Long-term event monitoring study of fluvastatin in Japanese patients with hypercholesterolemia: Efficacy and incidence of cardiac and other events in elderly patients (≥65 years old)

Methods Patients ( n = 21,139) who started fluvastatin between April 1, 2000 and March 31, 2002, across 2563 centers in Japan were prospectively registered and followed up for 3 years (secondary prevention cohort) or 5 years (primary prevention cohort). Results Of the patients registered, 19,084 were included in this analysis. Levels of low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) decreased significantly in the primary (−27.1% and −18.8%) and secondary (−25.3% and −18.4%) prevention cohorts. Reductions in LDL-C (−22.1 vs. −18.2%, p < 0.0001) and TC (−16.1 vs. −13.1%, p < 0.0001) levels were significantly greater among patients aged ≥65 than <65 years old. Overall, 1.7% (146/8563) and 1.1% (93/8563) of patients aged ≥65 years old experienced confirmed cardiac and cerebral events, compared with 1.1% (112/10,517) and 0.3% (28/10,517) of patients aged <65 years old ( p = 0.0002 and <0.0001, respectively). Incidence of cardiac and cerebral events was lowest in patients aged <65 years old in the primary prevention cohort and highest among patients aged ≥65 years old in the secondary prevention cohort. Adverse events were reported in 7.9% (1501/19,084) of patients. Conclusion This large-scale, prospective, uncontrolled study confirmed the lipid-lowering efficacy and safety of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients aged ≥65 years old. The higher incidence of cardiac and cerebral events in patients aged ≥65 years old in the secondary prevention cohort reflects a high-risk clinical profile with multiple classic risk factors warranting multifactorial interventions. Keywords Elderly Fluvastatin Hypercholesterolemia Local event monitoring Safety Introduction Fluvastatin (Lochol ® , Novartis A.G.), introduced in 1983, was the first chemically synthesized 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor for the treatment of hypercholesterolemia. Unlike prior HMG-CoA reductase inhibitors that were derived from microbial metabolites, fluvastatin contains an indole ring as its basic chemical structure and its side chain contains a heptene residue that is similar in chemical structure to HMG-CoA, the endogenous substrate of HMG-CoA reductase. Statin-type drugs (HMG-CoA reductase inhibitors) are generally well tolerated with a low incidence of potentially serious side effects. In particular, large-scale clinical trials such as the 4S (Scandinavian Simvastatin Survival Study) [1] , WOSCOPS (West of Scotland Coronary Prevention Study) Group [2] , and CARE (Cholesterol And Recurrent Events) Trial [3] , trials conducted in Europe/North America, and the J-LIT (Japan Lipid Intervention Trial) [4] and MEGA Study [5] in Japan have demonstrated the safety of long-term administration of natural statins (fermentation-derived statins), including pravastatin and simvastatin. Since relatively short-term (24–52 weeks) studies are conducted for drug approval, long-term cohort studies are an important facet of drug development and can demonstrate the long-term efficacy and safety of a drug. We conducted a long-term cohort study using long-term event monitoring (LEM) to evaluate the efficacy and safety of fluvastatin in Japanese patients with hypercholesterolemia in everyday clinical practice, focusing on primary and secondary prevention cohorts (patients without or with prior history of cardiac/cerebral events). In addition, because a large number of patients with hypercholesterolemia are aged ≥65 years old, a range in which the incidence of cardiac and cerebral events is relatively high, we also focused on the safety and efficacy of fluvastatin for patients aged ≥65 years old and compared to those <65 years old. Methods Subjects Patients with hypercholesterolemia or familial hypercholesterolemia who had not received therapy for hypercholesterolemia for 4 weeks and who started fluvastatin were eligible for this study. Patients who received any lipid-lowering therapy in the 4 weeks prior to receiving fluvastatin were excluded from this analysis. Patients who had previously used fluvastatin, including the 4 weeks prior to this study, were excluded, as were secondary cases other than hypercholesterolemia or familial hypercholesterolemia. Registry protocol All patients were registered using a central registry method. Event monitoring was conducted under everyday clinical use, and case report forms (CRFs) were completed by the physicians every 6 months and transferred to the central registry. The investigators explained the objective of the study to their patients requesting participation in this study. Informed consent was obtained from each patient prior to the registration. The regular event monitoring of the patients was conducted at 6-month interval for up to 5 years or 3 years for patients with a history of coronary artery diseases (CADs) or complications of CAD. At each visit (and between visits as necessary), the physicians recorded details of any events, including cerebral, cardiac, and other adverse events, and the time of the events, in addition to demographic characteristics, concomitant medications, drug compliance, blood pressure, body weight, serum parameters (low-density lipoprotein-cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], total cholesterol [TC], triglycerides [TG], creatinine kinase [CK], CK-myocardial band [Mb], aspartate transferase [AST], lactate dehydrogenase [LDH] and white blood cell count [WBC]), lifestyle factors (dietary/exercise guidance; alcohol intake, and smoking status) and performed electrocardiography (ECG). All data were recorded in case report forms. Adverse drug reactions were defined as adverse events for which a causal relationship with the study drug could not be excluded. Patients were initially registered between April 1, 2000 and March 31, 2002; the study follow-up was completed on March 31, 2007. This study was conducted in accordance with Good Post-marketing Surveillance Practice regulations [6] . Institutional Review Board (IRB) approval was obtained at all sites with an established IRB. Written informed consent was obtained from all patients. Treatments All patients included in the registry were given fluvastatin, once daily after dinner. The initial dosage was 20 mg; which could be increased to 60 mg/day, to achieve the appropriate LDL-C level recommended by the dyslipidemia guidelines published by the Japan Atherosclerosis Society [7] , [LDL-C to <140 mg/dL in patients without CAD or risk factors (≥45 years old for males, post-menopausal for women; family history of CAD; smoking; hypertension, systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg; obesity, body mass index (BMI) ≥26.4 kg/m 2 (≥25.0 kg/m 2 from 2005); impaired glucose tolerance according to Japan Diabetes Society criteria [8] ; hypertriglyceridemia, low HDL cholesterolemia, arteriosclerotic disease other than CAD); to <120 mg/dL in patients without CAD but with any of these risk factors; and to <100 mg/dL in patients with CAD, irrespective of other risk factors]. The study protocol did not provide any guidance on the use of antiplatelet drugs, cholesterol-lowering drugs, or other concomitant therapies, other than to continue standard therapy. Therefore, the use of concomitant therapies was at the discretion of each investigator. Definitions and endpoints Cardiac and cerebral events were reviewed by an Event Evaluation Committee (EEC). For cardiac events, the EEC reviewed the following parameters: ECG findings, clinical symptoms, biochemistry parameters (CK, CK-Mb, AST, LDH, and WBC), medical course, complications, outcomes, and any comments recorded by the chief physician. Cardiac events were defined as fatal/non-fatal myocardial infarction (MI), cardiac death, angina pectoris, or asymptomatic myocardial ischemia. Cerebrovascular events were also reviewed by EEC members, based on computed tomography/magnetic resonance imaging findings, clinical symptoms, biochemistry parameters, medical course, complications (atrial fibrillation, MI), outcomes, and any comments recorded by the chief physician. Cerebrovascular events were defined as cerebral infarction (cerebral thrombosis or cerebral embolism), intracranial hemorrhage, subarachnoid hemorrhage, and transient ischemic attack (TIA). All cerebrovascular and cardiac events were assessed based on standard diagnostic criteria ( Supplementary Table 1 ). The primary endpoint was the incidence of cardiac events and cerebral events during long-term treatment with fluvastatin. Secondary endpoints included the type, severity, and incidence of side effects other than the above events during long-term use of the drug. Secondary endpoints also included changes in serum lipid parameters. As described above, patients were included in the primary prevention group or in the secondary prevention group if they had prior history of cardiac (e.g. coronary arterial disease) or cerebral (e.g. cerebral infarction and cerebral hemorrhage) events. The presence or absence of prior cardiac or cerebral events was determined on a case-by-case basis by members of the Advisory Board. The secondary prevention cohorts were also stratified according to prior history of cardiac or cerebral events. LDL-C values were calculated using Friedewald's formula. LDL-C was not calculated for subjects with a TG value ≥400 mg/dL. However, if LDL-C was measured using a direct method, this value was used instead. Statistical analysis All data were analyzed for the full study population, and after stratification into the primary/secondary prevention cohorts and according to age <65/≥65 years old. Patients with only baseline data were excluded from efficacy and safety analyses. The incidence of cardiac and cerebral events was estimated using the Kaplan–Meier method followed by log-rank tests to compare groups. The associations between the incidence, LDL-C levels, and other risk factors (hypertension, glucose intolerance, obesity, age, sex, and smoking) before and after administration of the drug were also evaluated using the Cox proportional hazards model. Results Patient characteristics A total of 21,139 patients were initially registered in this study. CRFs were collected for 19,105 patients at the start of the study ( Supplementary Table 2 and Supplementary Fig. 1 ). Twenty-one patients were subsequently excluded by the Advisory Board and the safety evaluation set comprised 19,084 patients. Of these, follow-up data were collected for 13,005 (68.2%) patients at 1 year, 10,391 (54.5%) at 2 years, 8830 (46.3%) at 3 years, 6851 (39.9%) at 4 years and 6175 (35.9%) at 5 years. During years 1–5, 81, 51, 56, 34, and 29 patients died, respectively. Overall, 8165 (42.8%) patients discontinued from the study during the study period at the patient's request or because of their circumstances (e.g. patient was lost to follow-up/did not attend the visit; transfer to another department or hospital). Meanwhile, 1568 (8.2%) patients discontinued either because of no improvement in lipid levels, or because of the improvement in lipid levels meant lipid-lowering therapy was no longer deemed necessary by the physician. Furthermore, 779 (4.1%) patients discontinued because of adverse events, and 239 (1.3%) discontinued for another reason (e.g. hospitalization, changes in attending physician's situation). Of the 19,084 eligible patients, 1000 were excluded for the following reasons (3 patients met multiple exclusion criteria): 940 patients with initial TC <220 mg/dL (TC within the normal range), 60 patients with an unknown/unclear therapeutic category according to the Japan Atherosclerosis Society criteria and could not be assigned to the primary or secondary cohorts, and 3 patients received fluvastatin in an off-label manner. Thus, the efficacy evaluation set comprised 18,084 patients. The primary and secondary prevention cohorts comprised 17,189 (90.0%) and 1895 (9.9%), respectively. The mean dose of fluvastatin in the total cohort was 21.3 mg/day at study start. Table 1 shows the characteristics of the patients in the total cohort, the primary/secondary prevention cohorts and according to age group (<65 vs. ≥65 years old). The mean age of the total cohort was 62.3 ± 11.1 years (8563 aged ≥65 years), and most of the patients were female (70.6%). Overall, 1222 (6.4%) had a history of cerebrovascular disorders, 3056 (16.0%) had a history of cardiac disease, 3325 (17.4%) had diabetes or impaired glucose tolerance, and 8855 (46.4%) had hypertension. Only 249 (1.3%) patients had history of treatment with lipid-lowering drugs. As would be expected, there were significant differences between those aged <65 and those aged ≥65 years old, particularly in terms of the ‘classic’ risk factors, such as hypertension, cardiac disease, cerebrovascular disorders, and ECG abnormalities. The mean dose of fluvastatin was comparable between prevention cohorts and age groups. Prevalence of cardiac and cerebral events in the total cohort and in the primary and secondary prevention cohorts The EEC reviewed a total of 368 and 238 suspected cases of cardiac and cerebral events, respectively. Of these, 275 and 155 cases, respectively, were confirmed by the EEC, and 238 and 114, respectively, were included in the efficacy analysis set. Confirmed cardiac events included unstable ( n = 29), effort ( n = 10), and ‘other’ angina ( n = 152); asymptomatic ( n = 61), non-fatal ( n = 49), and fatal MI ( n = 13), and coronary spastic angina ( n = 9). Confirmed cerebral events included cerebral infarction ( n = 114), TIA ( n = 13), cerebral hemorrhage ( n = 20), subarachnoid hemorrhage ( n = 7), and cerebral venous thrombosis ( n = 1). Cumulative incidence of cerebral/cardiac events and death The cumulative incidences of major events in the primary and secondary prevention cohorts were 1.48% and 7.28%, respectively, for cardiac events, and 0.84% and 4.80%, respectively, for cerebral events. Thus, the cumulative incidences of cardiac and cerebral events in the secondary prevention cohort were 4.9- and 5.7-times higher, respectively, than those in the primary prevention cohorts. The cumulative mortality rates in the primary and secondary prevention cohorts were 2.05% and 3.59%, respectively. The incidence of cardiac and cerebral events was 4.98 (95% CI: 4.85, 5.11) and 2.40 (95% CI: 2.22, 2.58) events/1000 patients/year, respectively, and was higher in the secondary prevention cohort than in the primary prevention cohort ( Table 2 ). Similar trends were observed in terms of angina pectoris and MI ( Table 2 ). Effects of fluvastatin on lipid parameters in the primary and secondary cohorts Fluvastatin elicited sustained reductions in both LDL-C and TC by 28.7% and 20.0%, respectively, in the primary prevention cohort, and by 26.3% and 18.9%, respectively, in the secondary prevention cohort ( Table 3 ). Meanwhile, HDL-C increased by 1.4% and 0.4%, respectively, and TG decreased by 17.4% and 14.2%, respectively. Effects of long-term fluvastatin on the incidence of cardiac and cerebral events and lipid levels in patients aged ≥65 years old As shown in Table 4 , the incidences of cardiac and cerebral events in the primary cohort were higher in those aged ≥65 years old than in those aged <65 years old. By contrast, in the secondary cohort, the incidence of cardiac events was higher in patients aged <65 years old. There was little difference in the rate of cerebral events. This suggests that older patients without a history of an event are at increased risk of future events compared with younger patients without history of an event. Furthermore, among patients with a history of an event, the risk of future cardiac events seems to be higher among younger patients, while there is no difference in the risk of cerebral events. As shown in Fig. 1 , these overall patterns were maintained throughout the study. Fluvastatin exerted sustained reductions in LDL-C and TC in both age groups of patients ( Fig. 2 ). Interestingly, the magnitudes of changes in LDL-C (−47.4 vs. −50.2 mg/dL [−27.2 vs. −29.4%], p = 0.002) and TC (−50.3 vs. −54.2 mg/dL [−18.9 vs. −20.8%], p < 0.0001) were significantly greater among patients aged ≥65 years old compared with those aged <65 years old ( Table 3 ). Associations between risk factors with cardiac and cerebral events Because cardiovascular and cerebral events are strongly associated with a multitude of risk factors, including LDL-C levels, we also analyzed the association between these risk factors at baseline with the incidence of events using the Cox proportional hazards model ( Supplementary Fig. 2 ). Overall, 12 baseline factors were significant in the primary prevention group ( Supplementary Fig. 2A ), including sex, age in men (≥65 years), age group (55–60 and 70–75 years), obesity (BMI ≥25 kg/m 2 and diabetes), and complications (hypertension, diabetes, hypertension and diabetes, cardiac disease, cerebral disease, cerebral infarction, and atrial fibrillation). Five factors were significant in the secondary prevention group, namely menopause in women, sex, smoking, TG ≥150 mg/dL, and complications (diabetes). Meanwhile, 14 factors were significantly associated with cerebral events in the cerebral primary prevention cohort ( Supplementary Fig. 2B ). These included age in women (≥55 and ≥65 years), age in men (≥65 years), age group (55–60, 70–75, 75–80, and ≥80 years old), smoking, TG ≥150 mg/dL, and complications (hypertension and diabetes, cardiac disease, kidney disease, and atrial fibrillation). In the cerebral secondary prevention cohort, the following factors were significant: age group (55–60, 70–75, 75–80, and ≥80 years), obesity (BMI ≥25 kg/m 2 and diabetes), and complications (diabetes, cardiac disease, and atrial fibrillation). Relative risk of cardiac events according to lipid levels Fig. 3 shows the relative risk of cardiac events in the primary and secondary cohorts according to classes of LDL-C, TC, and HDL-C. As would be expected, in terms of LDL-C, the risk of cardiac events was the highest for patients with LDL-C ≥180 mg/dL ( Fig. 3 A and B) or with HDL-C <40 mg/dL ( Fig. 3 C and D) in both the primary and secondary cohorts. In terms of TC, the profiles showed a more complex relationship. In the primary prevention cohort, the risks were markedly elevated in patients with TC <180 mg/dL or ≥260 mg/dL ( Fig. 3 E). By contrast, in the secondary cohort, the risks were greater in patients with TC ≥260 mg/dL ( Fig. 3 F), but were actually lower than those in the reference category in the other sub-groups. Adverse events The incidence of adverse events was 7.9% (1501/19,084) in the total cohort. In terms of adverse drug reactions ( Table 5 ), the most common events included increased blood CK in 140 patients (0.7%), abnormal liver function in 126 patients (0.7%), muscle pain in 88 patients (0.5%), nausea in 78 patients (0.4%), and stomach discomfort in 68 patients (0.4%). Considering the side effects described in the package insert, there were no adverse drug reactions that have not already been described for fluvastatin and there were no confirmed episodes of rhabdomyolysis. Overall, there was a small, non-significant difference in the rate of adverse events between patients aged ≥65 and those aged <65 years old ( n = 792/10,517 vs. 709/8563 [8.3% vs. 7.5%], p = 0.058). Furthermore, the prevalence of adverse events was not dose-dependent, as the prevalence was not significantly different ( p = 0.65) among patients taking ≤20 mg/day (1763 events in 1320/16,706 [7.9%] patients), 30 mg/day (147 events in 188/1917 [7.7%] patients), or ≥40 mg/day (34 events in 48/461 [7.4%] patients). Discussion Based on their extensive clinical history, dating back over 20 years, statins are now widely used for the treatment of hypercholesterolemia, and have been shown to significantly reduce the incidence of cardiovascular disease and death. In the present study, fluvastatin elicited sustained reductions in both LDL-C and TC in the primary and secondary prevention cohorts of Japanese patients. Interestingly, these reductions in lipid parameters tended to be greater over time among patients aged ≥65 years old than in those aged <65 years ( Fig. 2 and Table 3 ). However, the magnitude of the differences between these groups of patients was small and may not be clinically relevant in terms of risk profiles. These results are broadly consistent with those of other similarly designed studies in Japanese patients, such as the J-LIT study of 51,321 patients treated with simvastatin, in which LDL-C and TC were reduced by 26.0% and 18.3%, respectively, in the total study population [9] . As expected, the incidence of cardiac and cerebral events was slightly higher in the secondary prevention cohort than that in the primary prevention cohort ( Table 2 ). Clearly, the secondary prevention cohort should be a major target for intervention. Many studies have already demonstrated that lipid-lowering therapy shows marked risk reduction on such events in high-risk primary [10–12] and secondary [13–16] prevention cohorts. Although we did not include a control or comparator group in this study, fluvastatin therapy for up to 5 years (3 years in the secondary prevention cohort) was associated with a low incidence of cardiac and cerebral events, such as MI and cerebral infarction, which was consistent with findings of other, shorter-term studies in Japan and worldwide [1,3,9,17,18] . As many patients with hypercholesterolemia are considered elderly (≥65 years old), we performed a sub-analysis according to age, <65 vs. ≥65 years old. The incidence of cardiac and cerebral events was significantly higher among patients aged ≥65 years than those aged <65 years in the primary cohort, but not in the secondary prevention cohort. Surprisingly, in the secondary prevention cohort, the incidence of cardiac events was higher among patients aged <65 years than in those aged ≥65 years. This population represents a very high-risk patient population with marked predisposition to future events, namely high incidence of hypertension, diabetes, and ECG irregularities. In fact, improvements in LDL-C and TC were significantly greater in patients aged ≥65 years old than in those aged <65 years old, although the clinical relevance of the difference between these groups remains to be established. To our knowledge, this is the first such study to determine the efficacy of fluvastatin in elderly patients in Japan. These findings support the previous findings of a short-term prospective double-blind study [19] and those of a pooled analysis [20] of 30 clinical trials in predominantly white patients (∼96%), aged <65 vs. ≥65 years old. Although it is unclear why improvements in LDL-C and TC were greater in those aged ≥65 years old, this may reflect more intensive lipid-lowering, blood glucose-lowering, and antihypertensive therapies to provide global health benefits, particularly among those with a prior history of events (i.e. in the secondary prevention cohort). By contrast, patients aged <65 years old with fewer ‘classic’ risk factors may receive less intensive intervention. In terms of the direct effects of lipid-lowering therapy, a sub-analysis of the 4S study [21] revealed a curvilinear relationship in the relative risk (RR) between post-treatment blood serum LDL-C levels and CAD events (fatal and non-fatal CAD and sudden cardiac death). Meanwhile, a sub-analysis of the CARE study [22] showed a threshold relationship in the RR between LDL-C levels and recurrent coronary events, as the event rate decreased with reductions in LDL-C from 174 mg/dL to 125 mg/dL, but no further reduction occurred with further decreases in LDL-C to 71 mg/dL. Thus, it remains unclear whether further reductions in LDL-C below 125 mg/dL provide further reductions in the incidence of coronary events. While the reduction in cardiovascular events by statin-type drugs is mainly thought to be due to their cholesterol-lowering effects, statins have been shown to exert many other beneficial effects including improvements in vascular endothelial function [23] , anti-inflammatory effects, antioxidant effects [24,25] , smooth muscle cell proliferation [26] , and enhanced stability of atherosclerotic plaques [27] . Abe et al. previously reported that fluvastatin, but not simvastatin, increased eNOS mRNA levels by enhancing the transcriptional activities of the eNOS gene and mRNA stability in human umbilical vein endothelial cells [28] . Therefore, lipid-independent effects may play a role in the moderate LDL-C reduction achieved with fluvastatin [29] . As shown in Fig. 3 , the relative risk for cardiac events according to mean LDL-C levels in the primary prevention group was significantly greatest at LDL-C ≥180 mg/dL, suggesting that fluvastatin acts as a vascular statin and reduces the risk of events in patients with LDL-C <180 mg/dL. Indeed, the ability of fluvastatin to protect vascular walls has been demonstrated in the SCAST (Statin and Coronary Artery Spasm Trial) [30] , in which fluvastatin in combination with conventional calcium channel blocker (CCB) therapy significantly suppressed the occurrence of vasospastic angina compared with CCB therapy alone. Of note, the prevalence of vasospastic angina is markedly higher in Japanese individuals than in Westerners. Thus, interventions that reduce the risk of such cardiac events should be considered in the multifactorial treatment of high-risk patients. In secondary prevention settings, the risk of cardiovascular events is significantly lower in patients with LDL-C <100 mg/dL. However, the required level of control to reduce the risk of events is less clear in primary prevention settings. For example, a sub-analysis of the results of the West of Scotland Coronary Prevention Study [2] showed that the cardiovascular event prevention effect does not increase, even when LDL-C decreased by ≥24%. Similarly, the J-LIT study [9] in Japanese patients revealed a plateau in the risk of coronary disease in patients with LDL-C <160 mg/dL. In our study, the risk of cardiovascular events reached a plateau at an LDL-C level of <180 mg/dL. Clearly, further studies are needed to ascertain the meaning of these findings and to provide clinical guidance on targets for primary prevention. Overall, adverse events were reported in 1501 patients (7.9%) in the total cohort. The most common events included elevated blood CK, abnormal liver function, muscle pain, nausea, and stomach discomfort, which is consistent with the package insert, and no new events were reported in this study, confirming the tolerability of fluvastatin in everyday clinical use. Although some patients reported muscle pain or elevated blood CK levels, none of these cases was found to be rhabdomyolysis, an adverse event that has gained increasing attention in patients treated with statins [31–33] . Nevertheless, appropriate assessment of muscle pain and measurement of blood CK levels can help the clinician to determine the possible risk of rhabdomyolysis and related events, and encourage changes in statin dosage or consider changes to the treatment regimen if deemed necessary [34] . Nevertheless, the incidence of such events in this long-term study was low and any changes to therapy should take into account the advantages of statin therapy on risk reduction for major cardiac and cerebral events [35] . Finally, the results of this study should be interpreted with care, taking into account the limitations of this study. First, this was an open-label, non-randomized, uncontrolled study without a comparator group. Second, the study was limited to Japanese patients who were selected for registration in this study by their physician. Thus, some bias may exist as the physicians may have selected their ‘least severe’ patients. However, this is unlikely, as a large number of patients were identified after registration for inclusion in a secondary prevention cohort, and the characteristics of the patients in this group suggest moderate to high risk for future events. Finally, the results may not be generalizable to other countries. Conclusions In conclusion, the results of this long-term cohort study confirm the efficacy and tolerability of fluvastatin in Japanese patients with or without prior history of cardiac or cerebral events. Furthermore, this analysis also revealed a low risk of events in patients aged ≥65 years old with or without prior history of cardiac or cerebral events, patient populations that are increasingly being encountered in everyday clinical practice. Finally, we found that long-term therapy with fluvastatin elicited significantly greater improvements in lipid control, particularly of LDL-C and TC, in patients aged ≥65 years than in patients aged <65 years, among those that persisted throughout the study. However, the magnitude of this difference is small and the clinical relevance remains to be established. Disclosure The seven authors were members of Novartis Pharma Japan Advisory Board and Event Evaluation Committee, and received nominal fees for their consultations. Study organization This study was overseen by an Advisory Board and an Event Evaluation Committee. The Advisory Board provided expert advice regarding the conduct of the study. The latter group provided advice on methods and standards of data handling and evaluation of cerebral and cardiac event data through neutral evaluation and discussion from a medical and expert viewpoint. Acknowledgments This study would not have been possible without the valuable data provided over the last 7 years by more than 6100 physicians nationwide that offered their cooperation in the LEM study, and we would like to take this opportunity to offer them our utmost thanks. We would also like to thank everyone at the Asklep Registration and Data Center who assisted in case registration and the collection and analysis of the data and everyone at the R&D Pharmacovigilance Operation Department at Novartis Pharmaceuticals who assisted in the compilation of this report. Appendix A Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jjcc.2010.09.003 . Appendix A Supplementary data References [1] Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet 344 1994 1383 1389 [2] J. Shepherd S.M. 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