Fluvastatin in severe hypercholesterolemia:Analysis of a clinical trial database

Fluvastatln in Severe Hypercholesterolemia: Analysis of a Clinical Trial Database Tim K. Peters, MD Many patients with severe primary hypercholesterolemic !owdensitylipopratein cholesterol (LDL-C) >240 m g / d L ~ a v e heterazygous familial hypercholesterolemia. In such familial hypercholesterolemic patients, the lipid-lowering efficacy of fluvastatin is related to genetic factors, and it is of interest whether the response to treatment differs from that in patients with more moderate hypercholesterolemia. Thus an exploratory analysis of randomized, controlled clinical trials and their open-label extensions (12-78 weeks), conducted worldwide with fluvastatin >20 mg/day (n = 1810) and placebo (n = 783), assessed whether, apart from the potential differences between familial hypercholesteralemic and nonfamilial hypercholesteralemic patients, the response to 40 mg of fluvastatin is influenced by baseline plasma lipid levels in relation to disease severity. Entry criteria included LDL-C >190 mg/dL with <1 risk factor and no coronary artery disease, or >_160 mg/dL with > 1 risk factor or definite coronary artery disease. Of these patients, 591 (33%) given fluvastatin (20-40 mg/day) and 187 (24%) given placebo had severe hypercholesterolemia with baseline LDL-C >240 mg/dL. In controlled studies, the mean -- SD duration of expo-

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evere primary hypercholesterolemia can be defined as a low density lipoprotein cholesterol (LDL-C) level >_ 240 mg/dL. 1 Many of these patients have heterozygous familial hypercholesterolemia and produce only half the number of LDL receptors and have twice the plasma cholesterol levels of those found in the normal population. These subjects are at considerably greater risk of ischemic heart disease, which often develops during the fourth or fifth decade of life.2 In this category of patients, drug therapy is justified even in the absence of other risk factors. 3 In patients with heterozygous familial hypercholesterolemia, the efficacy of fluvastatin to reduce LDL-C and raise high density lipoprotein cholesterol (HDL-C) has been shown to be related to genetic factors. 4 Baseline LDL-C levels are in the range of 265-325 mg/dL, depending on genetic grouping, and a reduction in LDL-C of up to 30% has been achieved with fluvastatin 40 mg/day.

sure was 21.1 - 16.1 and 19.4 - 15.5 weeks for fluvastatin and placebo, respectively, whereas longterm efficacy was assessed after 55.3 +- 21.7 weeks (fluvastatin) and 21.1 +-. 12.3 weeks (fluvastatin + cholestyramine, after previous monotherapy). In summary, fluvastatin at 40 mg/day lowered LDL-C by 25-26% from baseline in controlled studies (n = 622), and by 27% in long-term studies (3233% with fluvastatin + choleslyramine; n -- 386), irrespective of severity of cholesterolemia. High density lipopratein cholesterol (HDL-C) and triglyceride responses were enhanced, when at baseline HDL-C levels were low and triglycerides raised, irrespective of baseline cholesteralemia, whereas the LDL-C response was unrelated to baseline in patients with LDL-C levels >240 mg/dL. In patients in the highest triglyceride tertile, fluvastatin plus cholestyramine apparently abolished the triglyceride increase expected with cholestyramine. This influence of baseline levels on fluvastatin response can be considered beneficial, as hypercholesteralemic patients with low HDL-C and high triglyceride levels are at particularly high cardiovascular risk. (Am J Cardiol 1995; 76:71A-75A)

Overall, these figures are similar to those found in nonfamilial hypercholesterolemic patients who have more moderate hypercholesterolemia. However, to corroborate these findings on a larger scale, apart from a potential differentiation between familial and nonfamilial hypercholesterolemia, an analysis was carried out in patients with primary hypercholesterolemia to evaluate the lipid-lowering efficacy of fluvastatin at 40 mg/day in relation to severity of disease, and the influence of baseline lipids within a severity subgroup. This exploratory analysis was based on data from randomized, controlled clinical studies and their open-label extensions (12-78 weeks), conducted worldwide with fluvastatin > 20 mg/day (n = 1810) or placebo (n = 783).

METHODS Studies with fluvastatin have been conducted in North America, Europe, and Israel, and the international database includes approximately 2600 patients. The data include patients' demographic and From Sandoz Clinical Research,Basel,Switzerland. other baseline characteristics; efficacy in terms of Address for reprints: Tim K Peters, MD, Clinical Research and Development, Sandoz Pharma Ltd, Lichtstrasse35, CH-4002 Basel, response to treatment, based on plasma levels of LDL-C, HDL-C, and triglycerides; and major safety Switzerland. A SYMPOSIUM: MANAGEMENT OF HYPERLIPIDEMIA 71A

TABLE I Demographic and Baseline Charaderistics of Database Patients According to LDL-C Elevation Fluvastatin LDL-C> 240 mg/dL (n = 591) Age(years;mean -+ SD) > 6 5 years In (%)] White [n {%)] Male [n (%)] Weight (kg; mean _+ SD) BMI (kg/m2; mean -+ SD) > 28 kg/m 2 [n (%)] History of CAD In (%)]

Lipidsand lipoproteins (mg/dL; Total cholesterol LDL-C (range) HDL-C (range) TG (range) > 200 mg/dL In (%)]

49 65 561 305 75 26 148 93

-+ 1 2 . 4 t t t (2.9)ttt (95) (52)tt --- 14 _+ 3.8 (25) (16)t

Placebo LDL-C < 240 mg/dL (n = 1219)

54 107 1154 724 76 26 303 139

LDL-C> 240 mg/dL (n = 187)

-+ 10.8 (8.8) (95)## (59) -+ 14 --- 3.8 (25)# (11)

50 6 179 94 72 25 47 23

-+ 12.1ttt (3.2)t (96)'1" (50)tt --- 13tSl't - 3.5ttt (26) (12)

-+ 2 5 # # # -- 21 (139-240)### -+ 12 (23-125) +- 60 (38-447) (19)

382 303 50 143 35

+-- 56" _+ 54 (241-480)" "4- 13 (28-88) -+ 60 (47-331) (19)

LDL-C < 240 mg/dL (n = 596) 55 -- 10.6

45 (7.8) 544 (91)

374 (63) 7 7 _+ 15 26_+4

175 (29) 69 (I 2)

mean -+ SD)

375 298 48 147 112

+-- 55" -+ 53 (241-514)* -+ 12 ( 2 1 - 8 5 ) t t t # --- 63 (43-398) (19)

282 201 51 151 231

277 197 51 149 107

-- 25

-+ 25 (147-240) -+ 12 (26-105) +-- 58 (37-397)

(17)

•Statistical comparison not applicable. tP < 0.0S, t t p < 0.01, t t t p < 0.001 between subgroups; #p < 0.05 # # p < 0.01 # # # p < 0.001 within subgroups, versus placebo. BMI = body moss index; CAD = coronary after' disease; HDL-C = high density lipoprotein cholesterol; LDL-C = low density llpopratein cholesterol; TG = triglyceride.

data, based on plasma levels of alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase. The safety data, along with the reported adverse event data, have been published previously.5 These clinical trials all had consistent and comparable designs and a similar schedule of visits. Except for 24 patients in one clinical trial 6 who received 60 mg/day fluvastatin, the highest dosage used was 40 mg/day. The lipid criteria for entry into the trials included: LDL-C > 190 mg/dL (with < 1 risk factor and no coronary artery disease) or >160 mg/dL (with > 1 risk factor or definite coronary artery disease). Patients were excluded if triglycerides were > 450 mg/dL. Although not a primary objective in any of the trials on their own, pooling the data from multiple trials provided the opportunity to assess the efficacy of fluvastatin treatment in a subgroup of severe hypercholesterolemic patients, i.e., LDL-C > 240 mg/dL at baseline. Efficacy at endpoint was calculated as the percent change from baseline of lipids and lipoproteins, and was analyzed in those patients receiving 20 or 40 mg/day of fluvastatin, the two dosages expected to be recommended as lipid-lowering therapy in patients with primary hypercholesterolemia irrespective of associated risk factors. Baseline levels were defined as the average of 2 measurements taken from the last 2 blood samples prior to randomization during the placebo lead-in period of a given study; endpoint was defined as the last measurement from a given patient in a given study. For the purpose of assessing the influence of 7~I.

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baseline levels of lipids on the response within each severity subgroups, baseline levels were broken down by tertiles. For demographics and baseline characteristics, the mean percent change from baseline in efficacy parameters within groups was analyzed using the t test for the mean percentage change from zero. Statistical comparison of means between groups was based on a two-tailed t test, and for proportions was based on a two-tailed Z test. Significance testing was by analysis of variance for factors of severity, treatment, and baseline tertiles. Data are given as means --- SD.

RESULTS Patients' baseline characteristics: The baseline demographic characteristics of database patients according to LDL-C elevation are shown in Table I. Patients in the severe hypercholesterolemia group who received fluvastatin (n = 591) or placebo (n = 187) were, on average, 5 years younger than the groups with LDL-C < 240 mg/dL (n = 1219 for fluvastatin and n = 596 for placebo). The patients were predominantly white (91-96%), and there were relatively fewer men (52% and 50%) in the higher level groups than in the lower level groups (59% and 63%). In the fluvastatin-treated groups, there was no difference in overweight, defined as a body mass index > 28 kg/m 2. For patients receiving placebo, the percent overweight was slightly higher in the > 240 mg/dL group and significantly higher (p <0.05) in the <240 mg/dL group compared with fluvastatin. History of coronary artery disease was significantly higher in the fluvastatin-treated, higher level group (p < 0.05 vs placebo). JULY 13, 1995

Baseline total cholesterol was not significantly different between fluvastatin and placebo groups at the higher level ( 3 7 5 - 55 vs 382 ___56 mg/dL), although the level was significantly higher in the fluvastatin group at the lower level (282 _ 25 vs 2 7 7 _ 25; p <0.001). A similar pattern was observed with LDL-C. Mean baseline values for LDL-C in the fluvastatin group were 298 mg/dL in the higher level group and 201 mg/dL in the lower level group. The range of baseline LDL-C levels in the higher level group went as high as 514 mg/dL. The mean --- SD duration of exposure in controlled studies was 2 1 . 1 _ 16.1 weeks for fluvastatin and 19.4 _ 15.5 weeks for placebo. In the long-term studies, efficacy was assessed after exposure of 55.3 --- 21.7 weeks of fluvastatin as monotherapy and 21.1 __+12.3 weeks of combination therapy with fluvastatin plus cholestyramine after previous monotherapy. Approximately one-third of patients receiving fluvastatin and one-quarter of those receiving placebo were classified as being in the higher level ( > 240 mg/dL) group and having severe hypercholesterolemia. Lipids and lipoproteins: The effects of fluvastatin on lipids and lipoproteins are shown in Table II for patients in both the higher and the lower LDL-level groups who received 20 or 40 mg fluvastatin daily. In the higher LDL-level group, fluvastatin reduced LDL-C by 19.7% with 20 mg/day and by 26% with 40 mg/day. The overall response in the lower level group was not statistically significantly different from the higher level group (20 mg/day, -20.1%; 40 mg/day, -24.6%). Fluvastatin at either dose produced a slight, but significant, increase in HDL-C in both the higher and lower LDL-level groups. Fluvastatin at 40 mg/day was more effective than 20 mg/day in both groups. Reductions in triglyceride levels were more pronounced in the higher than the lower LDLlevel group and at 40 mg/day than with 20 mg/day. From these results, 40 mg/day fluvastatin was considered more relevant in severe hypercholesterolemia and was used in the subsequent analysis. Response by tertiles of baseline levels: The efficacy of 40 mg/day fluvastatin and placebo in reducing LDL-C and triglycerides and in increasing HDL-C, according to tertiles and severity of disease, are shown in Figure 1. In patients with baseline LDL-C <240 mg/dL, the response to fluvastatin of LDL-C and triglycerides was enhanced in the highest tertile of each subgroup. Thus, LDL-C was reduced by 21.2% in the lowest tertile, but by 26.4% in the highest tertile. Triglyc-

TABLE II Percent Changes in Main Lipid and Lipoprotein Parameters with Two Different Dosages of Fluvastatin According to Baseline LDL-C Elevation LDL-C >240 mg/dL

Fluvastatin 20rag 40 mg

LDL-C

HDL-C

TG

-19.7 -26.0

+4.3 +4.5

-5.2 - 7.7

LDL-C <240 mg/dL L D L - C HDL-C -20.1 -24.6

+4.1 +4.5

TG -3.1 -6.8

For abbreviations, see Table I.

erides were reduced by 3.2% in the lowest tertile and by 10.9% in the highest tertile. With HDL-C, the levels were most increased when the baseline levels were low: 8.1% in the lowest tertile and 0.9% in the highest (p < 0.001). For patients with severe hypercholesterolemia (LDL-C > 240 mg/dL), the LDL-C response appeared to be unrelated to baseline, but the HDL-C and triglyceride responses were similarly enhanced (p < 0.01). In the long-term open-label studies, LDL-C was decreased by 27% with fluvastatin monotherapy (n = 1114) and by 33% with the combination of fluvastatin plus cholestyramine (n = 386). With the exception of patients in the lowest tertile of moderate elevation of LDL-C, these effects appeared to be irrespective of severity of disease (Figure 2). For HDL-C, those patients in the lowest baseline tertile in both LDL-C groups ( > 240 and < 240 mg/dL) showed the greatest increase, with fluvastatin alone producing a better overall effect than combination therapy. In patients in the highest tertile for triglycerides, the addition of fluvastatin to cholestyramine appeared to abolish the triglyceride increase expected with cholestyramine monotherapy.

DISCUSSION The present analysis shows that fluvastatin is effective in modifying levels of lipids and lipoproteins in patients with severe hypercholesterolemia. The response of lipids and lipoproteins to fluvastatin tended to be enhanced when fluvastatin at 40 mg daily was taken. The responses to 40 mg/day, alone or in combination with cholestyramine, were similar regardless of the severity of hypercholesterolemia. With baseline LDL-C levels > 240 mg/dL--predominantly in patients with familial hypercholesterolemia--responses were enhanced with low HDL-C and moderately high triglyceride baseline levels, whereas LDL-C responses were not related to baseline, which ranged from >240 to 514 mg/dL. Overall, HDL-C was most increased when baseline levels were low, whereas triglycerides were most reduced when baseline levels were high. A SYMPOSIUM: MANAGEMENT OF HYPERLIPIDEMIA

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FIGURE 1. Efficacy of 40 mg/day fluvastatin (upper) and placebo (lower) according to baseline LDL-C (left), HDL-C (middle) and TG (r/ght) tertiles and disease severity subgroups (LDL-C, > 2 4 0 vs -<240 mg/dL).*p <0.05; **p <0.01; ***p <0.001. HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; TG = triglycerides. [] = terfile 1; [ ] -- tertile 2 ; I = terlile 3. LDL-C

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' FIGURE 2. Efficacy of long-term fluvastatin (FL; 40 mg/day) alone (upper) and with cholestyramine (CME; lower) according to baseline LDL-C (left), HDL-C (middle) and TG (right) tertiles and disease severity subgroups (LDL-C, > 2 4 0 vs -<240 m g / dL). *p <0.05; ***p <0.001. For abbreviations, see Figure 1. [] = terlile 1; [ ] = tertile 2; Ill = tertile 3.

The addition of fluvastatin to cholestyramine abolished the expected rise in triglycerides. The observed influence of baseline levels on fluvastatin response can be considered beneficial as patients with low HDL-C and raised triglycerides are at a particularly high cardiovascular risk. 7 Although not the specific subject of the present 74A

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analysis, some reference to the safety data is important to allow a potential risk assessment for the groups of patients reported here. Irrespective of the severity of hypercholesterolemia, the treatment also appears to be very safe in terms of elevations in levels of aminotransferases, as evident from a recent safety analysis. 8 In a group of

VOLUME 76 JULY 13, 1995

2284 patients receiving fluvastatin monotherapy in controlled trials at daily doses of 20-80 mg/day, the incidence of persistent increases in alanine or aspartate aminotransferases to > 3 times the upper limit of normal was found to be 1.0% (placebo, 0.2%; n = 960). For the patients with LDL-C > 240 mg/dL, who constituted 32% of the study population, this incidence was identical (1.0%). While patients with severe LDL-C elevations are at a higher risk than those with more moderate elevations to experience nonfatal and fatal cardiovascular morbid events, the incidence of cardiovascular and extracardiac vascular serious adverse events suggested that beneficial effects can be expected with fluvastatin in adequately treated patients. The respective event rates in 2969 patients receiving at least 20 mg/day and up to 80 mg/day of fluvastatin--representing 4051 patientyears of exposure with an average reduction in LDL-C of 26 ___14% when receiving fluvastatin monotherapy----could be seen as promising: in total, 84 serious adverse cardiovascular events (21/ 1000 patient-years) were observed in the patients treated with fluvastatin (placebo, 28.2/1000 patientyears), and in long-term studies this rate was even lower (18.8/1000 patient-years). In long-term trials, the more severe hypercholesterolemic patients constituted 38% of the study population, and, in total, 6 patients died from such events during these long-term studies (1.7/1000 patient-years), 3 of them having had baseline LDL-C levels>240 mg/dL. However, unlike the favorable outcome of the "4S" studyg--which showed a significantly decreased cardiovascular morbidity and mortality when LDL-C is lowered with another HMG-CoA reductase inhibitor--the positive safety and morbidity data presented above were not assessed prospectively. Consequently, they bear no weight in terms

of proof, but may serve as a promising tendency in terms of the safety and expected benefits of fluvastatin in hypercholesterolemia irrespective of the severity of the disease. In conclusion, an exploratory analysis of the efficacy of fluvastatin in patients with severe hypercholesterolemia shows a very positive outcome. The observed tendencies to improve the atherogenic risk are being further evaluated in prospective studies. Additional studies have been performed to determine the efficacy of 40 mg fluvastatin twice daily in patients with severe hypercholesterolemia. Results to date show a reduction in LDL-C of 32-35%. l°,n 1. Adult Treatment Panel II. Summat3, of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. JAMA 1993;268:3015-3023. 2. Goldstein JI., Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AC, Sly WS, Valle D, eds. The Metabo//c Bas/s of ln/umted Disease. New York: McGraw-Hill, 1989:1215-1250. 3. International Task Force for Prevention of Corona~ Heart Disease. Prevention of coronary heart disease: Scientific background and new clinical guidelines. Nutr Metab Cardiovasc Dis 1992;2:113-156. 4. Leitersdoff E, Eisenberg S, Eliav O, Friedlander Y, Berkman N, Dann El, Landsberger D, Sehayek E, Meiner V, Wurm M, Bard J-M, Fruchart J-C, Stein Y. Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor. Circulation 1993;87(suppl 11I):35--44. 5. Peters TK, Muratti EN, Mehra M. Fluvastatin in primary hypercholesterolemia: Efficacy and safety in patients at high risk. A m J Med 1994;96(Suppl 6A):79-83. 6. Leitersdorf E, Eisenberg S, Eliav O, Berkman N, Dann EJ, Landsberger D, Sehayek E, Meiner V, Peters TK, Muratti EM, Bard J-M, Fruchart J-C, Stein Y. Efficacy and safety of high dose fluvastatin in patients with FH. E u r J Clin Pharmaco11993;45:513-518.

7. Assmaun G, Schulte H. Diabetes mellitus and hypertension in the elderly:. Concomitant hypeflipidemia and coronary heart disease risk. A m J Cardiol 1989;63(suppl H):33-37. S. Data on file, Sandoz Pharma. 9. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with corona~ heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389. 10. Zavoral JH, Haggerty 13.I, Winick AG, Bergmann SD, on behalf of the FLUENT Study Group. Efficacy of fluvastatin, a totally synthetic 3-hydroxy-3methylgluta~l-counzyme A ieductase inh~itur. A m J Cardiol 1995;76(suppl): 37A--40A. ] 1. Data on file. Sandoz Pharma Ltd., Basel.

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