Q J Med 1999; 92: 387-394
© 1999 Association of Physicians
Atorvastatin compared with simvastatin-based therapies in the management of severe familial hyperlipidaemias
From the Department of Chemical Pathology and 1 Department of Diabetes and Metabolism, St Thomas' Hospital, London, UK
Received 23 November 1998 and in revised form 23 April 1999
Dr A.S. Wierzbicki, Department of Chemical Pathology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH. e-mail: Anthony.Wierzbicki{at}ukcl.ac.uk
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Summary |
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We compared atorvastatin with simvastatin-based therapies in a prospective observational study of 201 patients with severe hyperlipidaemia. Atorvastatin 10 mg therapy was substituted for simvastatin 20 mg, 20 mg for 40 mg, 40 mg for simvastatin 40 mg plus resin, and 80 mg for simvastatin-fibrate-resin therapy. Lipid and safety profiles were assessed. Atorvastatin reduced total cholesterol by 31±11–40±14% vs. 25±12–31±11%; LDL by 38±16–45±18% vs. 31±18–39±18% and geometric mean triglycerides by 29.3–37.3% vs. 16.6–24.8%, but reduced HDL 11%±47% at 80 mg compared with a 16%±34% increase with simvastatin-based therapy. Target LDL <3.5 mmol/l was achieved more often with atorvastatin (63% vs. 50%; p<0.001). Atorvastatin increased geometric mean fibrinogen by 12–20% vs. a 0–6% fall with simvastatin (p<<0.001). Side effects were noted in 10–36% of patients, including one case of rhabdomyolysis, and 36% discontinued therapy. These data suggest that atorvastatin is more effective than current simvastatin-based therapies in achieving treatment targets in patients with familial hypercholesterolaemia but at the expense of a possible increase in side-effects. This issue needs further study in randomized controlled trials.
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Introduction |
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The treatment of genetic hyperlipidaemias poses a severe problem in the field of cardiovascular therapeutics. Many patients fail to achieve LDL <4.5 mmol/l on current therapies. The recent availability of atorvastatin, a new hydroxy-methyl-glutaryl-coA reductase inhibitor (statin) with the capability of lowering LDL by 60%, and also lowering triglycerides, might enable a significant number of these patients to achieve the desired therapeutic target of LDL <3.5 mmol/l and triglycerides <1.7 mmol/l. This prospective observational study examined the efficacy of atorvastatin in further reducing LDL in patients with severe hyperlipidaemias by the use of a drug regimen in which atorvastatin replaced the four treatments commonly used in the clinic. These comprised 20 mg simvastatin, 40 mg simvastatin, simvastatin 40 mg plus cholestyramine, and triple therapy with simvastatin, fenofibrate and cholestyramine.
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Methods |
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This study was designed as a prospective open observational study and received ethical approval. The format was designed to maximize recruitment.
Patients
We recruited 201 patients with severe hyperlipidaemia not achieving a LDL target of 2.5 mmol/l. Patients unable to tolerate previous statin therapy were excluded.
Study design
Patients were recruited into four groups based on their current dose of simvastatin (20 or 40 mg) and the need for additional cholestyramine (group 3) or additional fibrate and cholestyramine therapy (group 4). All patients were on a NCEP stage II diet, and compliance was monitored by regular dietetic review. This diet comprises <100 mg/day of cholesterol, with <20% total calories as saturated fat and >50% as carbohydrate. Alcohol consumption was <30 units/week in all cases. A full lipid profile was obtained on current therapy, which had remained stable for at least 3 months. Patients stopped their current medication for 4 weeks to allow verification of baseline lipid profiles on dietary therapy alone. After re-investigation, they were treated with atorvastatin 10–80 mg on a theoretically matched LDL reduction protocol. Each group of 50 patients started on new therapies as follows: atorvastatin 10 mg for simvastatin 20 mg, and 20 mg for 40 mg; atorvastatin 40 mg for simvastatin 40 mg-32 g cholestyramine/ day; and atorvastatin 80 mg for therapy with simvastatin 40 mg-fenofibrate 200 mg-cholestyramine 32 g/day. After 12 weeks the patients were reviewed, and the fasting lipid and safety profiles were repeated. Patients were asked to report their assessment of side-effects during the study after being briefed that atorvastatin was likely to be more efficacious than their current therapy despite a lower dose of drug. Lipid parameters, fibrinogen and lipoprotein (a) were obtained from previous records at the 3-month time point after initiation of simvastatin or combination therapies.
Laboratory investigations
Total cholesterol and triglyceride were measured on a Vitros 950 analyser. HDL was measured after separation of LDL components by an anionic detergent method (Sigma Biochemical). Apolipoproteins A1, A2, B, lipoprotein (a) and fibrinogen were measured by turbidimetric analysis on a Cobas Fara II analyser. The safety profile comprised assessment of liver function tests: alanine transaminase (ALT), gamma-glutamyl transferase (GGT) and the muscle enzyme creatine kinase (CK).
Data analysis
Results were analysed by paired student's t test for normally distributed variables across the population. Variables showing skewed distributions were naturally logarithmically transformed before analysis. Comparisons were performed by Wilcoxon signed rank test for any variables that showed significant bias even after transformation. As the assay detection limit for lipoprotein (a) was 7.5 mg/dl, and high assay variances are common at these low levels, only patients with lipoprotein (a) results twice the detection limit were analysed. Differences in achieving targets were assessed by 
2 analysis with Yates' correction.
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Results |
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Demographics
Recruitment was 96% of the patients identified as suitable. The patients in the four groups were similarly aged at 54.0–56.0±12.0 years, and 50–56% were male in each group. The patients comprised 56% with definite familial hypercholesterolaemia (FH) based on the presence of autosomal dominant histories of early (<60 years) coronary heart disease in the family and, in some cases, tendon xanthomata and 16% with familial combined hyperlipidaemia (FCH) confirmed by the presence of hyperlipidaemia in other family members. The remainder had severe polygenic hyperlipidaemias (>8 mmol/l), but often had a family history of coronary heart disease or stroke prior to age 70. The baseline characteristics of the patients studied are shown in Table 1
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Drug therapy
All the patients had been treated with simvastatin with 27.8% receiving 20 mg, 69.6% receiving 40 mg and 2.5% receiving 40 mg bd. Additional therapy with cholestyramine was taken by 44% of patients and 25% received additional micronized fenofibrate 200 mg. Cholestyramine therapy was taken on questioning as 2.3x8 g sachets/day as opposed to the 4x8 g originally prescribed. Atorvastatin was prescribed at doses of 10 mg (29%), 20 mg (27%), 40 mg (19%) and 80 mg (25%).
Lipids and apolipoproteins
All patients reverted to within 5% of initial presentation total cholesterol on stopping therapy. Atorvastatin was generally well-tolerated and efficacious in each patient group. Results of its effects on lipid variables are shown in Table 2. Atorvastatin reduced total cholesterol by 31±11–40±14% vs. 25±12–31±11%; LDL by 38±16–45±18% vs. 31±18–39±18%, and geometric mean triglycerides by 29.3–37.3% versus 16.6–24.8% compared with simvastatin-based regimens. Atorvastatin was more efficacious at the lower doses than simvastatin-based regimens, but 80 mg was not significantly better than simvastatin-fenofibrate-cholestyramine triple therapy. At 80 mg, atorvastatin reduced HDL significantly by an average 11%±47%, with wide variations in individual response compared with a 16%±34% increase with simvastatin-based therapies. Reductions in HDL to <70% initial values were noted in 1.5% with atorvastatin therapy, compared with 0.7% with simvastatin regimes. This may be mitigated by a shift in the HDL profile towards HDL-2 particles (Lp : A1) containing apoA-1 alone at all doses of atorvastatin. The effects of atorvastatin on apolipoproteins (apo)A1, A2, and B were otherwise similar to those on lipoprotein subfractions.
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A number of indices of successful biochemical lipid control were evaluated and are detailed in Tables 3 and 4
. Atorvastatin significantly improved indices of successful treatment to LDL targets of <3.5 mmol/l and <2.5 mmol/l and for forward and reverse cholesterol transport: LDL : HDL ratio (<3.5 or <2.5), apoB : apoA1 ratio (<1.25 or <1.00) (p<0.05) except at 80 mg. The index of total apolipoprotein B particle series saturation (non-HDL cholesterol : apoB) was significantly improved by atorvastatin at all doses compared with simvastatin-based regimens (p<0.001). No differences were seen in the HDL saturation index (HDL : apoA1 ratio) at any dose with either drug regimen. Atorvastatin significantly improved the number of patients achieving LDL (23% vs. 10%), LDL : HDL (64% vs. 44%) and apoB : A1 ratio (71% vs. 42%) targets compared with simvastatin (p<0.001), as shown in Table 4.
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Other risk factors
The geometric mean lipoprotein (Lp) (a) was decreased significantly more by simvastatin (16%) than atorvastatin (14%) (n=158; p=0.003). Analysis of the data from patients with Lp(a)>30 mg/dl showed similar results (n=127; p=0.02). Fibrinogen results were available in 170 cases (85%) for atorvastatin and 95 cases (43%) for simvastatin. A further eight and 12 sets of results, respectively, were discarded on the basis of the presence of an acute-phase reaction (CRP>6 U/l). Atorvastatin caused a 16% rise in geometric mean fibrinogen (range 12–20% with dose) whilst simvastatin had little effect on plasma fibrinogen (-1.5%; range -5.6 to 0% with dose).
Biochemical safety profile
Results of the biochemical safety profile are shown in Table 2
. A dose-proportional slight increase was seen in ALT and CK with atorvastatin. This effect was significantly greater than that seen with simvastatin, and a significant increase over baseline at all doses. In only a few cases with simvastatin (6.5%) or atorvastatin (11%) were ALT results raised outside reference limits (55 IU/l). Six patients (3%) had ALT elevations severe enough (>165 IU/l) to warrant reduction of the dose used (four) or discontinuation of therapy (two). GGT was significantly raised at the highest dose of both simvastatin and highest two doses of atorvastatin. None of the cases of severe rise in ALT with therapy were associated with excess alcohol intake (>30 units/week). One patient developed a serious rise in CK on atorvastatin (vide infra).
Side-effect profile
The incidence and principal side-effects are listed in Table 5. A dose-proportional incidence of side-effects was seen and 36% of patients with stated side-effects asked to stop therapy with atorvastatin. There was an excess of gastrointestinal side-effects. Diarrhoea was noted in 14 patients, while 10 patients developed an erythematous rash, five patients rapidly gained weight (>3 kg) over the study period despite dietary advice, and eight suffered from joint effusions and acute joint pains. Four patients reported reduced myalgia and two had fewer headaches after stopping simvastatin therapy.
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Serious adverse events
One patient developed severe myositis verging on rhabdomyolysis on 10 mg atorvastatin, with severe myalgia and a significant CK elevation (x50) without evidence of myoglobinuria or deterioration in creatinine. This event resolved after 4 weeks off the drug.
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Discussion |
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Patients with severe hyperlipidaemias, many of whom have familial hypercholesterolaemia or familial combined hyperlipidaemias have a poor prognosis, as it is difficult to achieve target LDL levels <3.5 mmol/l in primary prevention or <2.5 mmol/l after events or surgery with current therapies. Few studies have examined the utility of atorvastatin in the treatment of this group of patients. The only data comes from randomized control trials (RCTs) in other populations where comparisons were made with similar doses of other agents.2–4 Study design in this area is difficult, as long-term placebo RCTs are unethical in this population. The necessary scale of a randomized drug comparison trial precluded this design being used in a single centre study of a moderately rare disease. A multi-centre design would introduce additional variables into any analysis and hence require larger numbers still. Crossover trial designs are superior to open trial designs, but cause difficulties in recruitment and hence bias patient selection. They also require lengthy multiple washout phases, which would pose ethical problems. Randomized trials give accurate estimates of physiological side-effects but underestimate psychological issues of drug/tablet compliance. Compliance is a significant factor in clinical practice especially in asymptomatic conditions such as hyperlipidaemia, and is best assessed in homogeneous trial populations where recruitment can be maximized. Recruitment to randomized controlled trials (RCTs) from eligible patients is about 30% at our centre, and less if a therapy is perceived by this well-informed patient group as less effective. Hence, the single-centre consecutive-recruitment prospective open trial design was adopted to reduce site or selection bias, maximize recruitment and avoid the need to analyse results by intention-to-treat. Large-scale randomized comparison trials are, however, essential to follow-up the initial findings of this type of study.
In this study, atorvastatin at doses of 10–20 mg was superior to simvastatin 20–40 mg-based therapies, as it reduced LDL-cholesterol by more than double the dose of simvastatin with/without cholestyramine. Similarly, it reduced triglycerides more than previous therapy and increased HDL by 2–5% at the lower two doses more than was achieved on previous therapy. These results are better at lower but not higher doses than those seen in the comparative CURVES study of statins in a general population, which showed equivalence of 10 mg atorvastatin and 20 mg simvastatin.4
In this study, the efficacy of atorvastatin 80 mg did not differ significantly from combination therapy, reducing LDL-cholesterol by 45%±18%5,6 as opposed to the 60% seen in early studies.7 A reduction of 11% in HDL compared to baseline values, with wide individual variations, was noted with atorvastatin 80 mg. Similar effects on HDL were seen in the CURVES study.4 This group has previously published data on the effects of 80 mg atorvastatin for 3 months in 63 patients compared to fenofibrate-simvastatin combination therapy.5 Notably, lipid parameters had improved little with triple therapy compared to statin-fibrate combination therapy, indicating that either cholestyramine therapy was interfering with absorption of the other medications, or that patient compliance with cholestyramine was worse than admitted.
The effects of atorvastatin on triglycerides seen in a study of 56 hypertriglyceridaemic patients were reproduced in this study. Atorvastatin reduced triglycerides significantly more than previous therapies at all doses.8 Triglyceride reduction is a property of all statins and dependent on both basal triglycerides, and potency in reducing LDL9 via actions on apolipoprotein B metabolism,10 so this action could be partially explained by the greater LDL reducing efficacy of atorvastatin.
There are few data on the effects of atorvastatin on non-classical risk factors for atherosclerosis.11 Though lipoprotein (a) and fibrinogen have long been established as cardiovascular risk factors, with an relative increased risk of 1.3–2.2 for concentrations >30 mg/dl and >3.5 g/l, respectively, no trials have demonstrated that reducing these risk factors alone can lead to benefit.12 We have previously shown in a subgroup of 89 patients from this study that atorvastatin raises median plasma fibrinogen at 12 weeks by 22.2%.13 Some anecdotal reports in studies on patients with familial hypercholesterolaemia have suggested that atorvastatin may increase fibrinogen by 28% at 80 mg once daily and by 63% when given as 40 mg twice daily at 4–6 weeks.14 However, this differs from data obtained in randomized controlled trials with atorvastatin using different time scales and different populations of patients which show a 5% increase at 52 weeks and little effect at 16 weeks.3,8,14 There is anecdotal evidence for a similar though lesser acute effect of simvastatin,15 but this again has not been replicated in larger studies. The complete findings from this study support our earlier data and confirm a difference between atorvastatin and simvastatin in effects on fibrinogen. The area of haematorheological effects of lipid-lowering agents is confused, and requires further study. The effect seen in this study could be transient, limited to patients with genetic hyperlipidaemias group, a marker of lesser fibrinogen consumption following stabilization of atheromatous plaques, or a marker of mild liver dysfunction. Its long-term significance is also unclear and data are awaited on the effects of atorvastatin on coronary arterial disease progression and events.
Data on the effects of atorvastatin on lipoprotein (Lp) (a) are limited. Lower values were excluded from analysis in this study, due to problems with reproducibility of results of Lp(a) assays. In this study, atorvastatin reduced Lp(a) less than did simvastatin when Lp(a) levels >15 mg/dl were considered. Previously, we have shown that the 10 mg dose atorvastatin may raise plasma Lp(a) in patients above the clinically significant threshold plasma concentration of 30 mg/dl (0.3 g/l), but in the complete study atorvastatin reduced Lp(a) less than simvastatin (27% vs. 30%), though individual responses were highly variable.16,17 In previous publications,8,13 atorvastatin had similar effects on Lp(a) to simvastatin, although assay variance at low concentrations would have diluted any differences.
The side-effect profile of atorvastatin has been similar to that of other statins in randomized controlled clinical trials in the general population.18 However, our results are at variance with this, showing a 10–36% incidence of side-effects with atorvastatin dependent on dose in patients with severe hyperlipidaemia. One patient suffered severe myositis verging on rhabdomyolysis with 10 mg atorvastatin, but she recovered completely. All patients had had no previous problems with simvastatin therapy though four did report a lessening of symptoms of myalgia and two reported reduced headaches on stopping simvastatin. This is a very compliant and long-suffering population of patients more likely to tolerate side-effects given the past history of coronary arterial disease in the family, and so would be expected to understate the incidence of side-effects, and be more reluctant to stop treatment with a lipid-lowering agent. A sharp increase in clinical side-effects would be expected at higher doses of drugs needed to manage adequately many patients with familial hypercholesterolaemia, and this was seen with both regimens. Yet the side-effect profile of atorvastatin was worse than simvastatin-based regimens at all doses in this study with, predictably, most side-effects at 80 mg. There are few comparative data in this type of patient on the higher doses of simvastatin used in five patients (80 mg) in this study, but one small study of simvastatin 80 mg and 160 mg showed a similar rise in side-effects at a dose of 160 mg daily.19 The incidence of side-effects with simvastatin 80 mg was comparable to that at 40 mg.19 The side-effect profile of atorvastatin differed from expectations in that 5% patients reported rashes including one case of erythema nodosum, 4% joint pains or joint swelling and 3% weight gain (>3 kg in 3 months) as well as other recognized side-effects of statin therapy. The role, in practice, of biochemically-defined side-effects is difficult to establish, as large elevations in CK are rare in the absence of rhabdomyolysis, and CK elevations have little correlation with the incidence of myalgia. Large elevations in ALT (>165 IU/l; 3xupper reference limit) are used as possible indicators of drug-induced hepatitis, and are an indication for discontinuing drug therapy. These were seen in six (3%) patients on atorvastatin, implying that this drug may require more frequent initial monitoring than simvastatin-based therapies.
In summary, atorvastatin is more effective, at lower doses than simvastatin for treating cases of severe hyperlipidaemia but this comes at the price of a possible increase in side-effects and fibrinogen, reduced HDL at 80 mg and a lesser reduction in Lp(a).
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References |
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1. Black DM. Atorvastatin: a step ahead for HMG-CoA reductase inhibitors. In: Jacotot B, Mathe D, Frucharty J-C, eds. Atherosclerosis X. Amsterdam, Elsevier, 1995:307–10.
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3. Davidson M, McKenney J, Stein E, Schrott H, Bakker-Arkema R, Fayyad R, Black D, for the atorvastatin study group. Comparison of one year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolaemia. Am J Cardiol 1997; 79:1475–81.[Web of Science][Medline]
4. Jones PJ, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin and fluvastatin patients with hypercholesterolaemia (the CURVES study). Am J Cardiol 1998; 81:582–7.[Web of Science][Medline]
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Wierzbicki AS, Lumb PJ, Semra YK, Crook MA. High-dose atorvastatin therapy compared with traditional therapeutic regimes in severe heterozygous familial hypercholesterolaemia.Q J Med 1998; 91:291–4.
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Bakker-Arkema R, Davidson MH, Goldstein RJ, Davignon J, Isaacson JL, Weiss SR, Keilson LM, Brown V, Miller T, Shurinske LJ, Black DM. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridaemia. JAMA 1996; 275:128–33.
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Marais AD, Firth JC, Bateman ME, Byrnes P, Martens C, Mountney J. Atorvastatin: an effective agent in familial hypercholesterolaemia. Arterioscler Thromb Vasc Biol 1997; 17:1527–32.
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15. Jerling JC, Vorster HH, Oosthuizen W, Vermakk WJH. Effects of simvastatin, a 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitor, on the haemostatic balance of familial hypercholesterolaemic subjects. Fibrinolysis Proteolysis 1997; 11:91–6.
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18. Black DM, Bakker-Arkema RG, Nawrocki JW. An overview of the clinical safety profile of atorvastatin (Lipitor), a new HMG-CoA reductase inhibitor. Ann Intern Med 1998; 158:577–84.
19. Davidson MH, Stein EA, Dujovne CA, Hunninghake DB, Weiss SR, Knopp RH, Illingworth DR, Mitchel YB, Melino MR, Zupkis RV, Dobrinska MR, Amin RD, Tobert JA. The efficacy and safety and six week tolerability of simvastatin 80 and 160 mg/day. Am J Cardiol 1997; 79:38–42.[Web of Science][Medline]
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