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Cholesterol lowering with statins

Systematic review
Results
Comment

Cholesterol-lowering drug prescriptions have increased seven fold in the last five years in the UK, with statins accounting for 92% of prescriptions and 95% of cost (about £350 million a year in 2001). Simvastatin (43%) and atorvastatin (32%) are the most commonly prescribed. Long-term benefits are reduced heart attacks and strokes, and the new Statin section on this Bandolier Internet site has summarised the evidence about benefit and harm from statins. What about knowing which dose gives best lipid lowering in long-term trials? A new systematic review [1] gives the answer.

Systematic review

Searching for randomised, double-blind controlled trials assessing the effect of statins on cholesterol in patients with hypercholesterolaemia was to September 2001, using the Cochrane Library and PubMed. Pharmaceutical companies known to manufacture statins were contacted for references. Reference lists of retrieved trials and reviews were checked to identify other studies.

Included trials were both randomised and double blind, had at least two treatment groups (placebo, different doses of the same statin, or different treatments), had a mean total cholesterol of at least 5.0 mmol/L at baseline (with or without dispersion), and provided baseline and outcome data for total cholesterol, LDL, HDL and triglycerides. Only those of at least three months were included, because trials of less than three months duration are unlikely to inform adequately about sustainable effects in terms of lipid lowering with statins.

Studies without baseline data were excluded, as were those with fewer than 20 patients per treatment group. Also excluded were trials with mean baseline concentration of total cholesterol below 5.0 mmol/L, combinations of a statin plus another drug, trials examining patients with familial hypercholesterolaemia, diabetes mellitus, renal or hepatic pathology, or trials in which patients were randomised to statin treatment within 24 hours of procedures such as angioplasty or cardiac surgery.

The main outcomes sought were mean change (absolute or percent) from baseline during double blind treatment for total cholesterol, LDL, HDL and triglycerides, or data allowing their calculation.

Results

Forty-two reviews and 509 reports regarded as potential randomised trials were retrieved, and 418 were excluded, mostly because they were shorter than 12 weeks, were not double blind, had fewer than 20 patients per group, or were duplicates. Ninety-one trials met the inclusion criteria and contributed to the analysis, with 43,404 patients on statins and 25,081 on placebo. In most trials initial average concentration of total cholesterol was between 6.5 and 7.8 mmol/L.

Most patient information was available for lovastatin, pravastatin and simvastatin, mainly because of the publication of large, long-term trials, with far less information available for atorvastatin, cerivastatin, fluvastatin and rosuvastatin. The most commonly used doses were atorvastatin 10 mg, fluvastatin 40 mg, lovastatin 40 mg, pravastatin 40 mg and simvastatin 40 mg. Information for both 5 mg and 10 mg of rosuvastatin was used since patient numbers were almost identical.

Neither duration of study beyond 12 weeks, nor initial concentration of cholesterol, nor use of placebo or active controls, nor the inclusion or exclusion of major trials had any effect on lipid-altering capacity. The cholesterol-lowering capacity of statins was generally unaffected by dose used, or by use of fixed dose or dose-titration. Figure 1 shows this for the statin with the largest amount of information, simvastatin.



Figure 1: Percentage change in LDL-cholesterol from baseline with different simvastatin doses





The cholesterol-lowering capacity of the most commonly used fixed doses was different between statins. Figure 2 shows the mean percentage reductions for total cholesterol, and Figure 3 for LDL-cholesterol. In both cases the rank order was the same, with 5 and 10 mg of rosuvastatin giving the largest reduction, and the two most prescribed statins ahead of the all other statins.



Figure 2: Percentage change in total cholesterol from baseline (number of subjects)







Figure 3: Percentage change in LDL-cholesterol from baseline (number of subjects)





The all cause discontinuation rate was about 10% and discontinuation because of adverse events was about 4% in these trials, with no major difference between statins.

Comment

So what are the take-home messages? One is that in the UK, and probably world wide, prescribing of statins has been evidence-based, since the most frequently used (atorvastatin 10 mg and simvastatin 40 mg) are the established statins with the most cholesterol-lowering impact. That is encouraging. Rosuvastatin, with less information, seems to have even more punch at 5 mg and 10 mg. This might help costing exercises based on local pricing regimes, though arguments about effects of statins above those of cholesterol lowering will probably continue.

Even so, it was surprising that there was only information on about 1,000 patients for atorvastatin and rosuvastatin, compared with 11,000 for simvastatin. The cholesterol-lowering effect for atorvastatin in the large ASCOT study [2] is in line with the effect found in the meta-analysis.

Perhaps the most surprising thing was the lack of dose response in these longer term studies. Law and colleagues [3] analysed trials of two to six weeks duration by drug and dose in 25,000 patients on statins and found good dose-response for all statins. This new meta-analysis [1] had data from 68,000 patients but in trials lasting 12 weeks or more. This may reflect better the long term use of statins, and if so may open a question about how long people should be on a statin before dose or drug change is considered. Bandolier could find no papers that looked at how long it took for the maximum reduction in cholesterol to be achieved.

References:

  1. JE Edwards, RA Moore. Statins in hypercholesterolaemia: A dose-specific meta-analysis of lipid changes in randomised, double blind trials. BMC Family Practice 2003, 4:18.
  2. PS Sever et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a multicentre randomised trial. Lancet 2003; 361: 1149-1158.
  3. MR Law et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003 326: 1423-1429.

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