroups and comprise the absolute number of events (and percentage of the subgroup population), and who experienced an event in the placebo and active treatment arms of the study. In addition, the benefit of fluvastatin in each subgroup is expressed as a risk reduction ratio (RR) with 95% confidence intervals
RR (95% CI)
CHD = pre-existing coronary heart disease, Time after Tx (transplant), TC = total cholesterol, LDL = low density lipoprotein cholesterol, HDL = high density lipoprotein cholesterol, TG = triglyceride, SBP/DBP = systolic and diastolic blood pressure.
Age (<49.3 years)
Age (≥49.3 years)
Tx (<4.5 years)
Tx (≥4.5 years)
TC (<6.4 mmol/L)
TC (≥6.4 mmol/L)
LDL (<4.1 mmol/L)
LDL (≥4.1 mmol/L)
HDL (<1.3 mmol/L)
HDL (≥1.3 mmol/L)
TG (<1.9 mmol/L)
TG (≥1.9 mmol/L)
DBP (<85 mmHg)
DBP ≥85 mmHg)
SBP (<140 mmHg)
SBP (≥140 mmHg)
Across all of the subgroups fluvastatin therapy was associated with reduced risk of cardiac death or definite nonfatal MI; the values of relative risk for fluvastatin therapy range from 0.52 to 0.88 (Table 2). In part, the relative benefit of fluvastatin therapy reflects the unequal size of some subgroups and the paucity of end-points in the study. An interaction analysis did not identify any significant differences between any subgroups (e.g. men vs. women) although there were occasions when fluvastatin use was associated with a significant reduction in one subgroup but not another. For example, fluvastatin use was associated with a significantly reduced event rate in men [RR – 0.67 (0.47, 0.96); RR (95% CI)] but not in women [RR – 0.59 (0.32, 1.08); Table 2) and in patients with hypertension RR – 0.67 (0.47, 0.90)] but not in those without hypertension [RR – 0.55 (0.29, 1.02)]. Similarly, there were significant benefits of statin therapy in younger patients [RR – 0.51 (0.30, 0.86)], nondiabetics [RR – 0.62 (0.43, 0.91)], patients with no prior history of CHD [RR – 0.63 (0.44, 0.89)], nonsmokers [RR – 0.56 (0.32, 0.98)] and ex-smokers [RR – 0.62 (0.40, 0.99) p = 0.043], patients with better renal function [RR – 0.54 (0.33–0.88)], least albuminuria [RR – 0.33 (0.13, 0.84)] and those less than 4.5 years following transplantation [RR – 0.44 (0.26, 0.74)].
These data are exploratory and merely show that it is easier to detect a significant reduction in some subgroups (Table 2) than in others. However, the overlapping 95% confidence intervals and negative interaction analysis indicate that there is no significance when individual subgroups (e.g. men and women) are compared with one another. The failure to achieve statistical significance in some subgroups is likely to reflect the low number of events and the low overall power of the study.
In the general population hyperlipidemia is associated with CVD, and the reduction of lipid levels by statins results in a reduction in CV events (5–13). In the placebo group of our study, subdivided by the median levels of lipid subfractions at baseline, there was a higher event rate in patients with higher total cholesterol (13.2 vs. 6.4% during follow up), LDL (12.6 vs. 6.9%), triglycerides (11.7 vs. 8.0%) and lower HDL concentrations (12.0 vs. 8.8%). Overall, fluvastatin use was associated with a reduction in RR to approximately two-thirds of placebo. This tended to be significant in those groups at highest risk, specifically those with high total and LDL cholesterol and low HDL cholesterol (Table 2). Again, there was no significant difference within subgroups in the analysis (e.g. high vs. low LDL cholesterol); a failure that is most likely to reflect the limited power of the study, and the low number of end-points in the low-risk subgroups.
More detailed information is provided in Figures 3 and 4, which show the relationship between quartiles of individual subgroups. In Figure 3, the placebo groups show a clear increase in event rate with each increasing quartile of total cholesterol and decreasing quartile of HDL cholesterol. The pattern for LDL cholesterol and triglycerides is similar, with the highest quartile having the highest event rate but no obvious trend. In all quartiles of lipid subfractions, fluvastatin use was associated with a reduction in the event rate (by approximately one-third). Figure 4 shows a similar relationship for blood pressure and outcome. There was an increase in event rate with each quartile of systolic blood pressure but diastolic blood pressure did not show this trend, as the event rate was highest in the lowest quartile. Patients with higher creatinine and albumin excretion tended to have higher event rates, although the latter is difficult to study owing to the high proportion of patients without detectable albumin excretion.
This study (15) is the largest interventional trial in renal transplant recipients, and provides a unique resource to investigate the pathophysiology and management of CVD in this population. Fluvastatin reduced LDL-cholesterol by 1 mmol/L and was associated with a lower cardiac event rate than placebo. In the main study we used a composite end-point of cardiac death, definite or probable myocardial infarction, or coronary intervention. The choice of primary end-point is arbitrary (16) and, in the event, this chosen primary end-point failed to achieve significance, limiting the potential for subgroup analyses. In order to exploit the potential of this large study, we performed a posthoc analysis, using an alternative primary composite end-point of definite myocardial infarction or cardiac death [as used in the WOSCOPS study (6)]. Fluvastatin treatment was associated with a highly significant reduction in cardiac death or definite nonfatal myocardial infarction in renal transplant recipients, thus enabling the detailed analysis of the outcome in subgroups (15). In addition, the placebo group provides information on the impact of risk factors and CV outcomes in this population, albeit limited by the inclusion criteria and recruitment patterns of the study, which resulted in the recruitment of a relatively low-risk population when compared with Registry data (15).
It should be recognised that the overall statistical power of the study is low. We estimated (15) that 6800 renal transplant recipients followed for 5 years are necessary in studies of cardiovascular risk reduction in this population. Furthermore, in this posthoc analysis we did not subject the results to correction for multiple comparisons. Thus, this is an exploratory analysis, the results of which should not be over-interpreted, but considered in the light of our understanding of the pathophysiology of cardiovascular disease in transplant recipients and the benefits of statins in other populations.
Lipids and outcome
In the original study report (15) we demonstrated a significant reduction in LDL cholesterol (that averaged 1 mmol/L throughout the course of the study) and total cholesterol. Figure 1 shows these data and data on triglycerides levels and HDL-cholesterol. Overall, the effects of fluvastatin (40–80 mg/day) that we observed in the ALERT study are similar to those reported in all other statin trials (Table 3). The primary composite end-point of cardiac death or definite nonfatal MI was significantly reduced by fluvastatin treatment (Figure 1). The magnitude of the reduction (approximately one-third) and the relationship between lipid lowering and end-point reduction (Table 3) suggests that fluvastatin is as effective as other statins with regard to achieving long-term lipid lowering and cardioprotection (5–13,17–19). These data also suggest that the cardioprotective and lipid-lowering effects of statins are likely to be generic across populations of patients at increased risk of premature cardiovascular disease.
Table 3. Magnitude of LDL and reduction in cardiac event rate (cardiac death and nonfatal myocardial infarction) in the ALERT study and other major statin outcome trials in other populations
Sample size (n)
Follow up (years)
Baseline LDL (mmol/L)
LDL-C net change (mmol/L)
CHD event rate/year
CHD risk reduction (%)
We have limited understanding of the pathogenesis of CV disease in renal transplant recipients and, in particular, the relationship between conventional cardiovascular risk factors (e.g. hypertension, cigarette smoking and hyperlipidemia) and outcome (1–3). Table 2 and Figures 3 and 4 provide information on the relationship between CV risk factors and outcome. In data from the placebo group (Table 2) we observed that, predictably, men have one-third more cardiac deaths and nonfatal myocardial infarctions than women. The event rate in diabetics was approximately twice that of nondiabetics, patients with a past history of coronary heart disease had threefold as many events, and older patients also had a higher event rate. These observations are completely consistent with previous reports that these, nonmodifiable, risk factors are associated with increased cardiac risk in renal transplant recipients (1–3,20–22). The relationship between cigarette smoking and outcome is more difficult to interpret. Ex-smokers had an event rate approximately twice that of nonsmokers, while the much smaller group who admitted to smoking cigarettes had an event rate that was only slightly higher than placebo. This may reflect inaccurate reporting of smoking cessation and, overall, cigarette smoking was associated with increased risk, consistent with previous studies (3,20).
Subdivision of lipid levels in the placebo group by the median value demonstrated that those patients with values of LDL and total cholesterol above the median value had approximately twice as many events; high triglycerides or low HDL cholesterol showed a similar, but lesser impact. Subdivision of the lipid levels by quartiles in a posthoc analysis (Figure 3) provides more insight into the relationship between lipids and cardiac events. With increasing values of HDL there is a progressive reduction in event rate. However, we did not observe a progressive increase in event rates with increasing levels of total cholesterol, LDL-cholesterol or triglycerides. For each of these parameters the lowest quartile had a higher event rate than the second lowest quartile, with a progressive increase in each quartile thereafter. Although such relationships have been reported in patients on dialysis (23–25) and other conditions [e.g. essential hypertension (23–25)], they have not been reported in transplant recipients.
The relationship between blood pressure and outcome was also nonlinear. Although systolic blood pressure (Figure 4) shows a modest trend towards higher event rates with higher values, those patients in the lowest quartile of diastolic blood pressure had the highest event rate. Similar relationships have been reported in hemodialysis patients (25), and imply that arterial stiffness (26) and high pulse pressure (27) are likely to be the major determinants of outcome in transplant recipients.
We also investigated renal function and proteinuria. The latter is difficult to interpret in view of the large proportion of patients without detectable protein excretion. There was a major increase in the cardiac event rate in patients divided by the serum creatinine (Table 2), which is clearly seen in the quartile analysis in Figure 4, but a more modest increase in patients divided by albumin excretion rates of 0.1 mmol/day (13 vs. 10%). The relationship between serum creatinine and event rate is consistent with observations in other populations (28).
Effect of fluvastatin in subgroups
The original study protocol [a summary of which has been published (14)] described the analysis of predetermined subgroups. The highly significant reduction in the end-point of cardiac death or definite nonfatal MI allows analysis of these subgroups, proscribed by the original choice of primary end-point (15). The data presented in Table 2 are not adjusted for multiple comparisons, the interaction tests (although of limited statistical power) were negative, and the groups are often of unequal size. As a consequence, these analyses are exploratory in nature.
Overall, the risk reductions (one-third) attributable to fluvastatin therapy are similar across all of the groups. The lack of statistical significance in some subgroups is more likely to reflect the small number of events in the study and the limited statistical power, rather than a true negative effect. Despite this caveat, those patients we would consider to be at lower risk, i.e. those patients who are younger, who have been on renal replacement therapy (dialysis or transplantation) for the shortest time and who have the fewest risk factors (nondiabetics, nonsmokers, no prior history of CVD), exhibited the clearest benefits from statin therapy (Table 2). Patients with the highest levels of LDL and total cholesterol and triglycerides and lowest levels of HDL-cholesterol also had statistically significant benefits from fluvastatin therapy (Table 2; Figure 3). This observation is likely to reflect the higher event rate in those patients with higher total and LDL-cholesterol levels and lower HDL-cholesterol, as the proportional reduction in events is similar across the range of cholesterol subfraction values.
The ALERT study involved a population of renal transplant recipients at high risk of drug interactions (15,19,20), malignancy and infection (29,30). The main study report confirmed the safety of fluvastatin in renal transplant recipients. Most importantly, we did not find an increased risk of malignancy, infection or musculoskeletal complications (15). The latter are of particular concern because many of the commonly used statin drugs share metabolism by the microsomal enzyme system (CyP 3A4) with calcineurin inhibitors, resulting in greatly increased statin levels and potential for adverse effects. Fluvastatin does not share this interaction (19,30), permitting its safe use in transplant recipients.
Statins are already used in a high proportion of renal transplant recipients, who are at high risk of premature cardiovascular disease, reflecting the acceptance of data showing the beneficial effects of statins in other populations (5–13,31). It is now recognised that mild renal failure is associated with increased cardiovascular risk (28); a risk that is significantly reduced by statin therapy (13). The ALERT study provides evidence that patients with advanced renal diseases, treated by renal transplantation, also benefit from statin therapy. From the current analysis, we estimate that it is necessary to treat 31 patients for 5 years to prevent a cardiac death or nonfatal myocardial infarction. The data from subgroup analyses suggest that statin therapy is effective in the early post-transplant period and is effective even in patients with few conventional cardiovascular risk factors. Overall, ALERT provides strong support for the early introduction of fluvastatin for the primary prevention of cardiac disease in renal transplant recipients.
We wish to thank all trial participants, physicians, and nurses in the participating centers for their important contribution to the study. We thank Georges Ette, MSc (BioStat SA), and John O. Logan, MSc (Novartis), for their statistical support and Beatrix Staffler, Marie-Odile Freudenreich, Bente-Helene Johanssen, Dag O. Solbu, Pascale Pfister and Michele Bortolini (Novartis) for assistance in managing the study.