A prospective open cohort study has examined and quantified the unintended risks and benefits of statins in a large representative primary care population over a six year period.
The study - unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database - has examined the unintended effects according to type, dose and duration of statin use
- setting 368 general practices in England and Wales supplying data to the QResearch database
- included in the study were 2 004 692 patients aged 30-84 years of whom 225 922 (10.7%) were new users of statins: 159 790 (70.7%) were prescribed simvastatin, 50 328 (22.3%) atorvastatin, 8103 (3.6%) pravastatin, 4497 (1.9%) rosuvastatin, and 3204 (1.4%) fluvastatin
- various effects were analysed including
- moderate or severe liver dysfunction, defined as an alanine transaminase concentration >120 IU/l (that is, more than three times the upper limit of normal) among patients without diagnosed chronic liver disease, as this is the severity at which guidelines recommend treatment is discontinued
- moderate or serious myopathic events, defined as a diagnosis of myopathy or rhabdomyolysis or a raised creatine kinase concentration of four or more times the upper limit of normal, as this represents an event where treatment is likely to be discontinued.
- Results
- individual statins were not significantly associated with risk of Parkinson’s disease, rheumatoid arthritis, venous thromboembolism, dementia, osteoporotic fracture, gastric cancer, colon cancer, lung cancer, melanoma, renal cancer, breast cancer, or prostate cancer
- statin use was associated with decreased risks of oesophageal cancer but increased risks of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy, and cataract
- a dose-response effect was apparent for acute renal failure and liver dysfunction
- all increased risks persisted during treatment and were highest in the first year
- after stopping treatment with a statin
- risk of cataract returned to normal within a year in men and women
- risk of oesophageal cancer returned to normal within a year in women and within 1-3 years in men
- risk of acute renal failure returned to normal within 1-3 years in men and women, and liver dysfunction within 1-3 years in women and from three years in men
- number needed to treat (NNT)
- based on the 20% threshold for cardiovascular risk, for women the NNT with any statin to prevent one case of cardiovascular disease over five years was 37 (95% confidence interval 27 to 64) and for oesophageal cancer was 1266 (850 to 3460) and for men the respective values were 33 (24 to 57) and 1082 (711 to 2807)
- number needed to harm NNH)
- in women the NNH for an additional case of acute renal failure over five years was 434 (284 to 783), of moderate or severe myopathy was 259 (186 to 375), of moderate or severe liver dysfunction was 136 (109 to 175), and of cataract was 33 (28 to 38). Overall, the NNHs and NNTs for men were similar to those for women, except for myopathy where the NNH was 91 (74 to 112)
Moderate or serious liver dysfunction
- overall, statins were associated with an increased risk of liver dysfunction in both men and women
- in women there was some indication of differences between the effects of individual statins (overall test P=0.058)
- highest risk was associated with fluvastatin (2.53, 1.84 to 3.47), which was significantly higher than that with simvastatin (1.52, 1.38 to 1.66)
- in men, differences between the effects of individual statins were significant (overall test P=0.0045)
- highest risk was associated with fluvastatin (1.97 1.43 to 2.72) and the lowest with pravastatin (1.21, 0.93 to 1.58)
- a dose-response effect was evident
- risk of liver dysfunction was highest within the first year of treatment with any statin: the adjusted hazard ratio for women was 2.38 (2.11 to 2.70) and for men was 2.32 (2.07 to 2.59). The hazard ratio in the 1-3 years after starting treatment for women was 1.39 (1.23 to 1.57) and for men was 1.35 (1.21 to 1.51). After stopping statins the risks returned to normal between one and three years in women and from three years in men
Cataract
- statin use was associated with an increased risk of cataract in both men and women, apart from fluvastatin in men, owing to small numbers in the analysis
- no significant difference between the effects of individual statins in men (P=0.32) or in women (P=0.82)
- no evidence of a dose-response relation
- risk was significantly increased within a year of starting statins, persisted during treatment, and returned to normal within the first year after stopping treatment
Oesophageal cancer
- risk of oesophageal cancer decreased in both men and women prescribed simvastatin (0.69, 0.50 to 0.94 and 0.82, 0.68 to 0.99, respectively)
- risk was also significantly decreased in men prescribed atorvastatin (0.73, 0.55 to 0.96). The hazard ratios for the other statins were of similar magnitude and all less than 1, but they did not reach statistical significance possibly because of small numbers
- direct comparison test showed no significant difference between the effects of individual statins in either men (P=0.76) or women (P=0.99)
Acute renal failure
- risk of acute renal failure was increased in both men and women prescribed simvastatin, atorvastatin, and pravastatin and in women prescribed fluvastatin. The magnitudes of the adjusted hazard ratios were similar for each statin, ranging from 1.50 to 2.19, and direct comparisons showed no difference in risk by type of statin (P=0.91 in men, P=0.37 in women)
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